Coupling compound drugs, methods for producing the same, and their use

Abstract

An anti-inflammatory medicinal compound for external use and its preparation and use, the structural formula of the compound is AYB, in which A is a hydrogen-free group of an amine compound having JAK inhibitory activity, and Y is a direct bond or -(CH 2 )-O- or -(CH 2 )-, and B is a carboxylic acid compound B 1 or a hydroxyl-containing compound B 2 The compound has special effects such as strong skin permeability, controlled drug release, and high therapeutic effect.

Description

[Technical Field]

[0001] This invention relates to topical anti-inflammatory drugs, and more specifically, to compound drugs synthesized by coupling and their use. [Background technology]

[0002] The JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signaling pathway involved in many important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. Many cytokines and growth factors, including IL (interleukin), GM-CSF (granulocyte-macrophage colony-stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PDGF (platelet-derived growth factor), and IFN (interferon), transmit signals via the JAK-STAT signaling pathway.

[0003] The JAK-STAT signaling pathway consists of three components: a receptor tyrosine kinase, a tyrosine kinase (JAK), and a transcription factor (STAT). The receptor tyrosine kinase binds to a ligand and then activates the bound JAK. The activated JAK then further activates its corresponding STAT protein. The activated STAT protein enters the cell nucleus, binds to target genes, and regulates gene transcription.

[0004] The JAK family includes JAK1, JAK2, JAK3, and TYK2. These kinases regulate seven different STATs: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. Cytokines and growth factors can control cell proliferation, differentiation, apoptosis, and immune regulation by regulating these STATs. Many diseases are caused by mutations in JAK and STAT. These diseases can be effectively treated by regulating and selectively inhibiting specific JAKs.

[0005] JAK-STAT is a relatively simple signaling pathway, but it is involved in many cellular functions. There are currently dozens of JAK inhibitors on the market or under development. Most JAK inhibitor projects aim to maximize therapeutic effect and minimize side effects by selectively inhibiting a specific JAK-STAT signaling pathway. However, systemic administration often makes it difficult to avoid a conflict between therapeutic effect and side effects. Local administration of JAK inhibitors can improve therapeutic effect while reducing systemic side effects. Many JAK inhibitor projects under development aim for organ selectivity as their ultimate goal in order to maximize therapeutic effect versus risk.

[0006] The objective of this invention is to maximize the therapeutic effect of topical (skin) administration and minimize systemic toxicity by optimizing the compound structure. The causes and mechanisms of treatment for many skin diseases, including psoriasis, vitiligo, and alopecia areata, have already been elucidated. The regulatory and control mechanisms of various JAK-STATs for commercially available or developing JAK inhibitors have also been clarified. By modifying the chemical structure of conventional known JAK inhibitors to allow greater penetration through the protective layer of the skin, the objective of selective skin administration can be achieved. Optimizing the structure of a known compound product has a relatively shorter development cycle, a lower risk of treatment failure, a smaller possibility of unknown toxicity, and lower development costs compared to developing a skin-selective administration product from an entirely new compound.

[0007] By optimizing the structure of compounds to improve their skin permeability, non-functional groups can be added to known compound structures to alter their physical and chemical properties, thereby allowing them to penetrate the protective layer of the skin more effectively. This technique is also known as prodrug technology and is widely used in drug development. [Overview of the project] [Problems that the invention aims to solve]

[0008] This invention addresses the technical challenge of high doses and side effects associated with conventional known JAK inhibitors by optimizing the structure of known JAK compounds to enable effective, selective cutaneous administration. This improves efficacy against skin diseases and reduces systemic doses and side effects. In other words, structural optimization and selective cutaneous administration are achieved by coupling known JAK inhibitors with other small molecule compounds. [Means for solving the problem]

[0009] Specifically, the present invention provides the following technical solutions.

[0010] 1. By selecting specific linkers and coupling molecules based on the structure of the JAK inhibitor compound, the final compound (prodrug) can penetrate the protective layer of the skin more effectively.

[0011] 2. The chemical bond between the linker and the JAK inhibitor is unstable in human skin, so it undergoes hydrolysis, releasing the JAK inhibitor as the active ingredient.

[0012] 3. The bond between the linker and the coupling molecule is also unstable, causing the coupling molecule to be released.

[0013] 4. The linker itself has a known, simple chemical structure and is non-toxic.

[0014] 5. Coupling molecules have clearly defined chemical structures, and their pharmacological and toxicological properties are well-established.

[0015] Specifically, the present invention provides the following technical solutions.

[0016] In one embodiment, the present invention provides anti-inflammatory compounds, or stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates thereof, the structure of which is shown in general formula (I). AYB(I) In the formula, A is a group obtained by removing a hydrogen atom from an amine compound having JAK inhibitory activity. Y is a direct connection, or -(CH2)-O- or -(CH2)-, B is a group formed by dehydration of a carboxylate compound B1 containing a carboxyl group or a group formed by dehydrogenation of a hydroxyl group-containing compound B2. Here, if B is a group formed by dehydration of the carboxylate compound B1 (i.e., B is B1), the Y group is directly connected or -(CH2)-O-, and if B is a group formed by dehydrogenation of the hydroxyl group-containing compound B2 (i.e., B is B2), the Y group is -(CH2)-.

[0017] In a particular embodiment, the anti-inflammatory compound of the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate, has a structure as shown by general formula (II) or general formula (IIa).

[0018] [ka]

[0019] In the formula, R1 is either unsubstituted or R a A pyrazolyl or pyrrolyl group substituted by, or selected from -N(CH3)-Cy, R 1a This represents a pyrrole ring substituted with a halogen-substituted C1-C6 alkylamine acyl group and / or a C1-C6 alkyl group. Cy is unsubstituted or R b A 5-membered or 6-membered carbon ring, a 5-membered or 6-membered nitrogen-containing heterocycle, and the R a and R beach independently contains at least one or two groups selected from the group consisting of an acyl group, a dithioyl group, a cyano group, an amino group or a C1-C6 alkyl-substituted amino group, a 4-membered or 5-membered or 6-membered nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group substituted by a C1-C6 alkyl group, and preferably, the R a and R b each independently is a group composed of one of an acyl group or a dithioyl group, and at least one group selected from the group consisting of a cyano group, an amino group or a C1-C6 alkyl-substituted amino group, a 4-membered or 5-membered or 6-membered nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group substituted by a C1-C6 alkyl group, where the C1-C6 alkyl group may be substituted by a halogen, that is, here, the R a and R b are each independently preferably a group composed of at least one acyl group and a dithioyl group, and a group containing at least one nitrogen atom, R2 in the general formula (II) and the general formula (IIa) is both -B, that is, it is a group -B1 formed by the elimination of a hydroxyl group from the carboxylic acid compound B1, and is selected from R4-Ar-R3-CO-, where R3 is selected from the group consisting of a C1-C6 alkylene group, -NH-, R5NH- and a C1-C6 alkylene group substituted by a C1-C6 alkoxyamide group, or is a direct connection, that is, the Ar group is directly connected to -CO-, and preferably R3 is a methyl group-substituted or unsubstituted methylene group, -C2H4-, or a direct connection, R5 is a C_{1}-C_{6} alkylene group, where the C1-C6 alkylene group may be substituted by a halogen (preferably, the halogen is selected from one or more of fluorine, chlorine and bromine), Ar is an aromatic ring group, preferably a benzene ring, a naphthalene ring, or an aromatic heterocycle, and a benzene ring, naphthalene ring, or aromatic heterocycle or aromatic condensed heterocycle substituted with one or more groups selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 acyl groups, or C1-C6 alkoxy groups (where the aromatic heterocycle is preferably a benzo-containing nitrogen or oxygen-containing heterocycle, for example, a benzopyrrole ring), and more preferably Ar is an aromatic heterocycle containing a nitrogen atom. R4 is a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkyl group including a C1-C6 cycloalkanoyl group, a C1-C6 alkaneamide group or an aromatic condensed heterocyclic amide group, a C1-C6 carbonyloxy group, a halogen-substituted benzoyl group, a C1-C6 alkyl group or halogen-substituted or unsubstituted phenoxy group, a C1-C6 alkyl group or halogen-substituted or unsubstituted phenyl group or aromatic condensed heterocyclic group, a C1-C6 alkyl group or halogen-substituted or unsubstituted phenylamine group, or R4 may be omitted, and the C1-C6 alkoxy group may form a crosslinked ring with Ar.

[0020] In another specific embodiment, in the aforementioned anti-inflammatory compounds of the present invention, or their stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates, Cy is a substituted cyclohexyl group or a substituted piperidinyl group, preferably the substituted cyclohexyl group is a cyclohexyl group substituted with an amino group and a dithiosyl group, and the substituted piperidinyl group is a piperidinyl group substituted with an acyl group or a dithiosyl group and -CN.

[0021] Preferably, the compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate, is a coupling compound obtained by a condensation reaction of amine compound A and carboxylic acid compound B1.

[0022] Preferably, in the aforementioned compounds of the present invention, or their stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates, A is a hydrogen-depleted group of any amine compound selected from the group consisting of the following compounds: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib, and delgocitinib. [ka] Preferably, A is a group formed by the dehydrogenation of tofacitinib, ruxolitinib, and baricitinib.

[0023] Preferably, in the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, -B1 is a group obtained by removing any hydroxyl group selected from the following carboxylic acid substances: ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid, and tolfenamic acid.

[0024] [ka]

[0025] More preferably, the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, is a coupling compound obtained by a condensation reaction of one amine compound A selected from tofacitinib, baricitinib, upadacitinib, oclacitinib and ruxolitinib and one carboxylic acid compound B1 selected from ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin, wherein the amine compound is preferably tofacitinib, ruxolitinib and baricitinib.

[0026] More specifically, the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate, wherein it is one of the following specific compounds:

[0027] [ka]

[0028] [ka]

[0029] [ka]

[0030] [ka]

[0031] [ka]

[0032] [ka]

[0033] More preferably, the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, is any of the following specific compounds:

[0034] [ka]

[0035] More preferably, the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, is one of the following specific compounds.

[0036] [ka]

[0037] [ka]

[0038] In another embodiment of the present invention, the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, has the structure shown in general formula (III).

[0039] [ka]

[0040] In the formula, R1 has the same meaning as R1 in general formula (II), and R 1a This is R in general formula (IIa). 1a It has the same meaning as, In general formulas (III) and (IIIa), R2' is YB, B is B1 in general formula (II) or (IIa), or B is B2, where the group B1 is a group formed by dehydration of carboxylic acid compound B1, in which case Y- is (CH2)-O-, the group B2 is a group formed by dehydrogenation of hydroxyl group-containing compound B2, in which case Y- is -(CH2)-, the group B1 has the same meaning as the R2 group in general formula (II) or general formula (IIa), and the group B2 is R c -CO-NH-R d And here, R c This refers to 4-hydroxy-benzothiadindioxide-3-yl shown in the following structural formula (a) (where the benzene ring may be substituted with a halogen or a C1-C6 alkyl group) or 4-hydroxy-R shown in the following structural formula (b) e This is a substituted thienothiazine dioxide-3-yl, where -CO-NH-R is located at the 3-position of the thiazine ring. d It is connected, [ka] Here, R d R is a thiazole, isothiazole, oxazole, isoxazole, or pyridine, or a group obtained by substituting them with a C1-C6 alkyl group or halogen, preferably a thiazole, isoxazole, or unsubstituted pyridinyl group substituted with a methyl group, e R is a C1-C6 alkyl group or halogen (preferably, the halogen is selected from the group consisting of fluorine, chlorine and bromine, one or more of the following), and R of formula (b) e The arrow next to it indicates that the substitution position in the thiophene ring can be any hydrogen atom connected to a carbon atom where substitution can occur.

[0041] More specifically, in the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, -B1 is a group formed by removing any hydroxyl group from the following group of carboxylic acid substances, namely, ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, aclaritide, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid.

Chemical formula

[0042]

Chemical formula

[0043] Furthermore, more specifically, in the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, it is obtained by a production method including the step of directly reacting the compound A-CH2-OH with an acyl chloride of B or the compound B. Here, it is preferable that the compound A-CH2-OH is prepared by step 1) of forming the compound A-CH2-OH from the amine compound A.

[0044] More specifically, in the aforementioned anti-inflammatory compound of the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, A is a group formed by removing hydrogen from any amine compound selected from the following group of compounds, namely, tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib.

Chemical formula

[0045] More specifically, in the aforementioned anti-inflammatory compound of the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, it is any of the following specific compounds.

[0046]

Chemical formula

[0047]

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050]

Chemical formula

[0051] [[ID=C50]]

Chemical formula

[0052]

Chemical formula

[0053] [Chemistry]

[0054] [Chemistry]

[0055] [Chemistry]

[0056] [Chemistry]

[0057] Also, in another aspect, the present invention provides a method for producing the above-mentioned anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, comprising the step of subjecting A and B to a condensation reaction in the presence of a catalyst and an organic solvent to lose water.

[0058] Preferably, in the production method described in the present invention, the catalyst is EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N-carbonyldiimidazole), DMTMM (4-(4,6-dimethoxytriazine)-4-methylmorpholinium chloride), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HCTU (6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazole-1-yl-oxytripyrrolidinophosphate) The organic solvent is one or more of phosphonium and NPC, preferably one or more selected from DCM (dichloromethane), DMF (dimethylformamide), petroleum ether, acetone, chloroform, ethyl acetate, acetonitrile, and THF (tetrahydrofuran), more preferably dichloromethane and / or dimethylformamide, and even more preferably the reaction takes place in the presence of a basic substance, where the basic substance is preferably one or more selected from DMAP (dimethylaminopyridine), triethylamine, DIPEA (N,N-diisopropylethylamine), and hydroxides or salts of sodium, potassium, lithium, and ammonium.

[0059] Preferably, a method for producing the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, includes a step of obtaining it by a condensation reaction with B using A-CH2OH, which loses water.

[0060] Preferably, in a method for producing the anti-inflammatory compound described in the present invention, or its stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate, the compound is: 2) Obtained by a production method comprising the step of directly reacting compound A-CH2-OH with the chloride acylate of B or compound B, Here, it is preferable that the compound A-CH2-OH is prepared by step 1) forming compound A-CH2-OH from amine compound A.

[0061] More preferably, in the production method described in the present invention, step 1) comprises a) adding (2-(chloromethoxy)ethyl)trimethylsilane to A to produce A-CH2O-C2H4-Si(CH3)3 in the presence of a catalyst and a solvent, and b) forming A-CH2OH from A-CH2O-C2H4-Si(CH3)3 in the presence of a catalyst and a solvent, and step 2) A-CH2OH directly reacts with acyl chloride formed from compound B1 or compound B2 to form A-CH2O-B. Here, preferably, in step b), the reaction takes place in the presence of TFA (trifluoroacetic acid) as a catalyst and DCM (dichloromethane) as a solvent, or in step 2), A-CH2OH reacts with the acyl chloride formed from compound B1 in the presence of Et3N (triethylamine) as a catalyst and DCM (dichloromethane) as a solvent, or A-CH2OH reacts with compound B2 in the presence of PPh3 (triphenylphosphine) and DIAD (diisopropyl azodicarboxylic acid) as catalysts and THF (tetrahydrofuran) as a solvent.

[0062] Furthermore, the present invention provides pharmaceutical applications, namely, uses for the anti-inflammatory compound, or its stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates, for the production of anti-inflammatory drug formulations or pharmaceutical compositions (preferably topical pharmaceutical compositions).

[0063] Furthermore, the present invention provides an anti-inflammatory drug preparation or pharmaceutical composition (preferably a topical pharmaceutical composition) containing an anti-inflammatory compound described in any one of the preceding paragraphs of the present invention, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof. [Effects of the Invention]

[0064] Upon synthesizing the above compounds, it was found that the compounds of the present invention have a dissolution rate of 0.04 to 50% per day. According to the present invention, the skin penetration ability of known JAK inhibitors is improved. [Brief explanation of the drawing]

[0065] [Figure 1] This is a PASI score curve diagram of a mouse psoriasis treatment model test using skin application of ointment prepared with CPD-029 of the present invention. [Figure 2] This is a PASI score curve diagram of a mouse psoriasis treatment model test using skin application of ointment prepared with CPD-028 of the present invention. [Figure 3] This is a PASI score curve diagram of a mouse psoriasis treatment model test using skin application of ointment prepared with CPD-027 of the present invention. [Figure 4] This is a PASI score curve diagram of a mouse psoriasis treatment model test using skin application of ointment prepared with CPD-017 of the present invention. [Figure 5] This is a PASI score curve diagram of a mouse psoriasis treatment model test using skin application of ointment prepared with CPD-002 of the present invention. [Modes for carrying out the invention]

[0066] Through diligent research, the inventors unexpectedly discovered that coupling compounds having an acyloxy group and / or a methoxy group, formed by coupling an anti-inflammatory drug compound containing a carboxylic acid or hydroxyl group with a JAK inhibitor compound, possess high therapeutic efficacy and a special effect in controlling the release of drug activity.

[0067] The anti-inflammatory compounds provided by the present invention, or their stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates, have the structure shown in general formula (I). AYB(I) In the formula, A is a group obtained by removing a hydrogen atom from an amine compound having JAK inhibitory activity. Y is either directly connected or -(CH2)-O-, B is a group formed by dehydration of carboxylic acid compound B1, which has anti-inflammatory effects, or a group formed by dehydrogenation of hydroxyl group-containing compound B2.

[0068] In other words, the compounds of general formula (I) provided by the present invention actually include two types, the first type of compound being the case where A is directly linked, and its structural formula is as shown in (II) or (IIa).

[0069] [ka]

[0070] In the formula, R1 is either unsubstituted or R a A pyrazolyl group substituted by, or selected from -N(CH3)-Cy, R 1a This represents a pyrrole ring substituted with a halogen-substituted C1-C6 alkylamine acyl group and / or a C1-C6 alkyl group. Cy is unsubstituted or R b A 5-membered or 6-membered carbon ring, a 5-membered or 6-membered nitrogen-containing heterocycle, and the R a , R b Each independently contains at least one or two groups selected from the group consisting of acyl groups, dithiosyl groups, cyano groups, amino groups, or C1-C6 alkyl-substituted amino groups, preferably the R a , R b However, each of these groups is independently composed of one acyl group or a dithiosyl group and at least one group selected from the group consisting of a cyano group, an amino group, or a C1-C6 alkyl-substituted amino group, where the C1-C6 alkyl group may be substituted with a halogen. In both general formulas (II) and (IIa), R2 is -B, that is, the group -B1 formed by the removal of a hydroxyl group from carboxylic acid compound B1, and is selected from R4-Ar-R3-CO-. Here, R3 is selected from the group consisting of a C1-C4 alkylene group, -NH-, R5NH-, or a C1-C6 alkylene group substituted with a C1-C6 alkoxyamide group, or is directly connected, i.e., the Ar group is directly connected to -CO-, and R3 is preferably a methyl-substituted or unsubstituted methylene group, -C2H4-, or directly connected, and R5 is a C1-C6 alkylene group, where the C1-C6 alkylene group may be substituted with a halogen (preferably, one or more halogens are selected from fluorine, chlorine, or bromine). Ar is an aromatic ring group, preferably a benzene ring, a naphthalene ring, or an aromatic heterocycle, and a benzene ring, naphthalene ring, or aromatic heterocycle or aromatic condensed heterocycle substituted with a group selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 acyl groups, or C1-C6 alkoxy groups (where the aromatic heterocycle is preferably a benzo-containing nitrogen or oxygen-containing heterocycle, for example, a benzopyrrole ring), and more preferably Ar is an aromatic heterocycle containing a nitrogen atom. R6 is a C1-C6 alkyl group containing a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 cycloalkanoyl group. Alternatively, R6 is a C1-C6 alkyl group or aromatic ring or aromatic condensed ring or aromatic condensed heterocycle containing an acyl group and / or an amine group, for example, a C1-C6 alkaneamide group or aromatic condensed heterocyclic amide group, a C1-C6 carbonyloxy group, a halogen-substituted benzoyl group, a C1-C6 alkyl group or halogen-substituted or unsubstituted phenoxy group, a C1-C6 alkyl group or halogen-substituted or unsubstituted phenyl group or aromatic condensed heterocycle, a C1-C6 alkyl group or halogen-substituted or unsubstituted phenylamine group, or R6 may be omitted, where the C1-C6 alkoxy group may form a crosslinked ring with Ar.

[0071] Here, in the aforementioned terms of the present invention and in all instances of "C1-C6" appearing below, the meaning is that the number of carbon atoms is 1 to 6. For example, "C1-C6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms. Similarly, in this specification, "C1-C6 alkoxy group" and "C1-C6 acyl group" refer to an alkoxy group having 1 to 6 carbon atoms and a group having 1 to 6 carbon atoms and containing -C=O, respectively. "C1-C6 alkaneamide group" refers to an alkyl group containing an amide group and having 1 to 6 carbon atoms. "C1-C6 carbonyloxy group" refers to an alkyl group or cycloalkyl group containing an acyloxy group -CO-O and having 1 to 6 carbon atoms. "Cloalkanoyl group" refers to a cyclic alkyl group containing a -C=O group and having 1 to 6 carbon atoms, and "C1 to C6 alkyl group containing a C1 to C6 cycloalkanoyl group" refers to an alkyl group having 1 to 6 carbon atoms in which the hydrogen atoms on the carbon atoms are substituted by a C1 to C6 cycloalkanoyl group. In other words, "C1 to C6 alkyl group containing a C1 to C6 cycloalkanoyl group" is equivalent to "C1 to C6 alkyl group substituted by a C1 to C6 cycloalkanoyl group". Specifically, "C1 to C6" as described in this invention may be "C1 to C6", "C1 to C5", "C1 to C4", "C1 to C3", or "C1 to C2", or it may be C1, that is, a single carbon atom.

[0072] The first type of compound described above is compound AB (specifically A-B1), formed by the dehydrogenation of amine compound A, which has JAK inhibitory activity, and the dehydration of carboxylic acid compound B1.

[0073] The second type of compound provided by the present invention, as a compound of general formula (I), has a structure as shown in general formula (III).

[0074] [ka]

[0075] In the formula, R1 has the same meaning as R1 in general formula (II), and R 1a This is R in general formula (IIa). 1a It has the same meaning as, In general formulas (III) and (IIIa), R2' is -YB, where Y is -(CH2)-O-, and B is -B1 in general formula (II) or (IIa), that is, the group -B1 formed by the removal of a hydroxyl group from the carboxylic acid compound B1, or B is -B2, where -B2 is R c -CO-NH-R d And here, R c This refers to 4-hydroxy-benzothiadindioxide-3-yl shown in the following structural formula (a) (where the benzene ring may be substituted with a halogen or a C1-C4 alkyl group) or 4-hydroxy-R shown in the following structural formula (b) e This is a substituted thienothiazine dioxide-3-yl, where -CO-NH-R is located at the 3-position of the thiazine ring. d It is connected, [ka] Here, R d R is a thiazole, isothiazole, oxazole, isoxazole, or pyridine, or a group obtained by substituting them with a C1-C6 alkyl group or halogen, preferably a thiazole, isoxazole, or unsubstituted pyridinyl group substituted with a methyl group, e R is a C1-C6 alkyl group or halogen (preferably, the halogen is selected from the group consisting of fluorine, chlorine and bromine, one or more elements), and R of formula (b) e The arrow next to it indicates that the substitution position in the thiophene ring can be any hydrogen atom connected to a carbon atom where substitution can occur.

[0076] The second type of compound described in the present invention is obtained by a condensation reaction using A-CH2OH, which loses water with B.

[0077] Specifically, the production of these two types of compounds is 2) The process includes the step of directly reacting compound A-CH2-OH with an acylated chloride of B or compound B, where compound A-CH2-OH is obtained by step 1) forming compound A-CH2-OH from A.

[0078] The scope of the compound of general formula (I) of the present invention actually further includes various stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates that a person skilled in the art can obtain from such compound based on common technical knowledge. In other words, these compounds, and their various stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates, and any substances obtained by a person skilled in the art through various modifications or improvements to the compound based on common technical knowledge, can all be used in the present invention to realize the special effects of the compound of the present invention, such as strong skin penetration, drug release control, and high therapeutic effect, and therefore all fall within the scope of protection of the present invention.

[0079] (Examples) The following examples illustrate the manufacturing procedure of the compound of the present invention and the verification of its performance.

[0080] The model numbers of the nuclear magnetic apparatus and mass spectrometer used in the following Examples 1 to 149 are as follows: NMR spectrometer:Bruker 400M NMR spectrometer Liquid Chromatography Mass Spectrometer: Agilent InfinityLab LC / MSD iQ Table 1 below shows the structural formulas and compound names of the target compounds produced in each example.

[0081] [Table 1-1]

[0082] [Table 1-2]

[0083] Table 1-3

[0084] Table 1-4

[0085] Table 1-5

[0086] Table 1-6

[0087] Table 1-7

[0088] Table 1-8

[0089] Table 1-9

[0090] Table 1-10

[0091] Table 1-11

[0092] Table 1-12

[0093] Table 1-13

[0094] Table 1-14

[0095] Table 1-15

[0096] Table 1-16

[0097] Table 1-17

[0098] Table 1-18

[0099] Table 1-19

[0100] Table 1-20

[0101] Table 1-21

[0102] Table 1-22

[0103] Table 1-23

[0104] Table 1-24

[0105] Table 1-25

[0106] Table 1-26

[0107] Table 1-27

[0108] Table 1-28

[0109] Table 1-29

[0110] Table 1-30

[0111] Table 1-31

[0112] Table 1-32

[0113] Table 1-33

[0114] [Table 1-34]

[0115] [Table 1-35]

[0116] (Example 1) 3-((3R,4R)-3-((7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0117] [ka]

[0118] Synthesis of 3-((3R,4R)-3-((7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol) and 2-(4-isobutylphenyl)propionic acid (ibuprofen, 412 mg, 2 mmol) were dissolved in dichloromethane (20 mL). Under an ice bath, 4-dimethylaminopyridine (DMAP, 134 mg, 1.1 mmol) and dicyclohexylcarbodiimide (DCC, 412 mg, 2 mmol) were added, and the mixture was stirred under reflux for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was diluted with dichloromethane, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1~2:1) to obtain 0.292 g of a white solid, with a yield of 58%. MS(m / z):[M+H] + C 29 H 36 The calculated value for N6O2 was 501.65, and the measured value was 501.2. 1 1H NMR (400 MHz, chloroform-d)δ 8.39(d,J=7.3Hz,1H),7.68(dd,J=15.2,4.2Hz,1H),7.44-7.33(m,2H),7.08-7. 03(m,2H),6.61(t,J=4.2Hz,1H),6.13(tt,J=7.3,3.5Hz,1H),5.09(s,1H),4.09 -3.70(m,2H),3.66-3.44(m,4H),3.33(d,J=16.4Hz,3H),2.39(d,J=7.2Hz,3H), 1.88-1.70(m,2H),1.67-1.60(m,4H),1.15-1.03(m,3H),0.86(d,J=6.6Hz,6H).

[0119] (Example 2) 3-((3R,4R)-3-((7-((S)-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0120] [ka]

[0121] Synthesis of 3-((3R,4R)-3-((7-((S)-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol) and (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 309 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). Under an ice bath, 4-dimethylaminopyridine (DMAP, 134 mg, 1.1 mmol) and dicyclohexylcarbodiimide (DCC, 412 mg, 2 mmol) were added, and the mixture was then refluxed and stirred for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was diluted with dichloromethane, and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1-2:1) yielded the target compound, which was 0.24 g of a white solid with a yield of 48%. MS(m / z):[M+H] + C 29 H 36 The calculated value for N6O2 was 501.65, and the measured value was 501.2. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,J=4.6Hz,1H),7.68(dd,J=4.3,2.8Hz,1H),7.29(dd,J=8.2,2.6Hz,2H),7.06(d ,J=7.9Hz,2H),6.88(d,J=4.2Hz,1H),6.09(qd,J=6.7,3.0Hz,1H),4.85(s,1H),4.18-3 .59(m,5H),3.41(q,J=5.3,4.9Hz,1H),3.24(d,J=2.4Hz,3H),2.36(d,J=7.2Hz,3H),1. 87-1.65(m,2H),1.63-1.48(m,4H),1.00(dd,J=7.2,2.6Hz,3H),0.81(d,J=6.6Hz,6H).

[0122] (Example 3) (4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate

[0123] [ka]

[0124] Step 1: Synthesis of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile

[0125] [ka]

[0126] Under nitrogen protection, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 9 g, 28.81 mmol) was dissolved in dichloromethane (180 mL) and diethyl acetate (3.745 g, 28.81 mol). After stirring at room temperature for 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (4.8 g, 28.81 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography yielded 9 g of a white solid with a yield of 71%. MS(m / z):[M+H] + C 22 H 34 The calculated value for N6O2Si is 443.25, and the measured value is 443.2.

[0127] Step 2: Synthesis of 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0128] [ka]

[0129] Under nitrogen protection and in an ice bath, trifluoroacetic acid (6.44 g, 56.5 mmol) was slowly added dropwise to a solution of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile (5 g, 11.3 mmol) in dichloromethane (100 mL). After 30 minutes, the ice bath was removed, and the mixture was stirred for 24 hours once the temperature rose to room temperature. At 0°C, saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. The mixture was then poured into a separatory funnel and separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 3.5 g of the target product, with a yield of 90%. MS(m / z):[M+H] + C 17 H 22 The calculated value for N6O2 was 343.18, and the measured value was 343.1.

[0130] Step 3: Synthesis of (4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate

[0131] [ka]

[0132] 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (6.63 g, 19.4 mmol), (S)-2-(4-isobutylphenyl)propionyl chloride (8.72 g, 38.8 mmol), and triethylamine (3.93 g, 38.8 mmol) were dissolved in dichloromethane (100 mL). The mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1~1:1) yielded 4.05 g of the target compound, with a yield of 39.4%. MS (m / z): [M+H] + C 30 H 38 The calculated value for N6O3 was 531.67, and the measured value was 531.2. 1 H NMR(400MHz,CDCl3)δ 8.32(d,J=7.4Hz,1H),7.11(dd,J=12.7,5.5Hz,3H),7.03(d,J=7.6Hz,2H),6.51(s,1H),6.18(dd,J=10.4,4.0Hz,1H),6 .14-6.06(m,1H),5.13(s,1H),4.06(dd,J=13.2,3.8Hz,1H),3.81(dd,J=18.3,10.5Hz,1H),3.69(q,J=7.1Hz,1H),3.61( t,J=11.8Hz,1H),3.55-3.47(m,2H),3.37(d,J=17.9Hz,3H),2.58-2.46(m,1H),2.42(d,J=7.1Hz,2H),2.05-1.91(m,1H) ),1.83(td,J=13.0,6.2Hz,2H),1.45(d,J=7.1Hz,3H),1.28(s,1H),1.09(dd,J=12.9,7.1Hz,3H),0.88(d,J=6.6Hz,6H).

[0133] (Example 4) 3-((3R,4R)-3-((7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0134] [ka]

[0135] 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 314 mg, 1.3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain 0.1 g of a yellow solid, with a yield of 18.6%. MS(m / z):[M+H] + C 31 H 33 The calculated value for N7O2 was 536.65, and the measured value was 536.2. 1H NMR(400MHz,DMSO)δ 8.60(d,J=16.4Hz,1H),8.14(d,J=7.5Hz,1H),7.55-7.43(m,1H),7.35(dt,J=17.9,8.5Hz,2H),7. 06(d,J=6.2Hz,2H),6.98(s,1H),6.87(t,J=12.4Hz,1H),6.80(d,J=8.4Hz,1H),6.73(t,J=7.4Hz,1 H),4.86(s,1H),4.20-3.90(m,3H),3.87-3.64(m,2H),3.42(s,1H),3.30(s,3H),2.39(d,J=5.3Hz ,1H),2.26(s,3H),2.10-1.96(m,3H),1.90-1.67(m,1H),1.66-1.53(m,1H),1.03(d,J=6.9Hz,3H).

[0136] (Example 5) 3-((3R,4R)-3-((7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0137] [ka]

[0138] 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 187 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.6 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 204 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain 0.12 g of a yellow solid, with a yield of 35.9%. MS(m / z):[M+H] + C 30 H 30 The calculated value for ClN7O2 was 557.07, and the measured value was 557.2. 1 H NMR(400MHz,DMSO-d6)δ 8.23(d,J=17.2Hz,1H),8.10(d,J=8.3Hz,1H),7.46(ddd,J=8.6,7.1,1.6Hz,1H),7.43-7.34(m,2H),7.0 7(tq,J=7.0,4.8,3.6Hz,3H),6.96(d,J=8.3Hz,1H),6.90(t,J=7.5Hz,1H),6.84(d,J=4.1Hz,1H),4.84(s ,1H),4.19-3.90(m,3H),3.74(dtd,J=34.8,14.2,13.1,7.4Hz,2H),3.50-3.39(m,1H),3.29-3.21(m,3H ),2.46-2.32(m,1H),2.06(d,J=8.5Hz,3H),1.92-1.66(m,1H),1.64-1.51(m,1H),1.03(d,J=7.1Hz,3H).

[0139] (Example 6) 3-((3R,4R)-3-((7-((S)-2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0140] [ka]

[0141] Synthesis of 3-((3R,4R)-3-((7-((S)-2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 506 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 863 mg, 4.5 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.7 g, with a yield of 66.8%. MS(m / z):[M+H] + C 30 H 32 The calculated value for N6O3 was 525.63, and the measured value was 525.3. 11H NMR (400MHz, DMSO) δ 8.41(s,1H),7.81-7.69(m,4H),7.50(dd,J=7.0,5.3Hz,1H),7.24(s,1H),7. 12(dd,J=8.9,2.3Hz,1H),6.88(d,J=3.7Hz,1H),6.25-6.16(m,1H),4.83(s, 1H),4.17-3.87(m,3H),3.84(s,3H),3.72-3.59(m,2H),3.41-3.39(m,1H),3 .23(s,3H),2.32(d,J=13.3Hz,1H),1.83-1.49(m,5H),0.99(d,J=7.1Hz,3H).

[0142] (Example 7) 3-((3R,4R)-3-((7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0143] [ka]

[0144] Synthesis of 3-((3R,4R)-3-((7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 559 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) as a white solid of 0.73 g, with a yield of 66.6%. MS(m / z):[M+H] + C 32 H 32 The calculated value for N6O3 was 549.65, and the measured value was 549.3. 1 H NMR(400MHz,DMSO)δ 8.33(d,J=7.4Hz,1H),7.79(d,J=1.6Hz,1H),7.76-7.63(m,5H),7.61(d,J=7.8Hz,1H),7 .57(d,J=8.5Hz,1H),7.54(s,1H),7.51(d,J=7.7Hz,1H),6.94(d,J=3.8Hz,1H),6.16(q, J=6.8Hz,1H),4.85(s,1H),4.14-3.90(m,3H),3.83-3.60(m,2H),3.46-3.39(m,1H),3.2 6(s,3H),2.44-2.29(m,1H),1.90-1.68(m,1H),1.67-1.51(m,4H),1.02(t,J=9.4Hz,3H).

[0145] (Example 8) 3-((3R,4R)-3-((7-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0146] [ka]

[0147] Synthesis of 3-((3R,4R)-3-((7-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 537 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.73 g, with a yield of 67.8%. MS(m / z):[M+H] + C 31 H 31 The calculated value for FN6O2 was 539.63, and the measured value was 539.2. 11H NMR (400MHz, DMSO) δ 8.41(dd,J=5.7,1.3Hz,1H),7.72(d,J=4.2Hz,1H),7.54-7.43(m,5H),7.41 -7.27(m,3H),6.93(s,1H),6.16(q,J=6.7Hz,1H),4.84(s,1H),4.16-3.99(m ,2H),3.98-3.87(m,1H),3.75-3.59(m,2H),3.45-3.39(m,1H),3.23(s,3H), 2.43-2.27(m,1H),1.88-1.66(m,1H),1.65-1.52(m,4H),1.04-0.93(m,3H).

[0148] (Example 9) 3-((3R,4R)-3-((7-(2-(2-(2-(2-(2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0149] [ka]

[0150] Synthesis of 3-((3R,4R)-3-((7-(2-(2-(2-(2-(2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 651 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 0.25 g, with a yield of 21.2%. MS(m / z):[M+H] + C 30 H 29 The calculated value for Cl2N7O2 is 590.51, and the measured value is 590.2. 1 H NMR(400MHz,DMSO)δ 8.41(d,J=5.9Hz,1H),7.75(d,J=4.1Hz,1H),7.51(d,J=8.1Hz,2H),7.35(d,J=12.7Hz,1H),7.28(d, J=7.0Hz,1H),7.20(t,J=8.1Hz,1H),7.07(t,J=7.7Hz,1H),6.96(d,J=3.8Hz,1H),6.83(t,J=7.4Hz, 1H),6.22(d,J=8.0Hz,1H),4.99-4.83(m,3H),4.16-3.99(m,3H),3.88-3.61(m,2H),3.40(d,J=14.4 Hz,1H),3.29(s,3H),2.45-2.29(m,1H),1.89-1.67(m,1H),1.65-1.52(m,1H),1.01(d,J=7.1Hz,3H).

[0151] (Example 10) 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile

[0152] [ka]

[0153] Synthesis of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 781 mg, 2.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 787.4 mg, 3.25 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 720.5 mg, 3.75 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 1.1 g, with a yield of 82%. MS(m / z):[M+H] + C 31 H 32 The calculated value for N6O3 was 537.64, and the measured value was 537.3. 1¹H NMR (400MHz, chloroform-d)δ 8.30 (dd, J=10.4, 4.8Hz, 1H), 7.77-7.61 (m, 1H), 7.36-7.16 (m, 5H), 7.10 (t, J=7.4Hz, 1H), 6.98-6.92 (m, 2H), 6.83 (dt, J=7.7, 2.0Hz, 1H), 6.62 (t, J=4.2Hz, 1H), 6.10 (qd, J=7.0, 4.5Hz, 1H), 5.09 (ddq, J=14.2, 9.9, 4.8) Hz,1H),4.12-3.67(m,2H),3.63-3.41(m,4H),3.33(d,J=15.6Hz,3H),2.48(ddt,J=17.9,12.9,5.9Hz,1H),1 .93(dddd,J=17.4,12.6,7.5,3.9Hz,1H),1.81-1.68(m,1H),1.66-1.58(m,3H),1.08(dd,J=12.6,7.1Hz,3H).

[0154] (Example 11) 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile

[0155] [ka]

[0156] Synthesis of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 541 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 0.48 g, with a yield of 44.4%. MS(m / z):[M+H] + C 31 H 36 The calculated value for N6O3 was 541.67, and the measured value was 541.3. 1 H NMR(400MHz,DMSO)δ 8.38(dd,J=6.2,1.5Hz,1H),7.80-7.60(m,1H),7.32(dd,J=17.9,16.2Hz,2H),7.10(d,J=7.9Hz ,2H),6.89(d,J=4.3Hz,1H),6.19-5.98(m,1H),4.84(s,1H),4.17-3.98(m,2H),3.96-3.57(m,3 H),3.40(t,J=5.9Hz,1H),3.21(s,3H),2.94-2.83(m,1H),2.41-2.25(m,3H),2.25-2.14(m,1H) ,2.09-2.02(m,1H),1.90-1.80(m,3H),1.72-1.48(m,5H),1.48-1.37(m,1H),1.07-0.93(m,3H).

[0157] (Example 12) 3-((3R,4R)-3-((7-(2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropionitrile

[0158]

Chem.

[0159] Synthesis of 3-((3R,4R)-3-((7-(2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 233 mg, 0.65 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. Further, it was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 2:3) to obtain the target compound, which was a white solid of 0.16 g and the yield was 49.1%. MS (m / z): [M+H] + C 35 H 34 Calculated value of C H ClN7O4 is 653.15, measured value is 653.3. 1H NMR(400MHz,DMSO-d6)δ 8.45(d,J=6.4Hz,1H),7.77-7.61(m,5H),7.11(t,J=2.8Hz,1H),6.97(t,J=6.7Hz,2H),6.71(dd,J=9.1,2.5Hz,1H),5.05-4.86(m,3H),4.21-3 .89(m,3H),3.86-3.64(m,5H),3.46-3.40(m,1H),3.31(s,3H),2.44-2. 38(m,1H),1.88-1.52(m,2H),1.32-1.21(m,3H),1.02(d,J=7.1Hz,3H).

[0160] (Example 13) N-(4-(2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide

[0161] [ka]

[0162] Synthesis of N-(4-(2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 156 mg, 0.5 mmol), 2-(4-acetylaminophenyl)acetic acid (actarit, 126 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8 mL) and stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:6) to obtain 0.118 g of a white solid, with a yield of 48.6%. MS(m / z):[M+H] + C 26 H 29 The calculated value for N7O3 was 488.56, and the measured value was 488.2. 1 H NMR(400MHz,DMSO-d6)δ 9.90(s,1H),8.39(d,J=5.8Hz,1H),7.70(d,J=4.1Hz,1H),7.51(d,J=8.1 Hz,2H),7.26(d,J=8.1Hz,2H),6.94(d,J=4.4Hz,1H),4.97-4.71(m,3H),4 .24-3.89(m,3H),3.85-3.59(m,1H),3.49-3.40(m,1H),3.28(s,3H),2.3 9(q,J=6.2Hz,1H),2.03(s,3H),1.88-1.46(m,2H),1.02(d,J=7.0Hz,3H).

[0163] (Example 14) 3-((3R,4R)-3-((7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile

[0164] [Chemistry]

[0165] Synthesis of 3-((3R,4R)-3-((7-(2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropionitrile 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (Tofacitinib, 156 mg, 0.5 mmol), 1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (Etodolac, 158 mg, 0.55 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. Further, it was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) to obtain the target compound, which was a white solid of 0.11 g and the yield was 37.8%. MS (m / z): [M+H] + C 33 H 39 Calculated value of C 1H NMR(400MHz,DMSO-d6)δ 10.50(s,1H),8.29(s,1H),7.67(td,J=4.5,2.2Hz,1H),7.23(dd,J=7.5,2.0Hz,1H),6.98-6.81(m,3H),4.84(s ,1H),4.67(ddd,J=14.7,8.6,6.3Hz,1H),4.20-3.98(m,3H),3.98-3.82(m,2H),3.81-3.61(m,3H),3.47-3.38( m,1H),3.27(s,3H),2.84(q,J=7.5Hz,2H),2.60(dt,J=9.4,4.7Hz,2H),2.45-2.30(m,1H),2.16(qq,J=6.9,4.5 ,3.9Hz,2H),1.83(s,2H),1.26(td,J=7.6,3.1Hz,3H),1.01(dt,J=7.2,2.8Hz,3H),0.69(td,J=7.1,3.4Hz,3H).

[0166] (Example 15) 2-(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carbonyl)phenyl acetate

[0167] [ka]

[0168] Synthesis of 2-(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carbonyl)phenyl acetate 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol), 2-acetoxybenzoic acid (aspirin, 216 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 14 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.06 g, with a yield of 12.6%. MS(m / z):[M+H] + C 25 H 26 The calculated value for N6O4 was 475.52, and the measured value was 475.2. 1 H NMR(400MHz,DMSO-d6)δ 8.02(d,J=6.8Hz,1H),7.69-7.57(m,2H),7.58(d,J=4.1Hz,1H),7.43-7.36(m,1H),7 .29(d,J=8.1Hz,1H),6.98(t,J=5.0Hz,1H),4.84(s,1H),4.19-3.87(m,3H),3.84-3. 62(m,2H),3.44-3.29(m,1H),3.28(s,3H),2.37(dq,J=12.0,6.7,5.6Hz,1H),1.92(d ,J=1.7Hz,3H),1.88-1.66(m,1H),1.58(p,J=8.0,7.0Hz,1H),1.01(d,J=7.1Hz,3H).

[0169] (Example 16) tert-butyl((S)-2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate

[0170] [ka]

[0171] Synthesis of tert-butyl((S)-2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol), N-Boc-L-phenylglycine (326 mg, 1.3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1~1:2) yielded the target compound, which was a white solid of 0.3 g with a yield of 55%. MS (m / z): [M+H] + C 29 H 35 The calculated value for N7O4 is 546.64, and the measured value is 546.3. 1 H NMR(400MHz,DMSO-d6)δ 8.38(d,J=4.7Hz,1H),7.85(d,J=7.3Hz,1H),7.70(d,J=4.1Hz,1H),7.48(t,J=7.4Hz,3H),7.35-7.21(m,3H),7.02-6.83(m,1H),4.86(s,1 H),4.08-3.97(m,3H),3.82-3.54(m,2H),3.42-3.39(m,1H),3.24(s,3H),2.35(s,1H),1.81-1.56(m,2H),1.39(s,9H),1.06-0.90(m,3H).

[0172] (Example 17) (S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0173] [ka]

[0174] Synthesis of (S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 488 mg, 4 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 453 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) as a 0.5 g white solid with a yield of 44.7%. MS(m / z):[M+H] + C 29 H 33 The calculated value for N7O3S was 560.69, and the measured value was 560.2. 1H NMR(400MHz,chloroform-d)δ 8.96(s,1H),8.41(s,1H),8.26(s,1H),8.03(d,J=4.2Hz,1H),7.47-7.34(m,2H),7.06 (d,J=7.9Hz,2H),6.81(d,J=4.1Hz,1H),6.06(q,J=6.9Hz,1H),4.62(d,J=9.2Hz,2H), 4.34-4.16(m,2H),3.40(s,2H),3.08(q,J=7.4Hz,2H),2.39(d,J=7.2Hz,2H),1.80(dp ,J=13.5,6.8Hz,1H),1.68(d,J=6.9Hz,3H),1.41(t,J=7.4Hz,3H),0.95-0.82(m,6H).

[0175] (Example 18) (S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0176] [ka]

[0177] Synthesis of (S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 305 mg, 2.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 230 mg, 1.1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.25 g, with a yield of 42.9%. MS(m / z):[M+H] + C 30 H 29 The calculated value for N7O4S was 584.67, and the measured value was 584.2. 1 H NMR(400MHz,DMSO)δ 9.03(s,1H),8.98(s,1H),8.49(s,1H),8.18(d,J=4.2Hz,1H),7.85(s,1H),7.80-7.74( m,2H),7.58-7.54(m,1H),7.40(d,J=4.2Hz,1H),7.25(d,J=2.2Hz,1H),7.12(dd,J=9.0 ,2.4Hz,1H),6.12(q,J=6.8Hz,1H),4.58(d,J=9.2Hz,2H),4.23(d,J=9.2Hz,2H),3.83( s,3H),3.68(s,2H),3.23(q,J=7.3Hz,2H),1.68(d,J=6.9Hz,3H),1.24(t,J=7.3Hz,3H).

[0178] (Example 19) 2-(3-(4-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile

[0179] [ka]

[0180] Synthesis of 2-(3-(4-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 244 mg, 2 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 280 mg, 1.1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by separation using silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2), yielding 0.2 g of a white solid with a yield of 32.9%. MS(m / z):[M+H] + C 32 H 29 The calculated value for N7O4S was 608.69, and the measured value was 608.3. 11H NMR (400MHz, DMSO) δ 9.00(s,1H),8.93(s,1H),8.51(s,1H),8.17(d,J=4.2Hz,1H),7.81(s,1H),7. 76(d,J=7.7Hz,1H),7.70-7.58(m,4H),7.52(t,J=7.6Hz,3H),7.43(d,J=4.2H z,1H),6.06(q,J=6.8Hz,1H),4.59(d,J=9.1Hz,2H),4.24(d,J=9.1Hz,2H),3. 68(s,2H),3.23(q,J=7.3Hz,2H),1.63(d,J=6.9Hz,3H),1.24(t,J=7.3Hz,3H).

[0181] (Example 20) 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0182] [ka]

[0183] Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 610 mg, 5 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 537 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.3 g, with a yield of 25.1%. MS(m / z):[M+H] + C 31 H 28 The calculated value for FN7O3S is 598.67, and the measured value is 598.2. 1 H NMR(400MHz,DMSO)δ 9.05(s,1H),9.02(s,1H),8.53(s,1H),8.20(d,J=4.2Hz,1H),7.54-7.35(m,9H),6.08(q,J=7.0Hz,1H),4.61(d,J= 9.2Hz,2H),4.25(d,J=9.2Hz,2H),3.70(s,2H),3.24(q,J=7.4Hz,2H),1.66(d,J=7.0Hz,3H),1.25(t,J=7.3Hz,3H).

[0184] (Example 21) 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0185] [ka]

[0186] Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 133 mg, 0.55 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 17 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 0.11 g, with a yield of 74.5%. MS(m / z):[M+H] + C 31 H 29 The calculated value for N7O4S was 596.68, and the measured value was 596.2. 1 H NMR(400MHz,DMSO-d6)δ 8.99(s,1H),8.86(s,1H),8.50(s,1H),8.12(d,J=4.2Hz,1H),7.40(d,J=4.2Hz,1H ),7.37-7.25(m,3H),7.21-7.10(m,2H),7.07(t,J=2.1Hz,1H),6.95-6.89(m,2H),6 .86-6.78(m,1H),5.94(d,J=6.9Hz,1H),4.60(d,J=9.1Hz,2H),4.24(d,J=9.1Hz,2H ),3.68(s,2H),3.23(q,J=7.3Hz,2H),1.57(d,J=6.9Hz,3H),1.24(t,J=7.4Hz,3H).

[0187] (Example 22) 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0188] [ka]

[0189] Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 136 mg, 0.55 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 17 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1~3:4) to obtain 0.13 g of a white solid, with a yield of 43.4%. MS(m / z):[M+H] + C 31 H 33 The calculated value for N7O4S was 600.71, and the measured value was 600.3. 1H NMR(400MHz,DMSO-d6)δ 8.99(d,J=3.4Hz,2H),8.50(s,1H),8.14(d,J=4.2Hz,1H),7.40(d,J=4.2Hz,1H),7.34(d,J=7.9Hz,2H),7.12(d, J=7.9Hz,2H),5.98(q,J=6.9Hz,1H),4.59(d,J=9.1Hz,2H),4.24(d,J=9.1Hz,2H),3.69(s,2H),3.33-3.19(m,2H) ,2.96-2.83(m,1H),2.44-2.27(m,2H),2.20(dd,J=18.5,8.5Hz,1H),2.03(ddd,J=18.6,10.1,8.6Hz,1H),1.95- 1.74(m,2H),1.70-1.61(m,1H),1.58(d,J=6.9Hz,3H),1.42(dd,J=10.6,6.9Hz,1H),1.24(dd,J=8.7,6.1Hz,3H).

[0190] (Example 23) 2-(3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile

[0191] [ka]

[0192] Synthesis of 2-(3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 197 mg, 0.55 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:5) as a white solid of 0.18 g, with a yield of 50.6%. MS(m / z):[M+H] + C 35 H 31 The calculated value for ClN8O5S was 712.19, and the measured value was 711.2. 1 1H NMR (400MHz, DMSO-d6)δ 9.05(d,J=2.4Hz,2H),8.56(s,1H),8.17(d,J=4.2Hz,1H),7.77-7.61(m,4H), 7.47(d,J=4.2Hz,1H),7.18(d,J=2.6Hz,1H),6.99(d,J=9.0Hz,1H),6.72(dd,J =9.0,2.6Hz,1H),5.04(s,2H),4.64(d,J=9.1Hz,2H),4.28(d,J=9.1Hz,2H),3. 71(d,J=6.8Hz,5H),3.25(q,J=7.3Hz,2H),2.27(s,3H),1.26(t,J=7.3Hz,3H).

[0193] (Example 24) N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide

[0194] [ka]

[0195] Synthesis of N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetylaminophenyl)acetic acid (actarit, 106 mg, 0.55 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and DMF (2 mL) and stirred at room temperature for 14 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) as a white solid of 0.03 g, with a yield of 10%. MS(m / z):[M+H] + C 26 H 26 The calculated value for N8O4S was 547.61, and the measured value was 547.3. 1H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),9.01(d,J=10.0Hz,2H),8.53(s,1H),8.14(d,J=4.2Hz,1H),7.54(d,J=8.1Hz,2H),7.44(d,J=4.2Hz,1H),7.30(d,J=8.0Hz ,2H),4.87(s,2H),4.62(d,J=9.0Hz,2H),4.26(d,J=9.1Hz,2H),3.71(s,2H),3.25(q,J=7.3Hz,2H),2.04(s,3H),1.26(t,J=7.4Hz,3H).

[0196] (Example 25) 2-(3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile

[0197] [ka]

[0198] Synthesis of 2-(3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 158 mg, 0.55 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 14 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) as a white solid of 0.18 g, with a yield of 56%. MS(m / z):[M+H] + C 33 H 36 The calculated value for N8O4S was 641.76, and the measured value was 641.2. 1 H NMR(400MHz,DMSO-d6)δ 10.59(s,1H),9.04(s,1H),8.95(s,1H),8.55(s,1H),8.15(d,J=4.2Hz,1H),7.44(d,J=4.2Hz,1H),7.27(d d,J=7.4,1.6Hz,1H),7.00-6.88(m,2H),4.71-4.56(m,3H),4.29(d,J=9.1Hz,2H),4.22(d,J=14.5Hz,1H),3 .91(ddd,J=11.7,7.1,4.9Hz,1H),3.83-3.76(m,1H),3.74(s,2H),3.27(q,J=7.3Hz,2H),2.89(q,J=7.5Hz, 2H),2.64(dt,J=6.8,4.2Hz,2H),2.21(q,J=7.2Hz,2H),1.29(td,J=7.4,4.3Hz,6H),0.76(t,J=7.3Hz,3H).

[0199] (Example 26) tert-butyl(S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate

[0200] [ka]

[0201] Synthesis of tert-butyl(S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), N-Boc-L-phenylglycine (301.5 mg, 1.2 mmol), 4-dimethylaminopyridine (DMAP, 183 mg, 1.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) as a white solid of 0.12 g, with a yield of 19.8%. MS(m / z):[M+H] + C 29 H 32 The calculated value for N8O5S was 605.69, and the measured value was 605.3. 1H NMR(400MHz,DMSO-d6)δ 9.00(d,J=3.7Hz,2H),8.51(s,1H),8.18(d,J=4.1Hz,1H),7.99(d,J=7.5Hz,1H),7.61-7.37(m,4H),7.36-7.23(m,3H) ,4.60(d,J=9.1Hz,2H),4.24(d,J=9.1Hz,2H),3.69(s,2H),3.23(q,J=7.3Hz,2H),1.40(s,9H),1.24(t,J=7.4Hz,3H).

[0202] (Example 27) 1-((1S,4R)-4-((7-((S)-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0203] [ka]

[0204] N-methyl-1-((1R,4R)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 338 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 122 mg, 1 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain 0.14 g of a white solid, with a yield of 26.6%. MS(m / z):[M+H] + C 28 H39 The calculated value for N5O3S was 526.71, and the measured value was 526.2. 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),7.66(d,J=4.2Hz,1H),7.29(d,J=8.1Hz,2H),7.06(d,J=7.8Hz,2H),6.93 -6.79(m,2H),6.10(q,J=6.9Hz,1H),4.63(s,1H),3.14(s,3H),2.94(d,J=6.2Hz,2H), 2.59(d,J=5.0Hz,3H),2.35(d,J=7.2Hz,2H),2.04(d,J=13.1Hz,2H),1.88-1.74(m,2H ),1.74-1.63(m,4H),1.52(d,J=7.0Hz,3H),1.27-1.21(m,2H),0.81(d,J=6.6Hz,6H).

[0205] (Example 28) (R)-3-Cyclopentyl-3-(4-(7-(S)-2-(4-isobutylphenyl)propionyl)-7H-Pyrrolo[2,3-d]pyrimidine-4-yl)-1H-Pyrazole-1-yl)propionitrile

[0206] [ka]

[0207] (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 306 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain 0.42 g of a white solid, with a yield of 85%. MS(m / z):[M+H] + C 30 H 34 The calculated value for N6O4 was 495.64, and the measured value was 495.2. 1 H NMR(400MHz,DMSO-d6)δ 8.96(s,1H),8.87(s,1H),8.40(s,1H),8.11(d,J=4.2Hz,1H),7.36-7.27(m,3H) ,7.07(d,J=8.0Hz,2H),6.00(q,J=6.9Hz,1H),4.53(td,J=9.6,4.3Hz,1H),3.23 (qd,J=17.1,6.9Hz,2H),2.47-2.38(m,1H),2.34(d,J=7.1Hz,2H),1.77(ddd,J= 27.2,12.6,7.2Hz,2H),1.66-1.47(m,5H),1.47-1.11(m,5H),0.88-0.76(m,6H).

[0208] (Example 29) 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(4-(1-oxoisoindorin-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropionitrile

[0209] [ka]

[0210] 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-piperidine-1-yl]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyrate (indobufen, 384 mg, 1.3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 249 mg, 1.3 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:5) as a white solid of 0.27 g, with a yield of 45.8%. MS(m / z):[M+H] + C 34 H 35 The calculated value for N7O3 was 590.70, and the measured value was 590.2. 1 H NMR(400MHz,DMSO-d6)δ 8.52-8.37(m,1H),7.84(d,J=8.1Hz,2H),7.74(dd,J=22.3,5.9Hz,2H),7.66(d,J=7.1Hz,2H), 7.57-7.50(m,1H),7.50-7.44(m,2H),6.90(d,J=4.6Hz,1H),6.01-5.91(m,1H),4.97(s,2H),4 .84(s,1H),4.18-4.00(m,2H),3.99-3.53(m,3H),3.41(d,J=6.3Hz,1H),3.24(s,3H),2.43-2. 30(m,1H),2.27-2.14(m,1H),1.95-1.50(m,3H),1.00(d,J=7.1Hz,3H),0.91(t,J=7.3Hz,3H).

[0211] (Example 30) 2-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(1-oxoisoindorin-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0212] [ka]

[0213] 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyrate (indobufen, 354 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain 0.46 g of a white solid, with a yield of 70.9%. MS(m / z):[M+H] + C 34 H 32 The calculated value for N8O4S was 649.74, and the measured value was 649.3. 1H NMR(400MHz,DMSO)δ 9.05(s,1H),8.98(s,1H),8.50(s,1H),8.16(d,J=3.9Hz,1H),7.86(d,J=8.4Hz,2H),7.73(t,J=14.0H z,1H),7.69-7.58(m,2H),7.52(d,J=8.4Hz,3H),7.40(d,J=3.9Hz,1H),5.85(t,J=7.2Hz,1H),4.96(s, 2H),4.59(d,J=9.0Hz,2H),4.24(d,J=9.0Hz,2H),3.68(s,2H),3.22(dd,J=14.5,7.2Hz,2H),2.26(dt, J=13.8,7.1Hz,1H),1.94(dd,J=13.6,7.2Hz,1H),1.23(dd,J=14.8,7.6Hz,3H),0.94(t,J=7.1Hz,3H).

[0214] (Example 31) (R)-3-Cyclopentyl-3-(4-(7-((S)-2-(6-Methoxynaphthalene-2-yl)propionyl)-7H-Pyrrolo[2,3-d]pyrimidine-4-yl))-1H-Pyrazole-1-yl)propionitrile

[0215] [ka]

[0216] (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 138 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.16 g, with a yield of 61.7%. MS(m / z):[M+H] + C 31 H 30 The calculated value for N6O2 was 519.62, and the measured value was 519.3. 1 H NMR(400MHz,DMSO)δ 8.99(s,1H),8.85(s,1H),8.39(s,1H),8.14(d,J=4.2Hz,1H),7.84(s,1H),7.81-7.73(m,2H),7. 55(dd,J=8.6,1.5Hz,1H),7.30(d,J=4.2Hz,1H),7.24(d,J=2.2Hz,1H),7.11(dd,J=9.0,2.4Hz,1H ),6.13(q,J=6.8Hz,1H),4.53(td,J=9.6,4.2Hz,1H),3.83(s,3H),3.29-3.14(m,2H),2.47-2.34( m,1H),1.81(td,J=11.7,7.3Hz,1H),1.68(d,J=6.9Hz,3H),1.63-1.38(m,4H),1.38-1.21(m,3H).

[0217] (Example 32) (3R)-3-(4-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile

[0218] [ka]

[0219] (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 152 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 0.18 g of a white solid, with a yield of 66.4%. MS(m / z):[M+H] + C 33 H 30 The calculated value for N6O2 was 543.64, and the measured value was 543.2. 1H NMR(400MHz,DMSO)δ 8.89(d,J=6.4Hz,2H),8.41(s,1H),8.14(d,J=4.2Hz,1H),7.82(s,1H),7.76(d,J =7.7Hz,1H),7.70-7.59(m,4H),7.53(t,J=7.6Hz,3H),7.33(d,J=4.1Hz,1H),6.08 (q,J=6.8Hz,1H),4.55(td,J=9.6,4.2Hz,1H),3.29-3.16(m,2H),2.42(dt,J=17. 0,8.5Hz,1H),1.82(td,J=11.6,7.3Hz,1H),1.70-1.39(m,7H),1.39-1.20(m,3H).

[0220] (Example 33) (3R)-3-cyclopentyl-3-(4-(7-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile

[0221] [ka]

[0222] (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 146 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.17 g, with a yield of 63.9%. MS(m / z):[M+H] + C 32 H 29 The calculated value for FN6O is 533.62, and the measured value is 533.2. 1 H NMR(400MHz,DMSO)δ 9.00(s,1H),8.88(s,1H),8.41(s,1H),8.15(d,J=4.1Hz,1H),7.52-7.29(m,9H),6.08(q,J=6.7Hz,1H),4.54(td,J=9.4 ,4.0Hz,1H),3.28-3.15(m,2H),2.43(dd,J=16.9,8.4Hz,1H),1.87-1.76(m,1H),1.70-1.38(m,7H),1.38-1.20(m,3H).

[0223] (Example 34) (3R)-3-cyclopentyl-3-(4-(7-(2-(4-(1-oxoisoindoline-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile

[0224] [ka]

[0225] (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyrate (indobufen, 177 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) as a white solid of 0.17 g, with a yield of 58.3%. MS(m / z):[M+H] + C 35 H 33 The calculated value for N7O2 was 584.70, and the measured value was 584.3. 1 H NMR(400MHz,DMSO)δ 9.01(s,1H),8.86(s,1H),8.39(s,1H),8.13(d,J=4.2Hz,1H),7.86(d,J=8.7Hz,2H),7.75(d,J=7.6Hz,1H) ,7.70-7.59(m,2H),7.52(t,J=7.0Hz,3H),7.30(d,J=3.9Hz,1H),5.86(t,J=7.4Hz,1H),4.96(s,2H),4.53 (td,J=9.5,4.2Hz,1H),3.28-3.14(m,2H),2.41(dt,J=17.2,8.5Hz,1H),2.25(td,J=14.2,7.2Hz,1H),1.9 7-1.88(m,1H),1.80(dt,J=11.9,5.8Hz,1H),1.65-1.39(m,3H),1.36-1.21(m,4H),0.94(t,J=7.3Hz,3H).

[0226] (Example 35) N-methyl-1-((trans)-4-(methyl(7-(2-(4-(1-oxoisoindorin-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide

[0227] [ka]

[0228] (N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-(4-(1-oxoisoindorin-2-yl)phenyl)butyrate (indobufen, 230 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 17 3 mg (0.9 mmol) was dissolved in 10 mL of dichloromethane and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1~1:1) yielded the target compound, which was 0.22 g of a white solid with a yield of 59.7%. MS(m / z):[M+H] + C 33 H 38 The calculated value for N6O4S was 615.77, and the measured value was 615.3. 1H NMR(400MHz,DMSO)δ 8.41(s,1H),7.83(d,J=8.3Hz,2H),7.76(d,J=7.4Hz,1H),7.67(dd,J=9.6,5.5Hz,3H),7. 59-7.42(m,3H),6.92-6.73(m,2H),5.97(t,J=7.1Hz,1H),4.96(s,2H),4.64(s,1H),3.14 (s,3H),2.94(d,J=5.8Hz,2H),2.57(t,J=9.7Hz,3H),2.26-2.13(m,1H),2.03(d,J=12.0H) z,2H),1.97-1.77(m,2H),1.68(s,4H),1.37-1.13(m,2H),0.90(dd,J=18.8,11.8Hz,3H).

[0229] (Example 36) 1-((trans)-4-((7-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0230] [ka]

[0231] N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 191 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) as a white solid of 0.22 g, with a yield of 65.1%. MS(m / z):[M+H] + C 30 H 34 The calculated value for FN5O3S is 564.69, and the measured value is 564.3. 1 H NMR(400MHz,DMSO)δ 8.39(s,1H),7.70(d,J=4.2Hz,1H),7.52-7.41(m,5H),7.35(dt,J=19.2,7. 4Hz,3H),6.92-6.82(m,2H),6.17(q,J=6.8Hz,1H),4.64(s,1H),3.16(s,3H) ),2.94(d,J=6.2Hz,2H),2.59(d,J=4.9Hz,3H),2.04(d,J=12.5Hz,2H),1.8 5(s,1H),1.65(d,J=26.0Hz,4H),1.59(d,J=7.0Hz,3H),1.37-1.19(m,2H).

[0232] (Example 37) 1-((trans)-4-((7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0233] [ka]

[0234] N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 224 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by separation using silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1), yielding 0.23 g of a white solid with a yield of 63.2%. MS(m / z):[M+H] + C 32 H 42 The calculated value for N6O4S was 607.79, and the measured value was 607.3. 1H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),8.27(s,1H),7.64(d,J=4.2Hz,1H),7.22(dd,J=7.4,1.6Hz,1H),6.98-6.78(m,4H), 4.66(d,J=14.6Hz,2H),4.03(d,J=7.5Hz,1H),3.89(s,1H),3.76(dt,J=10.7,4.4Hz,1H),3.16(s,3 H),2.94(d,J=6.2Hz,2H),2.84(q,J=7.5Hz,2H),2.59(t,J=3.8Hz,5H),2.15(tt,J=7.2,4.6Hz,2H ),2.09-2.01(m,2H),1.85(t,J=7.5Hz,1H),1.69(s,4H),1.35-1.21(m,5H),0.68(t,J=7.3Hz,3H).

[0235] (Example 38) 1-((trans)-4-((7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0236] [ka]

[0237] N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 198 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) as a white solid of 0.17 g, with a yield of 49.4%. MS(m / z):[M+H] + C 31 H 35 The calculated value for N5O4S was 574.71, and the measured value was 574.3. 1 1H NMR (400MHz, DMSO-d6)δ 8.30(s,1H),7.78(t,J=1.9Hz,1H),7.74-7.57(m,6H),7.52(dt,J=11.6,7.7H z,3H),6.86(t,J=4.9Hz,2H),6.16(q,J=6.9Hz,1H),4.64(s,1H),3.15(s,3H), 2.95(d,J=6.2Hz,2H),2.59(d,J=5.0Hz,3H),2.04(d,J=13.0Hz,2H),1.84(dq, J=13.3,6.8Hz,1H),1.68(d,J=8.5Hz,4H),1.58(d,J=7.0Hz,3H),1.28(s,2H).

[0238] (Example 39) 1-((trans)-4-((7-((S)-2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0239] [ka]

[0240] N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 180 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) as a white solid of 0.23 g, with a yield of 69.8%. MS(m / z):[M+H] + C 29 H 35 The calculated value for N5O4S was 550.69, and the measured value was 550.4. 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),7.78(d,J=7.8Hz,1H),7.74(t,J=8.9Hz,2H),7.68(d,J=4.1Hz,1H),7.50(dd,J=8.5 ,1.3Hz,1H),7.23(d,J=2.1Hz,1H),7.11(dd,J=8.9,2.4Hz,1H),6.87(q,J=4.5Hz,1H),6.79(d,J =3.0Hz,1H),6.21(q,J=6.8Hz,1H),4.61(s,1H),3.83(s,3H),3.10(s,3H),2.93(d,J=6.2Hz,2H) ,2.59(d,J=4.8Hz,3H),2.06-1.98(m,2H),1.83(s,1H),1.63(t,J=9.3Hz,7H),1.36-1.15(m,2H).

[0241] (Example 40) 2-(3-(4-(7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile

[0242] [ka]

[0243] 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 313 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) as a white solid of 0.22 g, with a yield of 35.7%. MS(m / z):[M+H] + C 30 H 27 The calculated value for ClN8O3S was 616.11, and the measured value was 616.3. 1H NMR(400MHz,DMSO-d6)δ 8.99(s,1H),8.73(s,1H),8.51(s,1H),8.21(s,1H),7.83(d,J=4.1Hz,1H),7.50(dd,J=8.3,6.5Hz,2H),7.37(d,J=4.1Hz,1H),7.09-7.04(m, 3H),7.00-6.90(m,2H),4.61(d,J=9.1Hz,2H),4.25(d,J=9.1Hz,2H),3.70(s,2H),3.24(q,J=7.3Hz,2H),2.01(s,3H),1.25(t,J=7.4Hz,3H).

[0244] (Example 41) 1-((trans)-4-((7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0245] [ka]

[0246] N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 204 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by separation using silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1), yielding 0.2 g of a yellow solid with a yield of 57.4%. MS(m / z):[M+H]+ C 29 H 33 The calculated value for ClN6O3S was 581.20, and the measured value was 581.4. 1 H NMR(400MHz,DMSO-d6)δ 8.24(s,1H),8.08(s,1H),7.45(dd,J=11.4,4.2Hz,1H),7.41-7.22(m,2 H),7.14-7.01(m,3H),6.96(d,J=8.3Hz,1H),6.93-6.75(m,3H),4.63(s, 1H),3.17(s,3H),2.95(d,J=6.1Hz,2H),2.60(d,J=4.9Hz,3H),2.13-2. 01(s,5H),1.89(d,J=22.2Hz,1H),1.78-1.62(m,4H),1.36-1.24(m,2H).

[0247] (Example 42) 1-((trans)-4-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0248] [ka]

[0249] Synthesis of 1-((trans)-4-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 233 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain 0.14 g of a yellow solid, with a yield of 41.4%. MS(m / z):[M+H] + C 34 H 37 The calculated value for ClN6O5S was 677.22, and the measured value was 677.3. 1 H NMR(400MHz,DMSO-d6)δ 8.42(s,1H),7.76-7.60(m,5H),7.11(d,J=2.6Hz,1H),6.98(d,J=9.0Hz,1H),6.89(dt ,J=9.9,4.5Hz,2H),6.71(dd,J=9.0,2.6Hz,1H),4.99(s,2H),4.69(s,1H),3.69(s,3H) ,3.20(s,3H),2.96(d,J=6.2Hz,2H),2.59(d,J=4.9Hz,3H),2.24(s,3H),2.06(d,J=12. 6Hz,2H),1.87(dt,J=15.5,5.8Hz,1H),1.72(dt,J=8.5,5.0Hz,4H),1.41-1.27(m,2H).

[0250] (Example 43) 1-((trans)-4-((7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0251] [ka]

[0252] Synthesis of 1-((trans)-4-((7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 157 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 7 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain 0.17 g of a yellow solid, with a yield of 60.7%. MS(m / z):[M+H] + C 30 H 36 The calculated value for N6O3S was 561.26, and the measured value was 561.3. 11H NMR (400MHz, DMSO-d6)δ 8.59(s,1H),8.12(s,1H),7.48(d,J=4.0Hz,1H),7.43-7.28(m,2H),7.13-6.9 6(m,3H),6.92-6.79(m,3H),6.77-6.66(m,1H),4.82-4.49(m,1H),3.19(s,3H) ),2.95(d,J=6.2Hz,2H),2.59(d,J=4.9Hz,3H),2.27(d,J=9.8Hz,3H),2.07(d ,J=21.6Hz,5H),1.92-1.82(m,1H),1.72(h,J=3.3Hz,4H),1.37-1.26(m,2H).

[0253] (Example 44) N-methyl-1-((trans)-4-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide

[0254] [ka]

[0255] Synthesis of N-methyl-1-((trans)-4-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 160 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) as a 0.2 g white solid with a yield of 70.7%. MS(m / z):[M+H] + C 30 H 39 The calculated value for N5O4S was 566.27, and the measured value was 566.4. 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),7.65(d,J=4.2Hz,1H),7.29(d,J=7.8Hz,2H),7.09(d,J=8.1Hz,2H), 6.95-6.79(m,2H),6.09(q,J=6.9Hz,1H),4.63(s,1H),3.14(s,3H),2.98-2.87(m, 3H),2.58(d,J=2.6Hz,3H),2.41-2.17(m,3H),2.10-2.00(m,3H),1.92-1.77(m,3H) ),1.75-1.60(m,5H),1.52(d,J=7.0Hz,3H),1.46-1.38(m,1H),1.35-1.22(m,2H).

[0256] (Example 45) (3R)-3-cyclopentyl-3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile

[0257] [ka]

[0258] Synthesis of (3R)-3-cyclopentyl-3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 224 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) as a white solid of 0.28 g, with a yield of 81.5%. MS(m / z):[M+H] + C 34 H 37 The calculated value for N7O2 was 576.30, and the measured value was 576.2. 1H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),8.88(d,J=3.1Hz,2H),8.42(s,1H),8.09(d,J=4.2Hz,1H),7.30(d,J=4.3Hz,1H),7.24(dd,J=7.4 ,1.5Hz,1H),6.96-6.87(m,2H),4.66-4.51(m,2H),4.19(dd,J=14.5,1.7Hz,1H),3.88(ddd,J=11.8,7.2,5.0Hz ,1H),3.76(dt,J=11.1,4.6Hz,1H),3.30-3.15(m,2H),2.86(q,J=7.5Hz,2H),2.64-2.56(m,2H),2.44(q,J=8.4 Hz,1H),2.18(q,J=7.2Hz,2H),1.89-1.78(m,1H),1.70-1.41(m,4H),1.41-1.22(m,6H),0.73(t,J=7.3Hz,3H).

[0259] (Example 46) tert-butyl((S)-2-(4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate

[0260] [ka]

[0261] Synthesis of tert-butyl((S)-2-(4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (163 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) as a white solid of 0.027 g, with a yield of 9.4%. MS(m / z):[M+H] + C 28 H 38 The calculated value for N6O5S was 571.26, and the measured value was 571.3. 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),7.80(d,J=7.7Hz,1H),7.68(d,J=4.1Hz,1H),7.56-7.45(m, 3H),7.29(d,J=7.7Hz,3H),6.86(d,J=4.9Hz,2H),4.63(s,1H),3.14(s,3 H),2.94(d,J=6.2Hz,2H),2.58(d,J=5.0Hz,3H),2.03(d,J=12.7Hz,2H), 1.90-1.79(m,1H),1.67(d,J=8.0Hz,4H),1.39(s,9H),1.32-1.21(m,2H).

[0262] (Example 47) 2-(3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile

[0263] [ka]

[0264] Synthesis of 2-(3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 289 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 289 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1), yielding 0.25 g of a yellow solid with a yield of 42%. MS(m / z):[M+H] + C 31 H 30 The calculated value for N8O3S was 595.22, and the measured value was 595.2. 11H NMR (400MHz, DMSO-d6)δ 9.01(s,1H),8.76(s,1H),8.53(s,1H),8.44(s,1H),7.90(d,J=4.1Hz,1H),7 .42(ddd,J=12.4,6.6,3.0Hz,3H),7.08-6.99(m,2H),6.94(dd,J=5.6,3.2Hz, 1H),6.91-6.75(m,2H),4.62(d,J=9.1Hz,2H),4.26(d,J=9.1Hz,2H),3.71(s ,2H),3.24(q,J=7.3Hz,2H),2.23(s,3H),1.97(s,3H),1.25(t,J=7.5Hz,3H).

[0265] (Example 48) 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(6-methoxynaphthalene-2-yl)propionate

[0266] [ka]

[0267] Synthesis of 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(6-methoxynaphthalene-2-yl)propionate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 170 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1~1:1) yielded the target compound, which was 0.107 g of a white solid with a yield of 38.6%. MS(m / z):[M+H] + C 31 H 34 The calculated value for N6O4 was 555.26, and the measured value was 555.3. 1 ¹H NMR (400MHz, chloroform-d)δ 8.31 (d, J=4.1Hz, 1H), 7.69-7.49 (m, 3H), 7.32 (dt, J=8.6, 2.5Hz, 1H), 7.20-7.02 (m, 3H), 6.47 (d, J=3.8Hz, 1H), 6.22-6.06 (m, 2H), 5.10 (d, J=8.2Hz, 1H), 4.06 (dd, J=13.4, 4.5Hz, 1H), 3.91 (s,3H),3.88-3.66(m,2H),3.66-3.44(m,4H),3.34(d,J=11.5Hz,3H),2.49(dt,J=20.2,6.2Hz ,1H),1.99-1.83(m,1H),1.81-1.65(m,1H),1.54(d,J=7.1Hz,3H),1.08(dd,J=9.5,7.0Hz,3H).

[0268] (Example 49) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-benzoylphenyl)propionate

[0269] [ka]

[0270] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-benzoylphenyl)propionate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 191 mg, 1.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) yielded the target compound, which was 0.153 g of a white solid with a yield of 52.9%. MS(m / z):[M+H] + C 33 H 34 The calculated value for N6O4 is 579.26, and the measured value is 579.3. 1¹H NMR (400MHz, chloroform-d)δ 8.29 (d, J=4.5Hz, 1H), 7.78-7.69 (m, 2H), 7.68-7.54 (m, 3H), 7.51-7.42 (m, 3H), 7.36 (td, J=7.6, 2.1Hz, 1H), 7.10-7.01 (m, 1H), 6.52-6.42 (m, 1H), 6.21-6.10 (m, 2H), 5.10 (dt, J=9.0, 4.7 Hz,1H),4.09-3.72(m,3H),3.67-3.43(m,4H),3.35(dd,J=13.1,4.9Hz,3H),2.56-2.41(m,1H ),2.00-1.85(m,1H),1.80-1.71(m,1H),1.50(d,J=7.2Hz,3H),1.07(dd,J=10.5,7.1Hz,3H).

[0271] (Example 50) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0272] [ka]

[0273] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 183 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) yielded the target compound, which was 0.083 g of a white solid with a yield of 29.2%. MS(m / z):[M+H] + C 32 H 33 The calculated value for FN6O3 was 569.26, and the measured value was 569.3. 1 1H NMR (400 MHz, chloroform-d)δ 8.31(d,J=2.2Hz,1H),7.53-7.47(m,2H),7.46-7.40(m,2H),7.39-7.28(m,2H) ,7.16-7.09(m,1H),7.08-6.85(m,2H),6.51(q,J=3.3Hz,1H),6.23-6.10(m,2H ),5.09(s,1H),4.08-3.69(m,4H),3.67-3.33(m,6H),2.55-2.37(m,1H),1.99- 1.81(m,1H),1.80-1.71(m,1H),1.49(dd,J=7.3,2.6Hz,3H),1.10-1.00(m,3H).

[0274] (Example 51) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

[0275] [ka]

[0276] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 222 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) yielded the target compound, which was 0.106 g of a white solid with a yield of 34.2%. MS(m / z):[M+H] + C 31 H 31 The calculated value for Cl2N7O3 is 620.19, and the measured value is 620.3. 1H NMR(400MHz,chloroform-d)δ 8.34(d,J=8.2Hz,1H),7.32(dd,J=8.1,1.8Hz,2H),7.18(dd,J=7.5,1.7Hz,1H),7.12(dd,J=9.3,5.7Hz ,2H),6.96(dt,J=15.1,7.8Hz,2H),6.64(d,J=9.4Hz,1H),6.53(dq,J=7.6,3.3Hz,2H),6.23(d,J=3.9Hz ,2H),5.13(s,1H),4.10-3.56(m,6H),3.52(t,J=7.6Hz,2H),3.39(s,1H),3.34(s,2H),2.50(ddd,J=19 .4,9.7,4.0Hz,1H),1.99-1.83(m,1H),1.76(dq,J=17.7,3.9,3.2Hz,1H),1.09(dd,J=13.9,7.1Hz,3H).

[0277] (Example 52) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-phenoxyphenyl)propionate

[0278] [ka]

[0279] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-phenoxyphenyl)propionate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 182 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) yielded the target compound, which was 0.13 g of a white solid with a yield of 45.9%. MS(m / z):[M+H] + C 32 H 34 The calculated value for N6O4 was 567.26, and the measured value was 567.3. 1 H NMR(400MHz,chloroform-d)δ 8.32(d,J=6.6Hz,1H),7.32(t,J=7.8Hz,2H),7.20(td,J=7.9,2.2Hz,1H),7.13-7.05(m,2H),6.96(d,J=7.2Hz ,3H),6.92-6.87(m,1H),6.83(d,J=8.2Hz,1H),6.51(t,J=3.1Hz,1H),6.21-6.07(m,2H),5.11(dp,J=9.4,4.8 ,4.4Hz,1H),4.10-3.65(m,3H),3.63-3.49(m,3H),3.47-3.41(m,1H),3.40-3.31(m,3H),2.48(dp,J=25.5,6. 1Hz,1H), 1.94(dt,J=9.4,4.6Hz,1H),1.80-1.66(m,1H),1.45(d,J=7.2Hz,3H),1.08(dd,J=12.3,7.1Hz,3H).

[0280] (Example 53) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate

[0281] [ka]

[0282] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 185 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1~1:1) yielded the target compound, which was 0.08 g of a white solid with a yield of 28%. MS(m / z):[M+H] + C 32 H 38 The calculated value for N6O4 is 571.30, and the measured value is 571.3. 1H NMR(400MHz,chloroform-d)δ 8.34-8.27(m,1H),7.11(tt,J=9.3,7.5,3.4Hz,3H),7.04(dt,J=8.3,2.9Hz,2H),6.51(s,1H),6.17(dd,J=10.5,4.6Hz,1 H),6.10(dt,J=10.6,2.8Hz,1H),5.12(qd,J=8.6,5.0Hz,1H),4.11-3.57(m,5H),3.50(q,J=9.1,7.3Hz,3H),3.40(d,J=2 .2Hz,1H),3.14-3.02(m,1H),2.49(ddd,J=23.3,11.0,4.9Hz,2H),2.33(dd,J=17.7,8.4Hz,2H),2.16-2.01(m,2H),1.95 (tdd,J=11.1,5.8,2.8Hz,2H),1.83-1.60(m,3H),1.58-1.47(m,1H),1.44(dd,J=7.2,1.8Hz,3H),1.08(t,J=7.2Hz,3H).

[0283] (Example 54) (3R)-3-cyclopentyl-3-(4-(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile

[0284] [ka]

[0285] Synthesis of (3R)-3-cyclopentyl-3-(4-(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 189 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain 0.2 g of a white solid, with a yield of 62.8%. MS(m / z):[M+H] + C 32 H 30 The calculated value for N6O2 was 531.24, and the measured value was 531.2. 1 H NMR(400MHz,DMSO-d6)δ 8.86(d,J=13.5Hz,2H),8.41(s,1H),8.09(d,J=4.2Hz,1H),7.40-7.26(m,4H),7.20- 7.09(m,2H),7.07(t,J=2.1Hz,1H),6.91(d,J=8.0Hz,2H),6.84(dd,J=8.1,2.5Hz,1H ),5.96(q,J=6.9Hz,1H),4.54(td,J=9.6,4.2Hz,1H),3.29-3.15(m,2H),2.42(p,J=8 .5Hz,1H),1.82(dtd,J=12.1,7.4,3.8Hz,1H),1.66-1.40(m,7H),1.37-1.18(m,3H).

[0286] (Example 55) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate

[0287] [ka]

[0288] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1~1:1) yielded the target compound, which was 0.036 g of a pale yellow solid with a yield of 10.5%. MS(m / z):[M+H] + C 36 H 36 The calculated value for ClN7O5 was 682.25, and the measured value was 682.3. 1H NMR(400MHz,chloroform-d)δ 8.32(s,1H),7.68-7.59(m,2H),7.51-7.43(m,2H),7.09(d,J=3.8Hz,1H),6.91-6.78(m,2H) ),6.65(dd,J=9.0,2.4Hz,1H),6.50(dd,J=8.2,3.8Hz,1H),6.19(s,2H),5.19-5.09(m,1H) ,4.10-3.73(m,6H),3.70-3.56(m,4H),3.55-3.45(m,3H),3.39(s,1H),2.58-2.42(m,1H), 2.29(d,J=10.3Hz,3H),2.03-1.85(m,1H),1.81-1.73(m,1H),1.09(dd,J=11.4,7.1Hz,3H).

[0289] (Example 56) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-acetoxybenzoic acid ester

[0290] [ka]

[0291] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-acetoxybenzoate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-acetoxybenzoic acid (aspirin, 135 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) as a pale yellow solid of 0.178 g, with a yield of 70.6%. MS(m / z):[M+H] + C 26 H 28 The calculated value for N6O5 is 505.21, and the measured value is 505.3. 1 H NMR(400MHz,chloroform-d)δ 8.34(d,J=6.5Hz,1H),8.01(d,J=7.9Hz,1H),7.60-7.50(m,1H),7.31-7.18(m,2H),7.07(d,J=8.1Hz,1H),6 .57(d,J=3.8Hz,1H),6.37(d,J=2.6Hz,2H),5.12(tt,J=8.3,4.6Hz,1H),4.25-3.98(m,1H),3.80(ddt,J=13. 2,8.8,4.7Hz,1H),3.62-3.50(m,3H),3.37(d,J=15.2Hz,3H),2.49(dp,J=24.6,6.0Hz,1H),2.25(d,J=12.7H) z,3H),1.93(dtt,J=17.8,9.0,4.5Hz,2H),1.74(dtt,J=17.9,7.6,3.5Hz,1H),1.08(dd,J=13.2,7.0Hz,3H).

[0292] (Example 57) (R)-3-(4-(7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile

[0293] [ka]

[0294] Synthesis of (R)-3-(4-(7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 306 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 261 mg, 1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 289 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain 0.26 g of a yellow solid, with a yield of 47.3%. MS(m / z):[M+H] + C 31 H 28 The calculated value for ClN7O is 550.20, and the measured value is 550.1. 1H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),8.70(s,1H),8.41(s,1H),8.23(s,1H),7.80(d,J=4.1Hz,1H),7.49(t,J=7 .7Hz,2H),7.27(d,J=4.1Hz,1H),7.12-7.00(m,3H),7.00-6.91(m,2H),4.55(td,J=9.6 ,4.2Hz,1H),3.29-3.17(m,2H),2.43(p,J=8.5Hz,1H),2.02(s,3H),1.83(dtd,J=11.9, 7.3,3.9Hz,1H),1.69-1.42(m,4H),1.41-1.27(m,2H),1.23(td,J=9.4,8.7,2.9Hz,1H).

[0295] (Example 58) N-(4-(2-(4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide

[0296] [ka]

[0297] Synthesis of N-(4-(2-(4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetylaminophenyl)acetic acid (Actarit, 126 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 0:1) as a white solid of 0.017 g, with a yield of 6.6%. MS(m / z):[M+H] + C 25 H 32 The calculated value for N6O4S was 513.22, and the measured value was 513.3. 1 H NMR(400MHz,DMSO-d6)δ 9.90(s,1H),8.37(s,1H),7.68(d,J=4.2Hz,1H),7.51(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),6.88(d,J=4.9Hz,2H),4.81(s,2H),4.67(s,1H) ),3.18(s,3H),2.95(d,J=6.2Hz,2H),2.59(d,J=4.9Hz,3H),2.03(s,5H),1.94-1.80(m,1H),1.70(dd,J=8.6,3.4Hz,4H),1.37-1.26(m,2H).

[0298] (Example 59) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-acetylaminophenyl)acetate

[0299] [ka]

[0300] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-acetylaminophenyl)acetate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetylaminophenyl)acetic acid (Actalit, 145 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.154 g of a white solid with a yield of 59.5%. MS(m / z):[M+H] + C 27 H 31 The calculated value for N7O4 is 518.24, and the measured value is 518.3. 1H NMR(400MHz,chloroform-d)δ 8.33(d,J=4.2Hz,1H),7.71(d,J=29.0Hz,1H),7.40(d,J=8.1Hz,2H),7.10(dt,J= 13.1,4.8Hz,3H),6.51(dd,J=8.4,3.9Hz,1H),6.16(s,2H),5.10(tt,J=9.2,4.4H z,1H),4.10-3.75(m,2H),3.63-3.44(m,6H),3.36(d,J=18.1Hz,3H),2.55-2.44( m,1H),2.00(s,3H),1.97-1.87(m,1H),1.83-1.67(m,1H),1.09(t,J=7.5Hz,3H).

[0301] (Example 60) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)(S)-2-(4-isobutylphenyl)methyl propionate

[0302] [ka]

[0303] Step 1: Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile Under nitrogen protection, 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 7420 mg, 20 mmol) and N,N-diisopropylethylamine (3.12 g, 24 mmol) were dissolved in dichloromethane (200 mL). After stirring at room temperature for 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (4 g, 24 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography yielded 5 g of a white solid with a yield of 49%. MS(m / z):[M+H] + C 22 H 31 The calculated value for N7O3SSi is 502.20, and the measured value is 502.3.

[0304] Step 2: Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile Under nitrogen protection and in an ice bath, trifluoroacetic acid (6.44 g, 56.5 mmol) was slowly added dropwise to a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (5 g, 11.3 mmol) in dichloromethane (100 mL). After 30 minutes, the ice bath was removed, and the mixture was stirred for 24 hours once the temperature rose to room temperature. At 0°C, saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. The mixture was then poured into a separatory funnel and separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 3.5 g of the target product, with a yield of 90%. MS(m / z):[M+H] + C 17 H 19 The calculated value for N7O3S was 402.13, and the measured value was 402.3.

[0305] Step 3: Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)(S)-2-(4-isobutylphenyl)propionate methyl 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 123.6 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) yielded the target compound, which was 0.025 g of a white solid with a yield of 8.4%. MS(m / z):[M+H] + C 30 H 35 The calculated value for N7O4S was 590.25, and the measured value was 590.3. 1H NMR(400MHz,DMSO-d6)δ 8.95(s,1H),8.77(s,1H),8.48(s,1H),7.70(d,J=3.8Hz,1H),7.16(d,J=3.8Hz,1H),7.06(d, J=7.8Hz,2H),6.96(d,J=7.8Hz,2H),6.25(d,J=3.2Hz,2H),4.60(d,J=9.1Hz,2H),4.25(d,J= 9.1Hz,2H),3.76(q,J=7.0Hz,1H),3.69(s,2H),3.24(q,J=7.3Hz,2H),2.32(d,J=7.1Hz,2H), 1.71(hept,J=6.7Hz,1H),1.34(d,J=7.1Hz,3H),1.26(d,J=7.4Hz,3H),0.77(d,J=6.5Hz,6H).

[0306] (Example 61) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)(S)-2-(6-methoxynaphthalene-2-yl)methyl propionate

[0307] [ka]

[0308] Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)(S)-2-(6-methoxynaphthalene-2-yl)propionate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (401 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 276 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 0.31 g of a white solid, with a yield of 50.5%. MS(m / z):[M+H] + C 31 H 31 The calculated value for N7O5S was 614.21, and the measured value was 614.3. 1 H NMR(400MHz,DMSO-d6)δ 8.94(s,1H),8.76(s,1H),8.48(s,1H),7.72(d,J=3.8Hz,1H),7.65(dd,J=10.9,8.8Hz,2H),7.56( d,J=1.9Hz,1H),7.29(dd,J=8.5,1.9Hz,1H),7.22(d,J=2.6Hz,1H),7.16(d,J=3.8Hz,1H),7.08(d d,J=8.9,2.6Hz,1H),6.28(s,2H),4.61(d,J=9.1Hz,2H),4.26(d,J=9.1Hz,2H),3.94(q,J=7.0Hz, 1H),3.83(s,3H),3.70(s,2H),3.24(q,J=7.3Hz,2H),1.44(d,J=7.1Hz,3H),1.26(t,J=7.4Hz,3H).

[0309] (Example 62) 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-benzoylphenyl)propionate

[0310] [ka]

[0311] Synthesis of 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(3-benzoylphenyl)propionate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (401 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 305 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) as a white solid of 0.43 g, with a yield of 67.5%. MS(m / z):[M+H] + C 33 H 31 The calculated value for N7O5S was 638.21, and the measured value was 638.2. 1H NMR(400MHz,DMSO-d6)δ 8.95(s,1H),8.75(s,1H),8.48(s,1H),7.71(d,J=3.8Hz,1H),7.69-7.62(m,3H),7.5 9(t,J=1.8Hz,1H),7.57-7.49(m,4H),7.43(t,J=7.6Hz,1H),7.17(d,J=3.8Hz,1H),6 .28(d,J=4.4Hz,2H),4.62(d,J=9.1Hz,2H),4.27(d,J=9.1Hz,2H),3.99(q,J=7.1Hz, 1H),3.71(s,2H),3.25(q,J=7.3Hz,2H),1.41(d,J=7.1Hz,3H),1.26(t,J=7.3Hz,3H).

[0312] (Example 63) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetate

[0313] [ka]

[0314] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 216 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.18 g of a white solid with a yield of 58.9%. MS(m / z):[M+H] + C 34 H 41 The calculated value for N7O4 is 612.32, and the measured value is 612.3. 1H NMR(400MHz,chloroform-d)δ 8.97(d,J=13.6Hz,1H),8.31(d,J=8.1Hz,1H),7.33(d,J=7.6Hz,1H),7.10-7.02(m,2H),7.00(d,J=7.3Hz,1H),6.51(d,J=4.1Hz,1H),6. 17(dtd,J=15.9,10.7,4.1Hz,2H),5.10(dp,J=14.0,4.6Hz,1H),4.09-3.70(m,5H),3.60-3.47(m,3H),3.35(d,J=14.9Hz,3H),3.02(d,J= 16.2Hz,1H),2.87(ddd,J=16.8,12.9,5.8Hz,3H),2.68(dt,J=15.4,4.3Hz,1H),2.56-2.41(m,1H),2.07(dt,J=14.3,6.8Hz,1H),1.98(s ,2H),1.90(d,J=24.6Hz,3H),1.79-1.65(m,1H),1.37(ddd,J=10.0,6.5,2.4Hz,3H),1.06(dt,J=13.8,6.3Hz,3H),0.74(t,J=7.3Hz,3H).

[0315] (Example 64) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ester

[0316] [ka]

[0317] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ester 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (189 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.148 g, with a yield of 51.4%. MS(m / z):[M+H] + C 30 H 37 The calculated value for N7O5 was 576.29, and the measured value was 576.3. 1 H NMR(400MHz,chloroform-d)δ 8.28(d,J=9.3Hz,1H),7.25(d,J=6.9Hz,5H),7.07(dd,J=16.0,3.9Hz,1H),6.51(dd,J=7.1,3. 7Hz,1H),6.23-6.14(m,2H),5.49(d,J=7.5Hz,1H),5.29(d,J=7.5Hz,1H),5.11(dt,J=9.7,4.5H z,1H),4.13-3.76(m,2H),3.63-3.46(m,4H),3.36(d,J=17.3Hz,3H),2.49(tt,J=13.9,6.0Hz, 1H),1.87(dd,J=9.5,4.6Hz,1H),1.82-1.67(m,1H),1.39(s,9H),1.08(dd,J=13.5,7.1Hz,3H).

[0318] (Example 65) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-(1-oxoisoindole-2-yl))phenyl)butyrate

[0319] [ka]

[0320] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-(1-oxoisoindole-2-yl))phenyl)butyrate 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (20 mg, 0.058 mmol), 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyrate (indobufen, 26 mg, 0.09 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 17 mg, 0.09 mmol) were dissolved in a mixed solvent of dichloromethane (0.5 mL) and N,N-dimethylformamide (0.05 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.012 g of a white solid with a yield of 33.4%. MS(m / z):[M+H] + C 35 H 37 The calculated value for N7O4 was 620.29, and the measured value was 620.3. 1H NMR(400MHz,chloroform-d)δ 8.30(d,J=8.7Hz,1H),7.90(d,J=7.5Hz,1H),7.80-7.69(m,2H),7.59(t,J=7.5Hz,1H),7.51(d,J=8.4Hz,2H ),7.33-7.22(m,2H),7.14-7.06(m,1H),6.53-6.45(m,1H),6.15(dt,J=18.9,10.9Hz,2H),5.08(s,1H),4.82 (s,2H),4.05(d,J=13.5Hz,1H),3.92-3.66(m,2H),3.53(q,J=6.6,5.1Hz,3H),3.37-3.27(m,3H),2.54-2.4 0(m,1H),2.07(dq,J=14.1,7.3Hz,2H),1.93(s,1H),1.76(tt,J=19.7,8.8Hz,2H),1.06(s,3H),0.82(s,3H).

[0321] (Example 66) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoic acid ester

[0322] [ka]

[0323] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoic acid ester 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (200 mg, 0.58 mmol), 4-dimethylaminopyridine (DMAP, 35 mg, 0.29 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 230 mg, 0.88 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 168 mg, 0.88 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N,N-dimethylformamide (0.2 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) yielded the target compound, which was 0.145 g of a yellow solid with a yield of 42.7%. MS(m / z):[M+H] + C 31 H 32 The calculated value for ClN7O3 was 586.23, and the measured value was 586.3. 1 ¹H NMR (400MHz, chloroform-d)δ 9.20(s,1H),8.37(d,J=7.1Hz,1H),7.95(dd,J=8.2,1.7Hz,1H),7.30-7.17(m,4H),7.12(t,J=7.9Hz,1H),6.75(d,J=8.5Hz,1H),6.65(t,J=7.6Hz,1H),6.60-6.55(m,1H),6.42(d,J=3.3Hz,2H),5.13(q ,J=6.0,5.5Hz,1H),4.12-3.75(m,2H),3.64-3.56(m,1H),3.53-3.46(m,2H),3.38(d,J=16.8Hz,3H) ,2.58-2.44(m,1H),2.32(s,3H),1.97-1.82(m,2H),1.81-1.68(m,1H),1.08(dd,J=12.9,7.0Hz,3H).

[0324] (Example 67) (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoic acid ester

[0325] [ka]

[0326] Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoic acid ester 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 181 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.129 g of a yellow solid with a yield of 45.6%. MS(m / z):[M+H] + C 32 H 35 The calculated value for N7O3 was 566.28, and the measured value was 566.3. 1H NMR(400MHz,chloroform-d)δ 9.14(s,1H),8.37(d,J=7.1Hz,1H),7.93(dd,J=8.1,1.7Hz,1H),7.29(dd,J=15.0,3.7Hz,1H),7.25-7.16(m,1H),7.16-7.06(m,2H),7 .03(d,J=6.8Hz,1H),6.68(d,J=8.6Hz,1H),6.63-6.53(m,2H),6.41(d,J=3.0Hz,2H),5.12(dt,J=9.7,4.7Hz,1H),4.05(dd,J=13.2,4. 4Hz,1H),3.78(ddd,J=15.8,13.2,8.1Hz,1H),3.58(td,J=11.3,10.3,5.0Hz,1H),3.54-3.47(m,2H),3.37(d,J=15.3Hz,3H),2.57-2. 41(m,1H),2.33(s,3H),2.17(s,3H),1.99(s,1H),1.97-1.84(m,1H),1.72(dtd,J=32.5,6.4,3.6Hz,1H),1.07(dd,J=13.3,7.0Hz,3H).

[0327] (Example 68) N-methyl-1-((trans)-4-(methyl(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide

[0328] [ka]

[0329] Synthesis of N-methyl-1-((trans)-4-(methyl(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 158 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1~5:3) to obtain 0.18 g of a white solid, with a yield of 64.1%. MS(m / z):[M+H] + C 30 H 35 The calculated value for N5O4S was 562.24, and the measured value was 562.4. 1 H NMR(400MHz,DMSO-d6)δ 8.26(s,1H),7.65(d,J=4.2Hz,1H),7.40-7.33(m,2H),7.29(t,J=7.9Hz,1H),7.18-7.11(m ,2H),7.05(t,J=2.1Hz,1H),6.98-6.90(m,2H),6.90-6.78(m,3H),6.06(q,J=6.9Hz,1H),4. 64(s,1H),3.15(s,3H),2.95(d,J=6.2Hz,2H),2.60(d,J=5.0Hz,3H),2.10-2.02(m,2H),1. 92-1.77(m,1H),1.70(tt,J=8.2,3.1Hz,4H),1.53(d,J=7.0Hz,3H),1.29(d,J=12.9Hz,2H).

[0330] (Example 69) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(2-fluoro-[1,1'-biphenyl]-4-yl)methyl propionate

[0331] [ka]

[0332] Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 146 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and N,N-dimethylformamide (1 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1~1:2) yielded the target compound, which was 0.27 g of a white solid with a yield of 86.1%. MS(m / z):[M+H] + C 32 H 30 The calculated value for FN7O4S is 628.21, and the measured value is 628.3. 11H NMR (400MHz, DMSO-d6)δ 8.95(s,1H),8.78(s,1H),8.48(s,1H),7.75(d,J=3.8Hz,1H),7.50-7.41(m,4 H),7.40-7.32(m,2H),7.19(d,J=3.8Hz,1H),7.17-7.08(m,2H),6.37-6.24(m ,2H),4.60(d,J=9.1Hz,2H),4.25(d,J=9.1Hz,2H),3.93(q,J=7.0Hz,1H),3.6 9(s,2H),3.23(q,J=7.3Hz,2H),1.40(d,J=7.1Hz,3H),1.25(t,J=7.2Hz,3H).

[0333] (Example 70) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(2-((2,6-dichlorophenyl)amino)phenyl)methyl acetate

[0334] [ka]

[0335] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(2-((2,6-dichlorophenyl)amino)phenyl)methyl acetate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 148 mg, 0.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and N,N-dimethylformamide (2 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1~1:2) yielded the target compound, which was 0.07 g of a white solid with a yield of 20.6%. MS(m / z):[M+H] + C 31 H 28 The calculated value for Cl2N8O4S is 679.13, and the measured value is 679.1. 1 H NMR(400MHz,DMSO-d6)δ 8.96(s,1H),8.80(s,1H),8.50(s,1H),7.76(d,J=3.8Hz,1H),7.49(d,J=8.1Hz,2 H),7.24-7.12(m,3H),7.04(td,J=7.7,1.6Hz,1H),6.92(s,1H),6.81(td,J=7.4,1 .2Hz,1H),6.32(s,2H),6.22(d,J=8.0Hz,1H),4.61(d,J=9.1Hz,2H),4.26(d,J=9 .1Hz,2H),3.86(s,2H),3.70(s,2H),3.24(q,J=7.4Hz,2H),1.26(t,J=7.4Hz,3H).

[0336] (Example 71) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(3-phenoxyphenyl)methyl propionate

[0337] [ka]

[0338] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(3-phenoxyphenyl)propionate methyl 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 1345 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 0.22 g, with a yield of 70.4%. MS(m / z):[M+H] + C 32 H 31 The calculated value for N7O5S was 626.21, and the measured value was 626.1. 1H NMR(400MHz,DMSO-d6)δ 8.96(s,1H),8.78(s,1H),8.50(s,1H),7.71(d,J=3.8Hz,1H),7.39-7.30(m,2H),7.24(t,J=7.9Hz,1H), 7.19(d,J=3.8Hz,1H),7.11(t,J=7.4Hz,1H),6.97(d,J=7.7Hz,1H),6.90(d,J=8.0Hz,2H),6.85(t,J=2.1 Hz,1H),6.79(dd,J=8.1,2.5Hz,1H),6.27(d,J=4.3Hz,2H),4.61(d,J=9.1Hz,2H),4.26(d,J=9.1Hz,2H) ,3.84(q,J=7.1Hz,1H),3.70(s,2H),3.24(q,J=7.3Hz,2H),1.35(d,J=7.1Hz,3H),1.25(t,J=7.2Hz,3H).

[0339] (Example 72) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-((2-oxocyclopentyl)methyl)phenyl)methyl propionate

[0340] [ka]

[0341] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate methyl 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 148 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 0.26 g, with a yield of 82.6%. MS(m / z):[M+H] + C 32 H 35 The calculated value for N7O5S was 630.24, and the measured value was 630.1. 1 H NMR(400MHz,DMSO-d6)δ 8.96(s,1H),8.78(d,J=1.6Hz,1H),8.49(s,1H),7.71(d,J=3.8Hz,1H),7.17(d,J=3.8Hz,1H),7.04(ddd ,J=25.3,8.1,2.3Hz,4H),6.26(d,J=4.2Hz,2H),4.60(d,J=9.1Hz,2H),4.25(d,J=9.1Hz,2H),3.77(q,J =7.1Hz,1H),3.69(s,2H),3.24(q,J=7.3Hz,2H),2.87(dd,J=13.3,3.7Hz,1H),2.40-2.15(m,3H),2.04( dd,J=10.2,8.5Hz,1H),1.80(d,J=12.9Hz,2H),1.70-156(m,1H),1.44-1.31(m,4H),1.28-1.23(m,3H).

[0342] (Example 73) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)methyl acetate

[0343] [ka]

[0344] (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)methyl acetate synthesis 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 214 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) to obtain 0.28 g of a yellow solid, with a yield of 75.6%. MS(m / z):[M+H] + C 36 H 33 The calculated value for ClN8O6S was 741.19, and the measured value was 741.1. 1H NMR(400MHz,DMSO-d6)δ 8.98(s,1H),8.79(s,1H),8.52(s,1H),7.76(d,J=3.8Hz,1H),7.63(s,4H), 7.21(d,J=3.8Hz,1H),6.96-6.87(m,2H),6.68(dd,J=9.0,2.5Hz,1H),6.31 (s,2H),4.63(d,J=9.2Hz,2H),4.27(d,J=9.1Hz,2H),3.83(s,2H),3.72(s, 2H),3.67(s,3H),3.25(q,J=7.4Hz,2H),2.14(s,3H),1.27(t,J=7.3Hz,3H).

[0345] (Example 74) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate methyl

[0346] [ka]

[0347] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate methyl 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), N-Boc-L-phenylglycine (151 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) as a white solid of 0.23 g, with a yield of 72.5%. MS(m / z):[M+H] + C 30 H 34 The calculated value for N8O6S was 635.23, and the measured value was 635.2. 1 H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),8.79(s,1H),8.51(s,1H),7.79(d,J=7.8Hz,1H),7.70(s,1H),7.41-7.16(m,6H),6.42-6.24(m,2H),5.20 (d,J=7.8Hz,1H),4.63(d,J=9.1Hz,2H),4.27(d,J=9.2Hz,2H),3.71(s,2H),3.25(q,J=7.3Hz,2H),1.38-1.21(m,12H).

[0348] (Example 75) (R)-3-Cyclopentyl-3-(4-(7-(2-(2-((2,6-Dichlorophenyl)amino)phenyl)acetyl)-7H-Pyrrolo[2,3-d]Pyrimidine-4-yl)-1H-Pyrazole-1-yl)Propionitrile

[0349] [ka]

[0350] Synthesis of (R)-3-cyclopentyl-3-(4-(7-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 231 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) as a white solid of 0.11 g, with a yield of 31.4%. MS(m / z):[M+H] + C 31 H 27 The calculated value for Cl2N7O is 584.17, and the measured value is 584.1. 1 H NMR(400MHz,DMSO-d6)δ 8.99(s,1H),8.91(s,1H),8.45(s,1H),8.17(d,J=4.1Hz,1H),7.51(d,J=8.1Hz,2H),7.4 1-7.29(m,2H),7.21(dd,J=17.2,9.1Hz,2H),7.15-7.02(m,1H),6.84(t,J=7.4Hz,1H),6. 25(d,J=8.1Hz,1H),5.01(s,2H),4.56(td,J=9.7,4.2Hz,1H),3.31-3.17(m,2H),2.45(q ,J=8.5Hz,1H),1.83(dtd,J=12.2,7.5,3.9Hz,1H),1.68-1.41(m,4H),1.39-1.21(m,3H).

[0351] (Example 76) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-(1-oxoisoindorin-2-yl)phenyl)methyl butyrate

[0352] [ka]

[0353] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-(1-oxoisoindorin-2-yl)phenyl)methyl butyrate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyric acid (indobufen, 177 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target compound, which was 0.28 g of a white solid with a yield of 82.5%. MS(m / z):[M+H] + C 35 H 34 The calculated value for N8O5S was 679.24, and the measured value was 679.2. 1H NMR(400MHz,DMSO-d6)δ 8.98(s,1H),8.83(s,1H),8.49(s,1H),7.87-7.77(m,4H),7.77-7.66(m,2H),7.62-7.53(m, 1H),7.36-7.27(m,2H),7.23(d,J=3.8Hz,1H),6.32(q,J=10.8Hz,2H),5.00(s,2H),4.63(d,J =9.1Hz,2H),4.28(d,J=9.1Hz,2H),3.72(s,2H),3.63(t,J=7.6Hz,1H),3.28(q,J=7.3Hz,2H ),2.04-1.97(m,1H),1.76(dt,J=13.6,7.0Hz,1H),1.32-1.28(m,3H),0.82(t,J=7.3Hz,3H).

[0354] (Example 77) (3R)-3-cyclopentyl-3-(4-(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile

[0355] [ka]

[0356] Synthesis of (3R)-3-cyclopentyl-3-(4-(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 192 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) as a pale yellow solid of 0.26 g, with a yield of 81.1%. MS(m / z):[M+H] + C 32 H 34 The calculated value for N6O2 was 535.27, and the measured value was 535.4. 1 H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),8.87(d,J=1.6Hz,1H),8.40(s,1H),8.11(d,J=4.2Hz,1H),7.34(d,J=7.8Hz,2H),7.30 (d,J=4.2Hz,1H),7.11(d,J=7.8Hz,2H),6.00(q,J=6.8Hz,1H),4.55(td,J=9.6,4.2Hz,1H),3.31-3. 15(m,2H),2.90(dd,J=13.2,3.4Hz,1H),2.38(tdd,J=20.0,14.0,5.9Hz,3H),2.20(ddd,J=18.1,8.2 ,2.8Hz,1H),2.05(dd,J=10.1,8.6Hz,1H),1.92-1.75(m,3H),1.68-1.50(m,7H),1.48-1.22(m,5H).

[0357] (Example 78) (R)-N-(4-(2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide

[0358] [ka]

[0359] Synthesis of (R)-N-(4-(2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxyethyl)phenyl)acetamide (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(4-acetylaminophenyl)acetic acid (actarit, 151 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1~2:3) as a pale yellow solid of 0.18 g, with a yield of 62.3%. MS(m / z):[M+H] + C 27 H 27 The calculated value for N7O2 was 482.22, and the measured value was 482.3. 1H NMR(400MHz,DMSO-d6)δ 9.90(s,1H),8.97(s,1H),8.90(s,1H),8.43(s,1H),8.12(d,J=4.2Hz,1H), 7.54(d,J=8.1Hz,2H),7.32(dd,J=16.1,6.1Hz,3H),4.87(s,2H),4.55(td, J=9.6,4.1Hz,1H),3.30-3.17(m,2H),2.43(p,J=8.5Hz,1H),2.04(s,3H),1 .83(dhept,J=12.4,4.1,3.7Hz,1H),1.67-1.41(m,4H),1.39-1.16(m,3H).

[0360] (Example 79) (R)-3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile

[0361] [ka]

[0362] Synthesis of (R)-3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 279 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) as a pale yellow solid of 0.3 g, with a yield of 77.5%. MS(m / z):[M+H] + C 36 H 32 The calculated value for ClN7O3 was 646.23, and the measured value was 646.1. 1 H NMR(400MHz,DMSO-d6)δ 9.03(s,1H),8.93(s,1H),8.47(s,1H),8.16(d,J=4.2Hz,1H),7.76-7.63(m,4H), 7.38(d,J=4.2Hz,1H),7.18(d,J=2.5Hz,1H),7.00(d,J=9.0Hz,1H),6.73(dd,J=9 .1,2.6Hz,1H),5.05(s,2H),4.58(td,J=9.6,4.3Hz,1H),3.71(s,3H),3.31-3.19 (m,2H),2.46(q,J=8.2Hz,1H),2.28(s,3H),1.90-1.80(m,1H),1.68-1.31(m,7H).

[0363] (Example 80) tert-butyl((S)-2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate

[0364] [ka]

[0365] Synthesis of tert-butyl((S)-2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-oxo-1-phenylethyl)carbamate (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), N-Boc-L-phenylglycine (196 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain 0.18 g of a yellow solid, with a yield of 55.6%. MS(m / z):[M+H] + C 30 H 33 The calculated value for N7O3 was 540.26, and the measured value was 540.3. 11H NMR (400MHz, DMSO-d6)δ 8.97(s,1H),8.87(s,1H),8.41(s,1H),8.14(d,J=4.2Hz,1H),7.95(d,J=7.6H z,1H),7.52(d,J=7.3Hz,2H),7.42(d,J=7.7Hz,1H),7.31(td,J=11.8,10.6,5 .4Hz,4H),4.54(td,J=9.6,4.3Hz,1H),3.29-3.12(m,2H),2.43(h,J=8.5Hz,1 H),1.82(dtd,J=11.9,7.4,4.2Hz,1H),1.65-1.50(m,3H),1.46-1.23(m,13H).

[0366] (Example 81) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-((3-chloro-2-methylphenyl)amino)methyl benzoate

[0367] [ka]

[0368] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-((3-chloro-2-methylphenyl)amino)methyl benzoate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 137 mg, 0.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) to obtain 0.26 g of a yellow solid, with a yield of 80.7%. MS(m / z):[M+H] + C 31 H 29 The calculated value for ClN8O4S was 645.17, and the measured value was 645.1. 1 1H NMR (400MHz, DMSO-d6)δ 9.12(s,1H),8.98(s,1H),8.84(s,1H),8.52(s,1H),7.93(d,J=3.8Hz,1H),7 .79(dd,J=8.4,1.7Hz,1H),7.37(td,J=7.6,7.1,1.7Hz,1H),7.33-7.21(m,4 H),6.78-6.70(m,2H),6.55(s,2H),4.62(d,J=9.1Hz,2H),4.26(d,J=9.1Hz, 2H),3.71(s,2H),3.24(q,J=7.3Hz,2H),2.24(s,3H),1.26(t,J=7.3Hz,3H).

[0369] (Example 82) (R)-3-Cyclopentyl-3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-Pyrrolo[2,3-d]pyrimidine-4-yl)-1H-Pyrazole-1-yl)propionitrile

[0370] [ka]

[0371] Synthesis of (R)-3-cyclopentyl-3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 188 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1~3:1), yielding 0.08 g of a yellow solid with a yield of 25.2%. MS(m / z):[M+H] + C 32 H 31 The calculated value for N7O was 530.26, and the measured value was 530.3. 1H NMR(400MHz,DMSO-d6)δ 8.88(s,1H),8.73(s,1H),8.44(d,J=13.9Hz,2H),7.87(d,J=4.0Hz,1H),7.42(ddd,J=7.7,4.5,2. 8Hz,2H),7.29(d,J=4.1Hz,1H),7.08-7.01(m,2H),6.94(dd,J=6.2,2.6Hz,1H),6.87-6.75(m,2H) ,4.56(td,J=9.7,4.2Hz,1H),3.29-3.15(m,2H),2.45(q,J=8.4Hz,1H),2.22(s,3H),1.98(s,3H), 1.83(dtd,J=12.3,7.4,3.8Hz,1H),1.55(tdt,J=32.5,29.7,18.3,6.6Hz,4H),1.39-1.22(m,3H).

[0372] (Example 83) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-((2,3-dimethylphenyl)amino)methyl benzoate

[0373] [ka]

[0374] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-((2,3-dimethylphenyl)amino)methyl benzoate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 22-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 127 mg, 0.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) to obtain 0.27 g of a yellow solid, with a yield of 86.5%. MS(m / z):[M+H] + C 32 H 32 The calculated value for N8O4S was 625.23, and the measured value was 625.2. 1 H NMR(400MHz,DMSO-d6)δ 9.06(s,1H),8.98(s,1H),8.85(s,1H),8.52(s,1H),7.94(d,J=3.8Hz,1H),7.76(dd, J=8.1,1.7Hz,1H),7.32(ddd,J=8.6,7.0,1.7Hz,1H),7.27(d,J=3.8Hz,1H),7.18-7.0 5(m,3H),6.70-6.59(m,2H),6.55(s,2H),4.61(d,J=9.1Hz,2H),4.25(d,J=9.1Hz,2H) ,3.70(s,2H),3.24(q,J=7.3Hz,2H),2.30(s,3H),2.09(s,3H),1.25(t,J=7.3Hz,3H).

[0375] (Example 84) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-acetylaminophenyl)methyl acetate

[0376] [ka]

[0377] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-acetylaminophenyl)methyl acetate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(4-acetylaminophenyl)acetic acid (Actalit, 116 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target compound, which was 0.22 g of a white solid with a yield of 76.3%. MS(m / z):[M+H] + C 27 H 28 The calculated value for N8O5S was 577.19, and the measured value was 577.2. 1H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),8.98(s,1H),8.84(s,1H),8.52(s,1H),7.78(d,J=3.8Hz,1H),7.49(d,J=8.0Hz,2H),7.19(dd,J=31.5,5.9Hz,3H),6.29( s,2H),4.63(d,J=9.1Hz,2H),4.27(d,J=9.1Hz,2H),3.69(d,J=20.8Hz,4H),3.26(q,J=7.3Hz,2H),2.04(s,3H),1.27(t,J=7.4Hz,3H).

[0378] (Example 85) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl acetate

[0379] [ka]

[0380] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl acetate 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 172 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1~1:2) yielded the target compound, which was 0.17 g of a white solid with a yield of 50.7%. MS(m / z):[M+H] + C 34 H 38 The calculated value for N8O5S was 671.27, and the measured value was 671.2. 1 H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),8.97(s,1H),8.80(s,1H),8.51(s,1H),7.61(d,J=3.8Hz,1H),7.20-7.10(m,2H) ,6.93-6.81(m,2H),6.27-6.12(m,2H),4.63(d,J=9.1Hz,2H),4.27(d,J=9.1Hz,2H),3.88-3.76 (m,2H),3.72(s,2H),3.25(q,J=7.3Hz,2H),3.06(d,J=13.6Hz,1H),2.86(d,J=13.6Hz,1H),2.8 1-2.75(m,2H),2.61-2.48(m,2H),2.01-1.80(m,2H),1.30-1.21(m,6H),0.58(t,J=7.3Hz,3H).

[0381] (Example 86) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate

[0382] [ka]

[0383] Step 1: Synthesis of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile Under nitrogen protection, (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 1000 mg, 3.26 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.9 mmol) were added to dichloromethane (8 mL). After stirring at room temperature for 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (0.65 g, 3.92 mmol) was added under an ice bath, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded 1.4 g of the target compound, with a yield of 98.5%. MS (m / z): [M+H] + C 23 H 32 The calculated value for N6OSi was 437.24, and the measured value was 437.3.

[0384] Step 2: Synthesis of (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile Under nitrogen protection and in an ice bath, trifluoroacetic acid (9 mL, 13.8 mg, 121 mmol) was slowly added dropwise to a solution of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (1.4 g, 3.2 mmol) in dichloromethane (90 mL). After 30 minutes, the ice bath was removed, and the mixture was stirred for 2 hours after the temperature rose to room temperature. At 0°C, saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. The mixture was then poured into a separatory funnel and separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the product was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to obtain 0.36 g of the target product, with a yield of 33.4%. MS(m / z):[M+H] + C 18 H 20 The calculated value for N6O was 337.17, and the measured value was 337.3. 1 H NMR(400MHz,DMSO-d6)δ 8.95-8.80(m,2H),8.49(s,1H),7.81(d,J=3.7Hz,1H),7.15(d,J=3.7Hz,1H),6.75(t,J=7.3Hz,1H),5.72(d,J=7.3Hz,2H),4.64(td,J =9.6,4.2Hz,1H),3.42-3.26(m,2H),2.53(q,J=8.5Hz,1H),1.92(dtd,J=11.8,7.5,4.2Hz,1H),1.76-1.50(m,4H),1.50-1.23(m,3H).

[0385] Step 3: Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (120 mg, 0.36 mmol), 4-dimethylaminopyridine (DMAP, 44 mg, 0.36 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 110 mg, 0.54 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 103 mg, 0.54 mmol) were dissolved in a mixed solvent of dichloromethane (2.5 mL) and dimethylformamide (0.25 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.106 g of a white solid with a yield of 56.1%. MS(m / z):[M+H] + C 31 H 36 The calculated value for N6O2 was 525.29, and the measured value was 525.3. 1 H NMR(400MHz,chloroform-d)δ 8.85(s,1H),8.31(d,J=10.9Hz,2H),7.41(d,J=3.8Hz,1H),7.10(d,J=8.1Hz,2H),7.00(d,J=7.9Hz,2H),6 .72(d,J=3.8Hz,1H),6.30-6.18(m,2H),4.28(ddd,J=10.1,8.6,4.0Hz,1H),3.71(q,J=7.1Hz,1H),3.14(d d,J=17.0,8.6Hz,1H),2.97(dd,J=17.0,4.0Hz,1H),2.61(ddd,J=16.8,8.2,4.6Hz,1H),2.40(d,J=7.1Hz, 2H),2.00-1.93(m,1H),1.85-1.53(m,6H),1.47(d,J=7.2Hz,3H),1.37-1.23(m,2H),0.86(d,J=6.6Hz,6H).

[0386] (Example 87) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(6-methoxynaphthalene-2-yl)propionate

[0387] [ka]

[0388] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(6-methoxynaphthalene-2-yl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (140 mg, 0.42 mmol), 4-dimethylaminopyridine (DMAP, 51 mg, 0.42 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 144 mg, 0.63 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 120 mg, 0.63 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.146 g, with a yield of 63.4%. MS(m / z):[M+H] + C 32 H 32 The calculated value for N6O3 was 549.25, and the measured value was 549.3. 1H NMR(400MHz,chloroform-d)δ 8.83(s,1H),8.29(d,J=7.0Hz,2H),7.60(t,J=8.6Hz,2H),7.54(d,J=1.8Hz,1H),7.39(d,J=3.8Hz ,1H),7.29(dd,J=6.6,1.9Hz,1H),7.14-7.03(m,2H),6.68(d,J=3.8Hz,1H),6.24(d,J=2.4Hz,2H) ,4.27(ddd,J=10.1,8.6,4.0Hz,1H),3.89(s,3H),3.14(dd,J=17.0,8.6Hz,1H),2.96(dd,J=17.0, 4.0Hz,1H),2.66-2.53(m,1H),2.05-1.92(m,1H),1.79-1.50(m,9H),1.29(td,J=12.8,6.5Hz,2H).

[0389] (Example 88) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate

[0390] [ka]

[0391] Step 1: Synthesis of N-methyl-1-((trans)-4-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide Under nitrogen protection, N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 1687 mg, 5 mmol) and N,N-diisopropylethylamine (780 mg, 6 mmol) were added to dichloromethane (50 mL). After stirring at room temperature for 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (1 g, 6 mmol) was added under an ice bath, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target compound, which was 2 g of an oily solid with a yield of 85.6%. MS(m / z):[M+H] + C 21 H 37 The calculated value for N5O3SSi was 468.24, and the measured value was 468.2.

[0392] Step 2: Synthesis of 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide Under nitrogen protection and in an ice bath, trifluoroacetic acid (6 mL, 9.2 g, 80.8 mmol) was slowly added dropwise to a solution of N-methyl-1-((trans)-4-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (2 g, 4.29 mmol) in dichloromethane (60 mL). After 30 minutes, the ice bath was removed, and the mixture was stirred for 24 hours after the temperature rose to room temperature. At 0°C, saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. The mixture was then poured into a separatory funnel and separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain 0.9 g, with a yield of 98.5%. MS(m / z):[M+H] + C 16 H 25The calculated value for N5O3S was 368.17, and the measured value was 368.2.

[0393] Step 3: Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (150 mg, 0.41 mmol), 4-dimethylaminopyridine (DMAP, 50 mg, 0.41 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 126 mg, 0.61 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 117 mg, 0.61 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by separation using silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) as a white solid of 0.086 g, with a yield of 37.7%. MS(m / z):[M+H] + C 29 H 41 The calculated value for N5O4S was 556.29, and the measured value was 556.3. 1H NMR(400MHz,chloroform-d)δ 8.32(s,1H),7.11(d,J=7.7Hz,2H),7.08-6.94(m,3H),6.48(d,J=3.8Hz,1H),6.22-6.04(m,2H),4.75 (s,1H),4.31(q,J=5.3Hz,1H),3.68(q,J=7.2Hz,1H),3.20(s,3H),2.96(d,J=6.2Hz,2H),2.82(d,J=5 .1Hz,3H),2.41(d,J=7.1Hz,2H),2.24-2.13(m,2H),2.06-1.95(m,1H),1.84(ddd,J=22.7,13.2,5.3H z,3H),1.76-1.62(m,2H),1.44(d,J=7.3Hz,3H),1.36(dd,J=12.4,9.1Hz,2H),0.87(d,J=6.6Hz,6H).

[0394] (Example 89) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(6-methoxynaphthalene-2-yl)propionate

[0395] [ka]

[0396] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(6-methoxynaphthalene-2-yl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (150 mg, 0.41 mmol), 4-dimethylaminopyridine (DMAP, 50 mg, 0.41 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 141 mg, 0.61 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 117 mg, 0.61 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) as a white solid of 0.056 g, with a yield of 23.5%. MS(m / z):[M+H] + C 30 H 37 The calculated value for N5O5S was 580.25, and the measured value was 580.3. 1 ¹H NMR (400MHz, chloroform-d)δ 8.31(s,1H),7.69-7.44(m,3H),7.40-7.22(m,1H),7.17-6.99(m,3H),6.43(d,J=3.8Hz,1H),6.14(q,J=10.6Hz,2H),4.72(s,1H),4.24(q,J=5.4Hz,1H),3.97-3.78(m,4H),3.17(s,3 H),2.95(d,J=6.2Hz,2H),2.82(d,J=5.3Hz,3H),2.16(d,J=13.1Hz,2H),1.99(s,1H),1.85 (d,J=11.1Hz,2H),1.74-1.60(m,2H),1.53(d,J=7.2Hz,3H),1.36(td,J=13.7,5.9Hz,2H).

[0397] (Example 90) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-benzoylphenyl)propionate

[0398] [ka]

[0399] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-benzoylphenyl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 198 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) as a white solid of 0.16 g, with a yield of 44.2%. MS(m / z):[M+H] + C 32 H 37 The calculated value for N5O5S was 604.25, and the measured value was 604.4. 1H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),7.71-7.65(m,3H),7.61-7.51(m,5H),7.46(t,J=8.0Hz,1H),7.23(d,J= 3.8Hz,1H),6.88(q,J=4.9Hz,1H),6.60(d,J=3.7Hz,1H),6.14(s,2H),4.63(s,1H),3. 95(q,J=7.1Hz,1H),3.13(s,3H),2.95(d,J=6.2Hz,2H),2.59(d,J=5.0Hz,3H),2.09-2 .01(m,2H),1.81(s,1H),1.72-1.62(m,4H),1.39(d,J=7.1Hz,3H),1.35-1.26(m,2H).

[0400] (Example 91) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ester

[0401] [ka] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ester 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), N-Boc-L-phenylglycine (196 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) as a white solid of 0.14 g, with a yield of 38.8%. MS(m / z):[M+H] + C 29 H 40 The calculated value for N6O6S is 601.27, and the measured value is 601.4. 1 H NMR(400MHz,DMSO-d6)δ 8.21(s,1H),7.85(d,J=8.0Hz,1H),7.39-7.25(m,6H),6.94(q,J=5.0Hz, 1H),6.67(d,J=3.8Hz,1H),6.27-6.16(m,2H),5.22(d,J=7.9Hz,1H),4.71 (s,1H),3.21(s,3H),3.01(d,J=6.2Hz,2H),2.64(d,J=5.0Hz,3H),2.10( d,J=12.7Hz,2H),1.95-1.85(m,1H),1.73(d,J=7.5Hz,4H),1.41(s,11H).

[0402] (Example 92) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

[0403] [ka]

[0404] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 444 mg, 1.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) as a white solid of 0.14 g, with a yield of 36.2%. MS(m / z):[M+H] + C 30 H 34 The calculated value for Cl2N6O4S is 645.17, and the measured value is 645.3. 1H NMR(400MHz,DMSO-d6)δ 8.17(s,1H),7.52(d,J=8.1Hz,2H),7.30(d,J=3.8Hz,1H),7.24-7.12(m,2H),7.05(td,J=7.7,1.6Hz ,1H),6.95(s,1H),6.87(q,J=4.9Hz,1H),6.82(td,J=7.4,1.2Hz,1H),6.64(d,J=3.8Hz,1H),6.23(dd ,J=8.0,1.2Hz,1H),6.19(s,2H),4.66(s,1H),3.82(s,2H),3.16(s,3H),2.95(d,J=6.2Hz,2H),2.59 (d,J=5.0Hz,3H),2.05(d,J=12.1Hz,2H),1.82(s,1H),1.75-1.65(m,4H),1.30(q,J=7.9,7.2Hz,2H).

[0405] (Example 93) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-acetylaminophenyl)acetate

[0406] [ka]

[0407] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-acetylaminophenyl)acetate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(4-acetylaminophenyl)acetic acid (Actalit, 151 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 0:1) as a white solid of 0.16 g, with a yield of 49.2%. MS(m / z):[M+H] + C 26 H 34 The calculated value for N6O5S was 543.23, and the measured value was 543.3. 1 H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),8.19(s,1H),7.54-7.39(m,2H),7.29(d,J=3.8Hz,1H),7.19- 7.09(m,2H),6.87(q,J=4.9Hz,1H),6.65(d,J=3.7Hz,1H),6.14(s,2H),4.6 7(s,1H),3.61(s,2H),3.17(s,3H),2.95(d,J=6.2Hz,2H),2.59(d,J=5.0H z,3H),2.03(s,5H),1.84(s,1H),1.70(q,J=6.7Hz,4H),1.37-1.27(m,2H).

[0408] (Example 94) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetate

[0409] [ka]

[0410] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 21,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 224 mg, 0.78 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 0:1) as a white solid of 0.14 g, with a yield of 36.6%. MS(m / z):[M+H] + C 33 H 44 The calculated value for N6O5S was 637.31, and the measured value was 637.3. 1H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),8.18(s,1H),7.20(dd,J=7.6,1.4Hz,1H),7.13(d,J=3.8Hz,1H),6.94-6.84 (m,3H),6.56(d,J=3.8Hz,1H),6.13-6.02(m,2H),4.66(s,1H),3.92-3.77(m,2H),3.17(s, 3H),3.06-2.92(m,3H),2.88-2.76(m,3H),2.69-2.56(m,5H),2.10-2.00(m,3H),1.93-1. 81(m,2H),1.76-1.64(m,4H),1.39-1.27(m,2H),1.26-1.18(m,3H),0.59(t,J=7.3Hz,3H).

[0411] (Example 95) 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile

[0412] [ka]

[0413] Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-3-azetidine acetonitrile (baricitinib, 1113 mg, 3 mmol), 4-dimethylaminopyridine (DMAP, 36.6 mg, 0.3 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 742 mg, 3.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 864 mg, 4.5 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) to obtain 1.2 g of the target compound, which was a white solid with a yield of 71.5%. MS(m / z):[M+H] + C 29 H 33 The calculated value for N7O3S was 560.69, and the measured value was 560.3. 1 H NMR(400MHz,DMSO-d6)δ 8.99(d,J=4.2Hz,2H),8.50(s,1H),8.14(d,J=4.2Hz,1H),7.40(d,J=4.2Hz,1H),7.37 -7.29(m,2H),7.08(d,J=7.9Hz,2H),5.99(q,J=6.9Hz,1H),4.59(d,J=9.1Hz,2H),4.2 4(d,J=9.1Hz,2H),3.68(s,2H),3.23(q,J=7.3Hz,2H),2.35(d,J=7.2Hz,2H),1.76(he pt,J=6.7Hz,1H),1.58(d,J=6.9Hz,3H),1.24(t,J=7.3Hz,3H),0.80(d,J=6.6Hz,6H).

[0414] (Example 96) 1-((trans)-4-((7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

[0415] [ka]

[0416] Synthesis of 1-((trans)-4-((7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 150 mg, 0.44 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.044 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 96 mg, 0.468 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 128 mg, 0.666 mmol) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1~2:1), yielding 0.07 g of a white solid with a yield of 30%. MS(m / z):[M+H] + C 28 H 39 The calculated value for N5O3S was 526.28, and the measured value was 526.1. 11H NMR (400MHz, DMSO-d6)δ 8.36(s,1H),7.66(d,J=4.2Hz,1H),7.33-7.26(m,2H),7.07(d,J=8.0Hz,2H),6 .95-6.81(m,2H),6.10(q,J=6.9Hz,1H),4.66(s,1H),3.15(s,3H),2.94(d,J=6 .2Hz,2H),2.58(d,J=5.0Hz,3H),2.36(d,J=7.1Hz,2H),2.10-1.96(m,2H),1.9 1-1.60(m,6H),1.52(d,J=7.0Hz,3H),1.35-1.22(m,2H),0.82(d,J=6.7Hz,6H).

[0417] (Example 97) 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide

[0418] [ka]

[0419] Synthesis of 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide (piroxicam, 66 mg, 0.2 mmol) and triphenylphosphine (PPh3, 79 mg, 0.3 mmol) were added to tetrahydrofuran (0.4 mL), stirred, and when the temperature dropped to -10°C, diisopropyl azodicarboxylic acid (DIAD, 53 mg, 0.26 mmol) was added dropwise to the mixture, stirred for 20 minutes while maintaining the temperature at -10°C, and then allowed to rise naturally to room temperature. Then, 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (68 mg, 0.2 mmol) was added, and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared (1 hour), the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.005 g of a yellow solid with a yield of 3.8%. MS(m / z):[M+H] + C 32 H 33 The calculated value for N9O5S was 656.23, and the measured value was 656.2. 1 ¹H NMR (400MHz, chloroform-d)δ 15.22 (d, J=17.7Hz, 1H), 8.52 (t, J=8.4Hz, 1H), 8.32 (d, J=9.2Hz, 1H), 8.23 ​​(d, J=3.1Hz, 1H), 8.07-7.91 (m, 2H), 7.83 (d, J=7.5Hz, 1H), 7.71-7.55 (m, 3H), 6.70-6.58 (m, 2H), 6.51 (dd, J=9.8, 3.8Hz, 1H), 4.95 (s ,1H),4.06(dd,J=13.0,4.4Hz,1H),3.85-3.67(m,1H),3.66-3.55(m,1H),3.54-3.36(m,4H),3.27(d,J=1 8.4Hz,3H),3.03(s,3H),2.53-2.39(m,1H),1.95-1.85(m,1H),1.73-1.61(m,1H),1.01(t,J=7.7Hz,3H).

[0420] (Example 98) (R)-3-Cyclopentyl-3-(4-(7-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile

[0421] [ka]

[0422] Synthesis of (R)-3-cyclopentyl-3-(4-(7-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (R)-3-(4-(7h-pyrrolo[2,3-d]pyridine-4-yl)-1h-pyrazole-1-yl)-3-cyclopentylpropane (ruxolitinib, 50 mg, 0.163 mmol), 4-dimethylaminopyridine (DMAP, 2 mg, 0.016 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 35.5 mg, 0.172 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 47 mg, 0.245 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1~3:1) to obtain 0.05 g of a white solid, with a yield of 61%. MS(m / z):[M+H] + C 30 H 34 The calculated value for N6O4 was 495.64, and the measured value was 495.2. 1H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),8.88(d,J=1.6Hz,1H),8.39(d,J=11.3Hz,1H),8.12(d,J=4.2 Hz,1H),7.40-7.28(m,3H),7.09(dd,J=7.9,5.8Hz,2H),6.00(q,J=6.9Hz, 1H),4.54(td,J=9.6,4.6Hz,1H),3.28-3.15(m,2H),2.47-2.31(m,3H),1. 88-1.71(m,2H),1.65-1.40(m,5H),1.40-1.16(m,5H),0.99-0.76(m,6H).

[0423] (Example 99) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(3-benzoylphenyl)propionate

[0424] [ka]

[0425] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(3-benzoylphenyl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 191 mg, 1.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.143 g, with a yield of 50%. MS(m / z):[M+H] + C 34 H 32 The calculated value for N6O3 was 573.25, and the measured value was 573.3. 1 H NMR(400MHz,DMSO-d6)δ 8.83(d,J=0.7Hz,1H),8.72(s,1H),8.38(s,1H),7.69(d,J=3.8Hz,1H),7.68-7.62(m,3H), 7.58(d,J=1.8Hz,1H),7.57-7.49(m,4H),7.44(t,J=7.6Hz,1H),7.08(d,J=3.8Hz,1H),6.3 3-6.22(m,2H),4.55(td,J=9.7,4.2Hz,1H),3.99(q,J=7.0Hz,1H),3.32-3.15(m,2H),2.48 -2.35(m,1H),1.87-1.76(m,1H),1.67-1.44(m,3H),1.42-1.37(m,3H),1.36-1.13(m,4H).

[0426] (Example 100) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0427] [ka]

[0428] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 183 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.15 g, with a yield of 53.3%. MS(m / z):[M+H] + C 33 H 31 The calculated value for FN6O2 was 563.25, and the measured value was 563.3. 1H NMR(400MHz,DMSO-d6)δ 8.83(s,1H),8.75(s,1H),8.39(s,1H),7.73(d,J=3.7Hz,1H),7.50-7.3 1(m,6H),7.17-7.07(m,3H),6.35-6.24(m,2H),4.54(td,J=9.7,4.2Hz, 1H),3.92(q,J=7.1Hz,1H),3.33-3.14(m,2H),2.42(h,J=8.5Hz,1H),1. 82(dtd,J=12.0,7.6,4.5Hz,1H),1.64-1.48(m,3H),1.48-1.11(m,7H).

[0429] (Example 101) (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

[0430] [ka]

[0431] Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 222 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.12 g, with a yield of 39.1%. MS(m / z):[M+H] + C 32 H 29 The calculated value for Cl2N7O2 is 614.18, and the measured value is 614.2. 1 H NMR(400MHz,DMSO-d6)δ 8.86-8.73(m,2H),8.40(s,1H),7.81-7.68(m,2H),7.49(d,J=8.1Hz,2H),7.26-6.9 4(m,4H),6.81(td,J=7.4,1.1Hz,1H),6.31(s,2H),6.21(d,J=8.1Hz,1H),4.55(td, J=9.7,4.2Hz,1H),3.87(d,J=14.3Hz,2H),3.24(qd,J=17.2,6.9Hz,2H),2.43(h,J= 8.3Hz,1H),1.82(qt,J=7.5,5.4,4.1Hz,1H),1.67-1.40(m,4H),1.40-1.13(m,3H).

[0432] (Example 102) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(3-phenoxyphenyl)propionate

[0433] [ka]

[0434] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(3-phenoxyphenyl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 182 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.133 g, with a yield of 457.5%. MS(m / z):[M+H] + C 33 H 32 The calculated value for N6O3 was 561.25, and the measured value was 561.4. 1H NMR(400MHz,DMSO-d6)δ 8.83(s,1H),8.74(s,1H),8.40(s,1H),7.67(d,J=3.8Hz,1H),7.33(dd,J=8.5,7.3Hz,2H),7.24(t,J=7.9H z,1H),7.14-7.05(m,2H),6.97(dt,J=7.7,1.2Hz,1H),6.93-6.86(m,2H),6.86-6.75(m,2H),6.32-6.20(m ,2H),4.55(td,J=9.7,4.2Hz,1H),3.83(q,J=7.0Hz,1H),3.28(dd,J=17.2,9.6Hz,1H),3.19(dd,J=17.2,4 .2Hz,1H),2.42(h,J=8.6Hz,1H),1.82(dtd,J=11.9,7.5,4.4Hz,1H),1.66-1.43(m,4H),1.43-1.12(m,6H).

[0435] (Example 103) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate

[0436] [ka]

[0437] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 185 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.125 g of a white solid with a yield of 44.3%. MS(m / z):[M+H] + C 33 H 36 The calculated value for N6O3 was 565.28, and the measured value was 565.3. 1 1H NMR (400MHz, DMSO-d6)δ 8.82(s,1H),8.74(d,J=1.7Hz,1H),8.39(s,1H),7.68(d,J=3.8Hz,1H),7.11 -6.96(m,5H),6.28-6.19(m,2H),4.54(td,J=9.6,4.2Hz,1H),3.76(q,J=7.0 Hz,1H),3.23(qd,J=17.1,6.9Hz,2H),2.92-2.82(m,1H),2.50-2.14(m,5H), 2.08-1.89(m,1H),1.86-1.74(m,3H),1.69-1.47(m,4H),1.40-1.12(m,7H).

[0438] (Example 104) (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate

[0439] [ka]

[0440] Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.176 g of a pale yellow solid with a yield of 52.1%. MS(m / z):[M+H] + C 37 H 34 The calculated value for ClN7O4 was 676.24, and the measured value was 676.3. 1H NMR(400MHz,DMSO-d6)δ 8.84(s,1H),8.75(s,1H),8.40(s,1H),7.71(d,J=3.8Hz,1H),7.62(s,4H),7.10(d,J=3 .8Hz,1H),6.95-6.85(m,2H),6.66(dd,J=9.0,2.5Hz,1H),6.29(s,2H),4.55(td,J=9.7 ,4.2Hz,1H),3.82(s,2H),3.65(s,3H),3.32-3.15(m,2H),2.42(p,J=8.5Hz,1H),2.13( s,3H),1.89-1.76(m,1H),1.59(dddd,J=26.4,12.6,7.1,4.5Hz,3H),1.41-1.12(m,4H).

[0441] (Example 105) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-(1-oxoisoindorin-2-yl)phenyl)butyrate

[0442] [ka]

[0443] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-(1-oxoisoindorin-2-yl)phenyl)butyrate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (20 mg, 0.058 mmol), 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyric acid (indobufen, 26 mg, 0.09 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 17 mg, 0.09 mmol) were dissolved in a mixed solvent of dichloromethane (0.5 mL) and N,N-dimethylformamide (0.05 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.152 g of a white solid with a yield of 49.6%. MS(m / z):[M+H] + C 36 H 35 The calculated value for N7O3 was 614.28, and the measured value was 614.4. 1 H NMR(400MHz,DMSO-d6)δ 8.83(s,1H),8.38(s,1H),7.79(t,J=8.5Hz,3H),7.74-7.67(m,2H),7.67-7.62(m,1H),7.54(td,J=7.2 ,1.5Hz,1H),7.29(d,J=8.4Hz,2H),7.10(d,J=3.7Hz,1H),6.35-6.21(m,2H),4.96(s,2H),4.53(td,J=9 .6,4.2Hz,1H),3.58(t,J=7.6Hz,1H),3.23(qd,J=17.2,6.9Hz,2H),2.42(h,J=8.4Hz,1H),2.07-1.88( m,1H),1.81(dtd,J=12.1,7.6,4.4Hz,1H),1.76-1.40(m,5H),1.40-1.11(m,4H),0.77(t,J=7.3Hz,3H).

[0444] (Example 106) (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoic acid ester

[0445] [ka]

[0446] Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoic acid ester (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 181 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) to obtain 0.147 g of a yellow solid, with a yield of 52.6%. MS(m / z):[M+H] + C 33 H 33 The calculated value for N7O2 was 560.27, and the measured value was 560.3. 1H NMR(400MHz,DMSO-d6)δ 9.08(s,1H),8.84(d,J=18.4Hz,2H),8.42(s,1H),7.91(d,J=3.8Hz,1H),7.75(dd,J=8.1,1. 6Hz,1H),7.32(ddd,J=8.8,7.2,1.7Hz,1H),7.20-7.00(m,4H),6.69-6.59(m,2H),6.54(s,2 H),4.55(td,J=9.7,4.2Hz,1H),3.24(qd,J=17.2,6.9Hz,2H),2.43(q,J=8.4Hz,1H),2.29(s ,3H),2.08(s,3H),1.82(dtd,J=12.0,7.4,3.9Hz,1H),1.65-1.50(m,3H),1.49-1.12(m,4H).

[0447] (Example 107) (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoic acid ester

[0448] [ka]

[0449] Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoate ester (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (200 mg, 0.58 mmol), 4-dimethylaminopyridine (DMAP, 35 mg, 0.29 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 230 mg, 0.88 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 168 mg, 0.88 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N,N-dimethylformamide (0.2 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.161 g of a yellow solid with a yield of 55.6%. MS(m / z):[M+H] + C 32 H 30 The calculated value for ClN7O2 was 580.21, and the measured value was 580.3. 1 H NMR(400MHz,DMSO-d6)δ 9.13(s,1H),8.83(d,J=18.6Hz,2H),8.42(s,1H),7.90(d,J=3.8Hz,1H),7.78(dd,J=8.0,1.6Hz ,1H),7.37(ddd,J=8.8,7.1,1.7Hz,1H),7.32-7.21(m,3H),7.17(d,J=3.8Hz,1H),6.78-6.68(m, 2H),6.54(s,2H),4.55(td,J=9.6,4.2Hz,1H),3.33-3.15(m,2H),2.43(q,J=8.4Hz,1H),2.24(s ,3H),1.82(dtd,J=11.9,7.4,4.2Hz,1H),1.59(ddd,J=23.3,7.9,5.7Hz,2H),1.47-1.12(m,5H).

[0450] (Example 108) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-isobutylphenyl)propionate

[0451] [ka]

[0452] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-isobutylphenyl)propionate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 123.6 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.145 g, with a yield of 55.3%. MS(m / z):[M+H] + C 31 H 36 The calculated value for N6O2 was 525.29, and the measured value was 525.3. 1H NMR(400MHz,DMSO-d6)δ 8.83(s,1H),8.74(s,1H),8.39(s,1H),7.68(d,J=3.8Hz,1H),7.12-7.02(m,3H),6.95(d ,J=7.9Hz,2H),6.25(q,J=10.7Hz,2H),4.55(td,J=9.7,4.2Hz,1H),3.76(q,J=7.0Hz,1H) ,3.30-3.15(m,2H),2.43(q,J=8.5Hz,1H),2.32(d,J=7.1Hz,2H),1.89-1.77(m,1H),1.7 0(hept,J=6.8Hz,1H),1.64-1.48(m,3H),1.41-1.13(m,7H),0.76(dd,J=6.6,1.0Hz,6H).

[0453] (Example 109) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetate

[0454] [ka]

[0455] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl) acetate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 216 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.153 g of a white solid with a yield of 50.5%. MS(m / z):[M+H] + C 35 H 39 The calculated value for N7O3 was 606.31, and the measured value was 606.3. 1 H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),8.83(s,1H),8.76(s,1H),8.40(s,1H),7.56(dd,J=3.8,1.5Hz,1H),7.15(dd,J=7.3,1.5Hz,1H ),7.01(d,J=3.7Hz,1H),6.90-6.79(m,2H),6.19(d,J=1.4Hz,2H),4.56(td,J=9.7,4.2Hz,1H),3.82(td,J=1 1.1,5.4Hz,2H),3.31-3.15(m,2H),3.05(d,J=13.6Hz,1H),2.88-2.69(m,3H),2.60(ddd,J=15.0,8.1,5.3Hz ,1H),2.44(q,J=8.4Hz,1H),2.07-1.76(m,3H),1.68-1.41(m,4H),1.41-1.14(m,7H),0.57(t,J=7.2Hz,3H).

[0456] (Example 110) (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-acetylaminophenyl)acetate

[0457] [ka]

[0458] Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-(4-acetylaminophenyl)acetate (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetylaminophenyl)acetic acid (Actalit, 145 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.133 g, with a yield of 52%. MS(m / z):[M+H] + C 28 H 29 The calculated value for N7O3 was 512.23, and the measured value was 512.3. 1H NMR(400MHz,DMSO-d6)δ 9.91(s,1H),8.83(d,J=20.0Hz,2H),8.41(s,1H),7.75(d,J=3.7Hz,1H),7.49(d,J=8.3Hz,2H),7.18-7.10(m,3H),6.27(s,2H),4.55(td,J =9.6,4.2Hz,1H),3.65(s,2H),3.30-3.15(m,2H),2.48-2.37(m,1H),2.03(s,3H),1.87-1.76(m,1H),1.66-1.42(m,4H),1.41-1.15(m,3H).

[0459] (Example 111) (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ester

[0460] [ka]

[0461] Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid ester (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propionitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (189 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.153 g, with a yield of 53.7%. MS(m / z):[M+H] + C 31 H 35 The calculated value for N7O4 is 570.28, and the measured value is 570.2. 1 H NMR(400MHz,DMSO-d6)δ 8.84(s,1H),8.75(s,1H),8.40(s,1H),7.82(d,J=7.8Hz,1H),7.66(d,J= 3.7Hz,1H),7.40-7.19(m,5H),7.09(d,J=3.8Hz,1H),6.37-6.22(m,2H),5 .19(d,J=7.8Hz,1H),4.55(td,J=9.7,4.2Hz,1H),3.29-3.15(m,2H),2.4 5-2.34(m,1H),1.88-1.77(m,1H),1.67-1.40(m,4H),1.39-1.11(m,12H).

[0462] (Example 112) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-isobutylphenyl)methyl propionate

[0463] [ka]

[0464] Synthesis of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)2-(4-isobutylphenyl)propionate methyl 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (143 mg, 0.356 mmol), 4-dimethylaminopyridine (DMAP, 44 mg, 0.356 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 110 mg, 0.534 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 103 mg, 0.534 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.191 g, with a yield of 91%. MS(m / z):[M+H] + C 30 H 35 The calculated value for N7O4S was 590.25, and the measured value was 590.3. 1H NMR(400MHz,chloroform-d)δ 8.85(s,1H),8.49(s,1H),8.31(s,1H),7.44(d,J=3.8Hz,1H),7.09(d,J=8.1Hz,2H),7 .00(d,J=8.1Hz,2H),6.71(d,J=3.8Hz,1H),6.27-6.17(m,2H),4.63(d,J=9.2Hz,2H), 4.29-4.22(m,2H),3.70(q,J=7.1Hz,1H),3.40(s,2H),3.08(q,J=7.4Hz,2H),2.38(d, J=7.2Hz,2H),1.79(dh,J=13.5,6.7Hz,1H),1.48-1.38(m,6H),0.85(d,J=6.6Hz,6H).

[0465] (Example 113) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0466] [ka]

[0467] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 183 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.072 g, with a yield of 24.2%. MS(m / z):[M+H] + C 31 H 36 The calculated value for FN5O4S is 594.25, and the measured value is 594.1. 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),7.54-7.44(m,4H),7.42-7.35(m,2H),7.29(d,J=3.7Hz,1H),7.12(d,J=9.9Hz, 2H),6.90(q,J=5.0Hz,1H),6.63(d,J=3.7Hz,1H),6.17(d,J=2.1Hz,2H),4.64(s,1H),3.89( q,J=7.1Hz,1H),3.15(s,3H),2.95(d,J=6.2Hz,2H),2.59(d,J=5.0Hz,3H),2.07-1.99(m,2H ),1.84(dt,J=11.8,6.9Hz,1H),1.75-1.61(m,4H),1.39(d,J=7.1Hz,3H),1.36-1.21(m,2H).

[0468] (Example 114) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-phenoxyphenyl)propionate

[0469] [ka]

[0470] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(3-phenoxyphenyl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 182 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.118 g, with a yield of 39.9%. MS(m / z):[M+H] + C 31 H 37 The calculated value for N5O5S was 592.25, and the measured value was 592.2. 11H NMR (400MHz, DMSO-d6)δ 8.22(s,1H),7.42(dd,J=8.5,7.3Hz,2H),7.35-7.28(m,2H),7.19(t,J=7.4Hz, 1H),7.07-6.85(m,6H),6.68(d,J=3.7Hz,1H),6.19(s,2H),4.71(s,1H),3.86(q ,J=7.1Hz,1H),3.21(s,3H),3.01(d,J=6.2Hz,2H),2.64(d,J=5.0Hz,3H),2.10 (d,J=12.9Hz,2H),1.97-1.82(m,1H),1.73(t,J=5.3Hz,4H),1.42-1.27(m,5H).

[0471] (Example 115) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate

[0472] [ka]

[0473] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 185 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.073 g of a white solid with a yield of 24.5%. MS(m / z):[M+H] + C 31 H 41 The calculated value for N5O5S was 596.28, and the measured value was 596.2. 1 H NMR(400MHz,DMSO-d6)δ 8.15(d,J=1.9Hz,1H),7.25(d,J=3.7Hz,1H),7.07(qd,J=8.3,2.9Hz,4H),6.89(q,J=4.9Hz, 1H),6.62(d,J=3.8Hz,1H),6.12(d,J=1.6Hz,2H),4.65(s,1H),3.74(q,J=7.0Hz,1H),3.16(s ,3H),3.00-2.80(m,3H),2.59(d,J=5.0Hz,3H),2.45-2.16(m,3H),2.05(dddd,J=14.5,10.1, 8.5,1.7Hz,3H),1.93-1.78(m,3H),1.74-1.60(m,5H),1.48-1.41(m,1H),1.36-1.21(m,5H).

[0474] (Example 116) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate

[0475] [ka]

[0476] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.136 g of a pale yellow solid with a yield of 38.5%. MS(m / z):[M+H] + C 35 H 39 The calculated value for ClN6O6S is 707.23, and the measured value is 707.0. 1H NMR(400MHz,DMSO-d6)δ 8.17(s,1H),7.64(s,4H),7.28(d,J=3.7Hz,1H),7.01-6.83(m,3H),6.70(dd,J=9. 0,2.6Hz,1H),6.64(d,J=3.8Hz,1H),6.17(s,2H),4.67(s,1H),3.80(s,2H),3.70(s ,3H),3.17(s,3H),2.96(d,J=6.2Hz,2H),2.60(d,J=4.9Hz,3H),2.14(s,3H),2.06( d,J=12.8Hz,2H),1.96-1.80(m,1H),1.77-1.63(m,4H),1.31(p,J=4.9,4.3Hz,2H).

[0477] (Example 117) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-(1-)oxoisoindorin-2-yl)phenyl)butyrate

[0478] [ka]

[0479] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-(1-)oxoisoindorin-2-yl)phenyl)butyrate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (20 mg, 0.058 mmol), 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindorin-2-yl)phenyl)butyric acid (indobufen, 26 mg, 0.09 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 17 mg, 0.09 mmol) were dissolved in a mixed solvent of dichloromethane (0.5 mL) and N,N-dimethylformamide (0.05 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.156 g of a white solid with a yield of 48.4%. MS(m / z):[M+H] + C 34 H 40 The calculated value for N6O5S was 645.28, and the measured value was 645.1. 1 H NMR(400MHz,DMSO-d6)δ 8.17(s,1H),7.86-7.75(m,3H),7.68(dd,J=6.3,1.2Hz,2H),7.55(ddd,J=8.1,6.3,2.0Hz,1H), 7.34-7.24(m,3H),6.88(q,J=5.0Hz,1H),6.62(d,J=3.8Hz,1H),6.22-6.08(m,2H),4.99(s,2H), 4.64(s,1H),3.55(t,J=7.6Hz,1H),3.14(s,3H),2.94(d,J=6.2Hz,2H),2.59(d,J=5.0Hz,3H),2. 06-1.91(m,3H),1.89-1.78(m,1H),1.77-1.61(m,5H),1.33-1.21(m,2H),0.79(t,J=7.3Hz,3H).

[0480] (Example 118) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoic acid ester

[0481] [ka]

[0482] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoic acid ester 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 181 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N,N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) to obtain 0.096 g of a yellow solid, with a yield of 32.5%. MS(m / z):[M+H] + C 31 H 38 The calculated value for N6O4S was 591.27, and the measured value was 591.2. 1H NMR(400MHz,DMSO-d6)δ 9.07(s,1H),8.21(s,1H),7.73(dd,J=8.1,1.6Hz,1H),7.47(dd,J=8.8,3.9Hz,1H),7.32(ddd,J =8.6,7.0,1.7Hz,1H),7.19-7.03(m,3H),6.90(q,J=4.9Hz,1H),6.66(ddd,J=20.2,9.1,4.5Hz,3 H),6.41(s,2H),4.68(s,1H),3.22-3.13(m,3H),2.95(d,J=6.2Hz,2H),2.59(d,J=4.9Hz,3H),2 .29(s,3H),2.06(d,J=14.3Hz,5H),1.92-1.79(m,1H),1.70(h,J=3.4Hz,4H),1.38-1.19(m,2H).

[0483] (Example 119) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-isobutylphenyl)propionate

[0484] [ka]

[0485] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl2-(4-isobutylphenyl)propionate 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 123.6 mg, 0.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 150:1 to 50:1) as a white solid of 0.142 g, with a yield of 51.1%. MS(m / z):[M+H] + C 29 H 41 The calculated value for N5O4S was 556.29, and the measured value was 556.2. 1 H NMR(400MHz,DMSO-d6)δ 8.15(s,1H),7.24(d,J=3.8Hz,1H),7.08(d,J=8.1Hz,2H),7.01(d,J=8.0Hz,2H),6.89(q, J=5.0Hz,1H),6.61(d,J=3.7Hz,1H),6.12(s,2H),4.66(s,1H),3.73(q,J=7.0Hz,1H),3.15 (s,3H),2.95(d,J=6.2Hz,2H),2.59(d,J=5.0Hz,3H),2.37(d,J=7.1Hz,2H),2.05(d,J=12 .9Hz,2H),1.91-1.80(m,1H),1.79-1.64(m,5H),1.37-1.25(m,5H),0.82(d,J=6.6Hz,6H).

[0486] (Example 120) (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoic acid ester

[0487] [ka]

[0488] Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoic acid ester 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (200 mg, 0.58 mmol), 4-dimethylaminopyridine (DMAP, 35 mg, 0.29 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 230 mg, 0.88 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 168 mg, 0.88 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N,N-dimethylformamide (0.2 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 150:1~50:1) yielded the target compound, which was 0.137 g of a yellow solid with a yield of 44.9%. MS(m / z):[M+H] + C 30 H 35 The calculated value for ClN6O4S is 611.21, and the measured value is 611.2. 1H NMR(400MHz,DMSO-d6)δ 9.18(s,1H),8.26(s,1H),7.81(dd,J=8.2,1.5Hz,1H),7.51(d,J=3.7Hz,1H),7.43(td,J=7. 7,7.1,1.7Hz,1H),7.40-7.20(m,3H),6.95(q,J=5.0Hz,1H),6.84-6.73(m,3H),6.47(s,2H), 4.74(s,1H),3.24(s,3H),3.01(d,J=6.2Hz,2H),2.65(d,J=4.9Hz,3H),2.29(s,3H),2.11(d d,J=10.1,5.0Hz,2H),2.00-1.86(m,1H),1.74(d,J=9.5Hz,4H),1.36(q,J=10.0,7.2Hz,2H).

[0489] (Example 121) 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide

[0490] [ka]

[0491] Synthesis of 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiazidine-3-carboxamide 1,1-dioxide (piroxicam, 103 mg, 0.312 mmol) and triphenylphosphine (PPh3, 164 mg, 0.624 mmol) are added to tetrahydrofuran (3 mL), stirred, and when cooled to -10°C, the mixture contains azodicarboxylic acid diisopropyl alcohol. Pyr (DIAD, 95 mg, 0.468 mmol) was added dropwise, and the mixture was stirred at -10°C for 20 minutes. After allowing it to rise naturally to room temperature, 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (150 mg, 0.374 mmol) was added and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared (1 hour), the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.012 g of a yellow solid with a yield of 5.3%. MS(m / z):[M+H] + C 32 H 30 N 10 The calculated value for O6S2 was 715.18, and the measured value was 715.2. 1 1H NMR (400 MHz, chloroform-d)δ 8.79(s,1H),8.48(s,1H),8.24(s,1H),8.12(s,1H),7.94-7.85(m,2H),7.76- 7.68(m,2H),7.51(d,J=8.3Hz,1H),7.38-7.32(m,1H),7.24(d,J=3.8Hz,1H), 6.92-6.86(m,1H),6.60(d,J=3.8Hz,1H),6.05(s,2H),4.56(d,J=9.3Hz,2H), 4.18(d,J=9.3Hz,2H),3.35(s,2H),3.08-2.96(m,5H),1.36(t,J=7.4Hz,3H).

[0492] (Example 122) 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(5-methylthiazole-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide

[0493] [ka]

[0494] Synthesis of 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(5-methylthiazole-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(5-methylthiazole-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide (meloxicam, 147 mg, 0.42 mmol) and triphenylphosphine (PPh3, 137 mg, 0.52 mmol) are added to tetrahydrofuran (2.8 mL), stirred, and when cooled to -10°C, the mixture contains azodicarboxylic acid dioxide. Isopropyl (DIAD, 92 mg, 0.45 mmol) was added dropwise, and the mixture was stirred at -10°C for 20 minutes. After allowing it to rise naturally to room temperature, 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (140 mg, 0.35 mmol) was added and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared (1 hour), the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.005 g of a yellow solid with a yield of 1.9%. MS(m / z):[M+H] + C 31H 30 N 10 The calculated value for O6S3 was 735.15, and the measured value was 735.1. 1 1H NMR (400MHz, DMSO-d6)δ 14.61(s,1H),8.94(s,1H),8.77(s,1H),8.49(s,1H),8.02(d,J=7.7Hz,1H), 7.88-7.78(m,3H),7.73(d,J=3.7Hz,1H),7.28(s,1H),7.15(d,J=3.7Hz,1H) ,5.62(s,2H),4.60(d,J=9.1Hz,2H),4.24(dd,J=9.1,2.4Hz,2H),3.69(d,J= 2.7Hz,2H),3.27-3.20(m,2H),2.85(s,3H),2.32(s,3H),1.27-1.20(m,3H).

[0495] (Example 123) (3S,4R)-3-ethyl-4-(3-((S)-2-(4-isobutylphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0496] [ka]

[0497] Synthesis of (3S,4R)-3-ethyl-4-(3-((S)-2-(4-isobutylphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 338 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 122 mg, 1 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1-25:1) yielded the target compound, which was 0.05 g of a white solid with a yield of 17.6%. MS(m / z):[M+H] + C 30 H 35 The calculated value for F3N6O2 is 569.28, and the measured value is 569.3. 1 H NMR(400MHz,DMSO-d6)δ 8.88(s,1H),8.04(d,J=4.2Hz,1H),7.63(s,1H),7.37-7.29(m,2H),7.19-7.04(m,3H),6 .97(t,J=6.3Hz,1H),5.99(q,J=6.9Hz,1H),4.34(q,J=6.5Hz,1H),3.91-3.71(m,4H),3.7 1-3.61(m,1H),3.25(dd,J=10.2,5.7Hz,1H),2.38(dd,J=23.9,7.1Hz,3H),1.83-1.72(m ,1H),1.59(d,J=6.9Hz,3H),1.07-0.93(m,1H),0.92-0.80(m,7H),0.60(t,J=7.3Hz,3H).

[0498] (Example 124) (3S,4R)-3-ethyl-4-(3(2-(4-isobutylphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0499] [ka]

[0500] Synthesis of (3S,4R)-3-ethyl-4-(3(2-(4-isobutylphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 54 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 25:1) as a white solid of 0.097 g, with a yield of 34.1%. MS(m / z):[M+H] + C 30 H 35 The calculated value for F3N6O2 is 569.28, and the measured value is 569.3. 1¹H NMR (400MHz, chloroform-d)δ 8.79 (s, 1H), 7.93 (t, J=3.7Hz, 1H), 7.52 (d, J=4.3Hz, 1H), 7.36-7.26 (m, 2H), 7.06-6.94 (m, 3H), 6.78 (dd, J=4.2, 1.5Hz, 1H), 5.98 (qd, J=6.9, 3.4Hz, 1H), 4.70 (t, J=6.5Hz, 1H), 4.08 (dt, J=12.2, 6.2Hz, 1H) ,3.98-3.61(m,4H),3.29(d,J=8.3Hz,1H),2.62-2.46(m,1H),2.31(dd,J=9.0,7.2Hz,2H),1.82-1.67( m,1H),1.61(dd,J=6.9,1.2Hz,3H),1.27-1.09(m,1H),0.87-0.73(m,7H),0.66(dt,J=10.3,7.3Hz,3H).

[0501] (Example 125) (3S,4R)-3-ethyl-4-(3(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0502] [ka]

[0503] Synthesis of (3S,4R)-3-ethyl-4-(3(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 64 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1-25:1) yielded the target compound, which was 0.03 g of a white solid with a yield of 9.9%. MS(m / z):[M+H] + C 32 H 30 The calculated value for F4N6O2 is 607.24, and the measured value is 607.3. 1 H NMR(400MHz,DMSO-d6)δ 8.93(d,J=2.0Hz,1H),8.10(dd,J=4.2,2.5Hz,1H),7.65(d,J=6.9Hz,1H),7.58-7.32(m ,9H),6.98(t,J=5.8Hz,1H),6.09(p,J=6.9Hz,1H),4.36(s,1H),3.95-3.74(m,4H),3.6 9(dt,J=10.7,6.1Hz,1H),3.26(dd,J=10.2,5.3Hz,1H),3.09(td,J=7.3,4.7Hz,1H),1. 66(d,J=6.9Hz,3H),1.12-0.96(m,1H),0.93-0.75(m,1H),0.63(dt,J=10.2,7.3Hz,3H).

[0504] (Example 126) (3R,4S)-3-(3-(2-(3-benzoylphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0505] [ka]

[0506] Synthesis of (3R,4S)-3-(3-(2-(3-benzoylphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 67 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 25:1) as a white solid of 0.13 g, with a yield of 84.4%. MS(m / z):[M+H] + C 33 H 31 The calculated value for F3N6O3 is 617.24, and the measured value is 617.2. 1H NMR(400MHz,DMSO-d6)δ 8.80(d,J=5.8Hz,1H),8.07(dd,J=4.3,1.8Hz,1H),7.85-7.71(m,2H),7.71-7.57(m,5H),7. 57-7.47(m,3H),7.45(d,J=4.3Hz,1H),6.97(t,J=6.3Hz,1H),6.09(p,J=7.0Hz,1H),4.35(q ,J=6.5Hz,1H),3.90-3.63(m,5H),3.26(dt,J=10.1,5.1Hz,1H),2.58-2.49(m,1H),1.64(dd ,J=7.0,2.1Hz,3H),1.03(dp,J=20.6,7.0Hz,1H),0.81(s,1H),0.61(dt,J=14.6,7.3Hz,3H).

[0507] (Example 127) (3R,4S)-3-(3(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0508] [ka]

[0509] Synthesis of (3R,4S)-3-(3(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 78 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 25:1) as a white solid of 0.011 g, with a yield of 6.6%. MS(m / z):[M+H] + C 31 H 28 The calculated value for Cl2F3N7O2 is 658.16, and the measured value is 658.1. 1 H NMR(400MHz,chloroform-d)δ 8.85(s,1H),8.00(d,J=4.1Hz,1H),7.58(s,1H),7.38(dd,J=7.5,1.5Hz,1H),7.26(d,J=8.1Hz,2H ),7.08(td,J=7.8,1.6Hz,1H),6.93-6.85(m,4H),6.52(d,J=8.0Hz,1H),5.11(s,2H),4.69(t,J=6 .3Hz,1H),4.15(q,J=6.1Hz,1H),3.89(tt,J=15.6,8.6Hz,4H),3.72-3.66(m,1H),3.30(t,J=8.2H z,1H),2.57(dd,J=11.0,6.3Hz,1H),1.27-1.14(m,1H),0.84-0.77(m,1H),0.69(t,J=7.3Hz,3H).

[0510] (Example 128) (3S,4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0511] [ka]

[0512] Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 64 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 25:1) as a white solid of 0.101 g, with a yield of 66.8%. MS(m / z):[M+H] + C 32 H 31 The calculated value for F3N6O3 is 605.24, and the measured value is 605.2. 1H NMR(400MHz,DMSO-d6)δ 8.74(d,J=6.8Hz,1H),8.04(t,J=3.9Hz,1H),7.65(d,J=6.7Hz,1H),7.49-7.26(m, 4H),7.23-6.80(m,7H),5.97(p,J=6.8Hz,1H),4.38-4.30(m,1H),3.92-3.75(m,3H ),3.69(dd,J=8.4,6.0Hz,2H),3.26(dt,J=10.3,6.7Hz,1H),2.52-2.48(m,1H),1. 62-1.55(m,3H),1.07-0.98(m,1H),0.90-0.78(m,1H),0.63(td,J=7.4,3.7Hz,3H).

[0513] (Example 129) (3R,4S)-3-(3-(2-((2,3-dimethylphenyl)amino)benzoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0514] [ka]

[0515] Synthesis of (3R,4S)-3-(3(2-((2,3-dimethylphenyl)amino)benzoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-((2,3-dimethylphenyl)amino)benzoic acid (mefenamic acid, 64 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1~25:1) yielded the target compound, which was 0.129 g of a yellow solid with a yield of 85.5%. MS(m / z):[M+H] + C 32 H 32 The calculated value for F3N7O2 is 604.264, and the measured value is 604.2. 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),8.57(s,1H),7.77(d,J=3.9Hz,1H),7.61(s,1H),7.48-7.3 6(m,3H),7.09-6.95(m,4H),6.88-6.74(m,2H),4.38(t,J=6.5Hz,1H),3 .92-3.70(m,5H),3.31-3.25(m,1H),2.63-2.52(m,1H),2.23(s,3H),2. 00(s,3H),1.19-1.04(m,1H),0.90-0.82(m,1H),0.68(t,J=7.3Hz,3H).

[0516] (Example 130) (3R,4S)-3-(3-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0517] [ka]

[0518] Synthesis of (3R,4S)-3-(3-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-((3-chloro-2-methylphenyl)amino)benzoic acid (tolfenamic acid, 68 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1-25:1) yielded the target compound, which was 0.09 g of a yellow solid with a yield of 29.7%. MS(m / z):[M+H] + C 31 H 29 The calculated value for ClF3N7O2 is 624.20, and the measured value is 624.2. 11H NMR (400MHz, DMSO-d6)δ 8.61(s,1H),8.25(s,1H),7.67-7.58(m,1H),7.56-7.44(m,2H),7.36(d,J =4.2Hz,1H),7.22(d,J=4.9Hz,1H),7.10-6.85(m,5H),6.81-6.75(m,1H),4 .36(d,J=6.6Hz,1H),3.96-3.65(m,5H),3.34-3.21(m,1H),2.62-2.53(m, 1H),1.96(s,3H),1.16-1.01(m,1H),0.93-0.76(m,1H),0.72-0.66(m,3H).

[0519] (Example 131) (3S,4R)-3-ethyl-4-(3-((S)-2-(6-)methoxynaphthalene-2-yl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0520] [ka]

[0521] Synthesis of (3S,4R)-3-ethyl-4-(3-((S)-2-(6-)methoxynaphthalene-2-yl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 60 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1-25:1) yielded the target compound, which was 0.028 g of a white solid with a yield of 18.9%. MS(m / z):[M+H] + C 31 H 31 The calculated value for F3N6O3 is 593.24, and the measured value is 593.2. 1 H NMR(400MHz,DMSO-d6)δ 8.92(s,1H),8.08(d,J=4.2Hz,1H),7.91-7.68(m,3H),7.63(s,1H),7.57(dd,J=8.5,1.8Hz,1H),7.43-7 .39(m,1H),7.25(d,J=2.6Hz,1H),7.12(dd,J=9.0,2.6Hz,1H),6.96(t,J=6.2Hz,1H),6.13(q,J=6.9Hz, 1H),4.33(d,J=6.7Hz,1H),3.97-3.72(m,7H),3.65(dd,J=10.3,6.7Hz,1H),3.24(dd,J=10.3,5.7Hz,1H ),2.53-2.42(m,1H),1.68(d,J=6.9Hz,3H),1.03-0.92(m,1H),0.89-0.71(m,1H),0.57(t,J=7.3Hz,3H).

[0522] (Example 132) (3S,4R)-3-ethyl-4-(3-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0523] [ka]

[0524] Synthesis of (3S,4R)-3-ethyl-4-(3(2-(4-((2-oxocyclopentyl)methyl)phenyl)propionyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen, 65 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1~25:1) yielded the target compound, which was 0.066 g of a white solid with a yield of 43.4%. MS(m / z):[M+H] + C 32 H 35 The calculated value for F3N6O3 is 609.27, and the measured value is 609.3. 1H NMR(400MHz,DMSO-d6)δ 8.88(d,J=0.9Hz,1H),8.04(t,J=3.9Hz,1H),7.63(d,J=7.0Hz,1H),7.44-7.30(m,3H),7.22-7.07(m,2H),6.97(t,J=6.3Hz,1H),6.0 0(p,J=7.0Hz,1H),4.34(d,J=6.2Hz,1H),3.96-3.72(m,4H),3.67(ddd,J=10.9,6.7,4.6Hz,1H),3.25(dt,J=10.3,5.1Hz,1H),2.93- 2.84(m,1H),2.56-2.51(m,1H),2.43-2.26(m,2H),2.20(dd,J=18.6,8.4Hz,1H),2.12-1.96(m,1H),1.91-1.73(m,2H),1.72-1.50(m ,4H),1.48-1.36(m,1H),1.02(ddq,J=19.7,12.8,7.1,6.6Hz,1H),0.80(ddt,J=16.9,13.8,6.5Hz,1H),0.62(dt,J=10.3,7.3Hz,3H).

[0525] (Example 133) (3R,4S)-3-(3(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0526] [ka]

[0527] Synthesis of (3R,4S)-3-(3(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 95 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1-25:1) yielded the target compound, which was a pale yellow solid of 0.139 g with a yield of 77.3%. MS(m / z):[M+H] + C 36 H 33 The calculated value for ClF3N7O4 is 720.22, and the measured value is 720.1. 1 H NMR(400MHz,DMSO-d6)δ 8.95(s,1H),8.10(d,J=4.1Hz,1H),7.75-7.63(m,5H),7.50(d,J=4.2Hz,1H),7.18(d,J=2.6Hz,1H ),7.00(dd,J=7.7,5.0Hz,2H),6.73(dd,J=9.0,2.5Hz,1H),5.06(d,J=4.3Hz,2H),4.41(q,J=6.4H z,1H),3.93-3.83(m,3H),3.83-3.67(m,5H),3.27(dd,J=10.2,5.9Hz,1H),2.58(s,1H),2.27(s,3 H),1.07(ddd,J=12.8,7.4,4.9Hz,1H),0.82(ddd,J=13.3,10.0,7.0Hz,1H),0.65(t,J=7.3Hz,3H).

[0528] (Example 134) (3R,4S)-3-(3-(2-(4-acetylaminophenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0529] [ka]

[0530] Synthesis of (3R,4S)-3-(3-(2-(4-acetylaminophenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(4-acetylaminophenyl)acetic acid (Actarit, 51 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 25:1) as a white solid of 0.082 g, with a yield of 59%. MS(m / z):[M+H] + C 27 H 28 The calculated value for F3N7O3 is 556.22, and the measured value is 556.1. 1H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),8.89(s,1H),8.06(d,J=4.2Hz,1H),7.65(s,1H),7.57-7.48(m,2H),7.46(d,J=4 .1Hz,1H),7.35-7.27(m,2H),6.99(t,J=6.4Hz,1H),4.88(d,J=3.6Hz,2H),4.39(q,J=6.7Hz, 1H),3.92-3.74(m,4H),3.70(dd,J=10.2,6.7Hz,1H),3.26(dd,J=10.2,5.9Hz,1H),2.56(s,1 H),2.03(s,3H),1.06(ddd,J=12.9,7.7,5.2Hz,1H),0.89-0.73(m,1H),0.64(t,J=7.3Hz,3H).

[0531] (Example 135) (3R,4S)-3-(3-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0532] [ka]

[0533] Synthesis of (3R,4S)-3-(3-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (etodolac, 76 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1-25:1) yielded the target compound, which was 0.108 g of a white solid with a yield of 66.5%. MS(m / z):[M+H] + C 34 H 38 The calculated value for F3N7O3 is 650.30, and the measured value is 650.3. 1H NMR(400MHz,DMSO-d6)δ 10.55(d,J=10.5Hz,1H),8.79(s,1H),8.01(t,J=4.1Hz,1H),7.62(d,J=2.5Hz,1H),7.40(d,J=4.2Hz,1H),7.22(td,J=7.5,1.6Hz,1H),6 .99(t,J=6.3Hz,1H),6.89(td,J=7.4,5.1Hz,2H),4.61(dd,J=47.7,14.4Hz,1H),4.36(d,J=6.7Hz,1H),4.13(dd,J=41.9,14.4Hz,1H),3 .95-3.74(m,6H),3.69(dd,J=10.3,6.9Hz,1H),3.26(dd,J=10.3,5.8Hz,1H),2.90-2.81(m,2H),2.60(q,J=4.7Hz,2H),2.24-2.14(m,2H) ),1.25(td,J=7.4,2.7Hz,4H),1.10-1.00(m,1H),0.82(dtd,J=13.7,7.0,3.4Hz,1H),0.71(q,J=7.1Hz,3H),0.64(td,J=7.3,2.8Hz,3H).

[0534] (Example 136) 2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrroridine-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carbonyl)phenyl acetate

[0535] [ka]

[0536] Synthesis of 2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carbonyl)phenyl acetate (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-acetoxybenzoic acid (aspirin, 47.5 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1~25:1) as a white solid of 0.025 g, with a yield of 18.4%. MS(m / z):[M+H] + C 26 H 25 The calculated value for F3N6O4 is 543.19, and the measured value is 543.1. 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),7.85(d,J=4.2Hz,1H),7.78-7.71(m,2H),7.60(s,1H),7.51-7.44(m,2 H),7.34(dd,J=8.1,1.0Hz,1H),6.99(t,J=6.3Hz,1H),4.43-4.35(m,1H),3.92-3.7 5(m,4H),3.70(dd,J=10.2,6.9Hz,1H),3.27-3.20(m,1H),2.62-2.49(m,1H),1.89( s,3H),1.08(ddd,J=12.9,7.4,4.9Hz,1H),0.83-0.75(m,1H),0.64(t,J=7.3Hz,3H).

[0537] (Example 137) tert-butyl((S)-2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrroridine-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-yl)-2-oxo-1-phenylethyl)carbamate

[0538] [ka]

[0539] Synthesis of tert-butyl((S)-2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrroridine-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-yl)-2-oxo-1-phenylethyl)carbamate (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), N-Boc-L-phenylglycine (66 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1~25:1) as a white solid of 0.088 g, with a yield of 57.4%. MS(m / z):[M+H] + C 30 H 34 The calculated value for F3N7O4 is 614.26, and the measured value is 614.2. 11H NMR (400MHz, DMSO-d6)δ 8.89(s,1H),8.07(t,J=4.2Hz,1H),7.99(dd,J=7.5,4.5Hz,1H),7.67-7.24( m,8H),6.97(td,J=6.3,2.3Hz,1H),4.37-4.29(m,1H),3.91-3.72(m,4H),3.6 7(dt,J=10.3,6.4Hz,1H),3.28-3.18(m,1H),2.52-2.43(m,1H),1.40(d,J=2. 5Hz,9H),1.05-0.92(m,1H),0.88-0.68(m,1H),0.62(dt,J=14.5,7.3Hz,3H).

[0540] (Example 138) (3S,4R)-3-ethyl-4-(3(2-(4-(1-)oxoisoindolin-2-yl)phenyl)butyryl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0541] [ka]

[0542] Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(4-(1-)oxoisoindoline-2-yl)phenyl)butyryl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyrate (indobufen, 78 mg, 0.264 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:methanol = 50:1~25:1) yielded the target compound, which was 0.145 g of a white solid with a yield of 88.2%. MS(m / z):[M+H] + C 35 H 34 The calculated value for F3N7O3 is 658.27, and the measured value is 658.2. 1H NMR(400MHz,DMSO-d6)δ 8.93(d,J=1.8Hz,1H),8.07(dd,J=7.3,4.1Hz,1H),7.91-7.80(m,2H),7.75(dd,J=7.6,3.0Hz,1H),7.71-7.59(m,3H),7.58-7.46( m,3H),7.41(t,J=4.7Hz,1H),6.96(td,J=6.3,2.1Hz,1H),5.86(t,J=7.4Hz,1H),4.96(d,J=6.1Hz,2H),4.37-4.29(m,1H),3.91-3 .73(m,4H),3.67(dt,J=10.2,6.4Hz,1H),3.25(dd,J=10.3,5.8Hz,1H),2.56-2.49(m,1H),2.34-2.19(m,1H),1.94(dtd,J=12.8,7 .5,4.7Hz,1H),1.12-0.99(m,1H),0.95(td,J=7.3,5.7Hz,3H),0.80(ddd,J=16.9,14.2,7.4Hz,1H),0.62(dt,J=17.9,7.3Hz,3H).

[0543] (Example 139) 3-((3S,4R)-6-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octo-1-yl)-3-oxopropionitrile

[0544] [ka]

[0545] Synthesis of 3-((3S,4R)-6-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octo-1-yl)-3-oxopropionitrile 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), 2-(4-isobutylphenyl)propionic acid (ibuprofen, 65 mg, 0.31 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:acetonitrile = 30:1~10:1) as a white solid of 0.081 g, with a yield of 67.7%. MS(m / z):[M+H] + C 29 H 34 The calculated value for N6O2 was 499.27, and the measured value was 499.2. 1 H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),7.67(d,J=4.1Hz,1H),7.31(d,J=8.1Hz,2H),7.07(d,J=8.0Hz,2H),6.90( d,J=4.1Hz,1H),6.10(q,J=6.8Hz,1H),4.20-4.06(m,2H),4.04-3.24(m,3H),3.68(d,J =3.3Hz,2H),3.65-3.53(m,1H),2.72-2.55(m,2H),2.36(d,J=7.1Hz,2H),2.20(s,1H), 1.82-1.75(m,1H),1.54(d,J=6.9Hz,3H),1.13(d,J=7.0Hz,3H),0.82(d,J=6.6Hz,6H).

[0546] (Example 140) 3-((3S,4R)-6-(7-((S)-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octo-1-yl)-3-oxopropionitrile

[0547] [ka]

[0548] Synthesis of 3-((3S,4R)-6-(7-((S)-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octo-1-yl)-3-oxopropionitrile 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 65 mg, 0.31 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 30:1-10:1) yielded the target compound, which was 0.071 g of a white solid with a yield of 59.4%. MS(m / z):[M+H] + C 29 H 34 The calculated value for N6O2 was 499.27, and the measured value was 499.3. 1H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),7.67(d,J=4.1Hz,1H),7.31(d,J=8.1Hz,2H),7.07(d,J=8.0Hz,2H),6.90(d ,J=4.1Hz,1H),6.10(q,J=6.8Hz,1H),4.20-4.05(m,2H),4.04-3.24(m,3H),3.68(d,J=3. 3Hz,2H),3.65-3.53(m,1H),2.73-2.55(m,2H),2.36(d,J=7.1Hz,2H),2.20(s,1H),1.77 (hept,J=6.8Hz,1H),1.54(d,J=6.9Hz,3H),1.13(d,J=7.0Hz,3H),0.82(d,J=6.6Hz,6H).

[0549] (Example 141) 3-((3S,4R)-6-(7-((S)-2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octan-1-yl)-3-oxopropionitrile

[0550] [ka]

[0551] Synthesis of 3-((3S,4R)-6-(7-((S)-2-(6-methoxynaphthalene-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octan-1-yl)-3-oxopropionitrile 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 70 mg, 0.31 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 30:1-10:1) yielded the target compound, which was 0.013 g of a white solid with a yield of 10.3%. MS(m / z):[M+H] + C 30 H 30 The calculated value for N6O3 was 523.24, and the measured value was 523.2. 1 H NMR(400MHz,chloroform-d)δ 8.38(s,1H),7.76(d,J=1.7Hz,1H),7.67-7.56(m,2H),7.51(dd,J=8.6,1.8Hz,1H),7.40-7 .35(m,1H),7.08-6.98(m,2H),6.53(d,J=4.2Hz,1H),6.19(q,J=6.9Hz,1H),4.30-3.91(m,2 H),3.82(d,J=13.5Hz,5H),3.69(s,1H),3.63-3.57(m,2H),3.20-3.05(m,1H),2.84-2.74( m,1H),2.63(p,J=7.6,7.2Hz,1H),2.10-1.99(m,1H),1.21-1.08(m,3H),0.85-0.75(m,3H).

[0552] (Example 142) 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(5-methylthiazole-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide

[0553] [ka]

[0554] Synthesis of 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(5-methylthiazole-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(5-methylthiazole-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide (meloxicam, 246 mg, 0.7 mmol) and triphenylphosphine (PPh3, 190 mg, 0.73 mmol) are added to tetrahydrofuran (3.4 mL), stirred, and when cooled to -10°C, the mixture contains azodicarboxylic acid. Diisopropyl (DIAD, 148 mg, 0.73 mmol) was added dropwise, and the mixture was stirred at -10°C for 20 minutes. After allowing it to rise naturally to room temperature, 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (170 mg, 0.5 mmol) was added and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared (1 hour), the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.009 g of a yellow solid with a yield of 2.6%. MS(m / z):[M+H] + C 31 H33 The calculated value for N9O5S2 is 676.20, and the measured value is 676.2. 1 H NMR(400MHz,chloroform-d)δ 14.01(s,1H),8.28(s,1H),8.03(dd,J=7.6,1.4Hz,1H),7.84(dd,J=7.4,1.5Hz,1H),7.73-7.52(m,3H),7.30 (d,J=4.5Hz,1H),6.51(dd,J=11.0,3.8Hz,1H),6.42(s,2H),5.01(d,J=26.1Hz,1H),4.04(dd,J=13.2,4.2Hz, 1H),3.86-3.68(m,1H),3.64(dd,J=13.2,8.7Hz,1H),3.56-3.39(m,3H),3.29(d,J=18.7Hz,3H),3.09(s,3H) ,2.53-2.39(m,1H),2.21(d,J=1.4Hz,3H),2.00-1.80(m,1H),1.73-1.63(m,1H),1.02(dd,J=9.5,7.1Hz,3H).

[0555] (Example 143) 3-((3S,4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindorin-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3,4]octan-1-yl)-3-oxopropionitrile

[0556] [ka]

[0557] Synthesis of 3-((3S,4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindoline-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3,4]octan-1-yl)-3-oxopropionitrile 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butyrate (indobufen, 92 mg, 0.31 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 30:1-10:1) yielded the target compound, which was 0.018 g of a white solid with a yield of 12.7%. MS(m / z):[M+H] + C 34 H 33 The calculated value for N7O3 was 588.26, and the measured value was 588.0. 1 ¹H NMR (400MHz, chloroform-d)δ 8.37(s,1H),7.86-7.79(m,1H),7.70(dd,J=8.7,1.1Hz,2H),7.60(dd,J=4.2,1.5Hz,1H),7.56-7.46(m,3H),7.46-7.39(m,2H),6.55(t,J=4.1Hz,1H),5.93(t,J=7.5Hz,1H),4.74(s,2H),4.26(t,J=8.4Hz,1H),4.16(dd,J=12.0,8.2Hz,1H),4.12- 3.94(m,2H),3.73(s,1H),3.62(ddd,J=8.4,6.0,2.4Hz,1H),3.14(d,J=3.0Hz,2H),2.81(tt,J=13.0,5.9Hz,1H),2.67(s,1 H),2.22(dt,J=14.2,7.3Hz,1H),2.09(s,1H),1.96-1.86(m,1H),1.16(dd,J=7.1,4.4Hz,3H),0.92(td,J=7.3,1.2Hz,3H).

[0558] (Example 144) (4-((3S,4R)-1-(2-cyanoacetyl)-3-methyl-1,6-diazaspiro[3,4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate

[0559] [ka]

[0560] Step 1: Synthesis of 3-((3S,4R)-3-methyl-6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile Under nitrogen protection, 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (delgocitinib, 200 mg, 0.644 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.966 mmol) were added to dichloromethane (2 mL). After stirring at room temperature for 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (140 mg, 0.838 mmol) was added under an ice bath, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was separated by silica gel column chromatography (dichloromethane:methanol = 200:1 to 20:1) to obtain 0.234 g, with a yield of 82.5%. MS(m / z):[M+H] + C 22 H 32 The calculated value for N6O2Si is 441.24, and the measured value is 441.2.

[0561] Step 2: Synthesis of 3-((3S,4R)-6-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octan-1-yl)-3-oxopropionitrile Under nitrogen protection and in an ice bath, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of 3-((3S,4R)-3-methyl-6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (0.234 g, 0.53 mmol) in dichloromethane (15 mL). After 30 minutes, the ice bath was removed, and the mixture was stirred for 2 hours after the temperature rose to room temperature. At 0°C, saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. The mixture was then poured into a separatory funnel and separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target product was separated by silica gel column chromatography (dichloromethane:methanol = 50:1 to 9:1) to obtain 0.055 g, with a yield of 30.4%. MS(m / z):[M+H] + C 17 H 20 The calculated value for N6O2 was 341.16, and the measured value was 341.1.

[0562] Step 3: Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl(S)-2-(4-isobutylphenyl)propionate 3-((3S,4R)-6-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropionitrile (55 mg, 0.16 mmol), 4-dimethylaminopyridine (DMAP, 19 mg, 0.16 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 32 mg, 0.17 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 50 mg, 0.26 mmol) were dissolved in a mixed solvent of dichloromethane (1 mL) and dimethylformamide (0.25 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 30:1~10:1) yielded the target compound, which was 0.02 g of a white solid with a yield of 23.6%. MS(m / z):[M+H] + C 30 H 36 The calculated value for N6O3 was 529.28, and the measured value was 529.2. 1 H NMR(400MHz,chloroform-d)δ 8.28(s,1H),7.09-6.92(m,5H),6.45(d,J=3.7Hz,1H),6.10(d,J=10.6Hz,1H),6.01(d,J=10.6 Hz,1H),4.31-4.14(m,2H),4.03(d,J=11.9Hz,2H),3.77(s,1H),3.67-3.59(m,2H),3.16(s,2H) ),2.83(dt,J=13.0,7.5Hz,1H),2.67(h,J=7.0Hz,1H),2.35(d,J=7.2Hz,2H),2.10(s,1H),1.7 5(dt,J=13.5,6.7Hz,1H),1.38(d,J=7.2Hz,3H),1.18(d,J=2.8Hz,3H),0.81(d,J=6.7Hz,6H).

[0563] (Example 145) 3-((3S,4R)-6-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octo-1-yl)-3-oxopropionitrile

[0564] [ka]

[0565] Synthesis of 3-((3S,4R)-6-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-methyl-1,6-diazaspiro[3,4]octo-1-yl)-3-oxopropionitrile 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octo-1-yl)-3-oxopropionitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 79 mg, 0.31 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Furthermore, the target compound was obtained by silica gel column chromatography (dichloromethane:acetonitrile = 30:1~10:1) as a white solid of 0.038 g, with a yield of 29%. MS(m / z):[M+H] + C 32 H 30 The calculated value for N6O3 was 547.24, and the measured value was 547.1. 1¹H NMR (400MHz, chloroform-d)δ 8.35(s,1H),7.94(s,1H),7.81-7.63(m,5H),7.61-7.55(m,1H),7.50-7.43(m,2H),7.40(t,J=7.7Hz,1H),6.65(dd,J=4.3,1.5Hz,1H),6.19(q,J=7.0Hz,1H),4.32(t,J=8.4Hz,1H),4.24(dd,J=12.1,7.2Hz,1H),4.14( s,1H),4.04(dd,J=12.1,8.4Hz,1H),3.85-3.77(m,1H),3.69(dd,J=8.3,5.9Hz,1H),3.21(d,J=2.7Hz,2H),2 .93-2.80(m,1H),2.78-2.68(m,1H),2.17(dq,J=13.2,7.3Hz,1H),1.65(d,J=7.0Hz,3H),1.26-1.19(m,3H).

[0566] (Example 146) 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-thieno[3,2-e][1,2]thiadin-3-carboxamide 1,1-dioxide

[0567] [ka]

[0568] Synthesis of 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidine-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-thieno[3,2-e][1,2]thiazin-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(pyridine-2-yl)-2H-thieno[3,2-e][1,2]thiadin-3-carboxamide 1,1-dioxide (tenoxicam, 98 mg, 0.292 mmol) and triphenylphosphine (PPh3, 230 mg, 0.876 mmol) are added to tetrahydrofuran (2 mL), stirred, and when cooled to -10°C, the mixture contains azodicarboxylic acid dioxide. Sopropyl (DIAD, 88 mg, 0.438 mmol) was added dropwise, and the mixture was stirred at -10°C for 20 minutes. After allowing it to rise naturally to room temperature, 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile (100 mg, 0.292 mmol) was added and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared (1 hour), the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.011 g of a yellow solid with a yield of 5.6%. MS(m / z):[M+H] + C 30 H 31 The calculated value for N9O5S2 is 662.19, and the measured value is 662.2. 1 H NMR(400MHz,DMSO-d6)δ 16.02(s,1H),8.63(t,J=10.2Hz,1H),8.38-8.23(m,2H),8.19-8.10(m,1H),8.06(dd,J=5.2,2 .2Hz,1H),7.75(dd,J=6.7,3.8Hz,1H),7.49(dd,J=5.2,1.8Hz,1H),7.25-7.17(m,1H),6.81-6 .63(m,3H),4.85(s,1H),4.19-3.88(m,3H),3.81-3.59(m,3H),3.27(d,J=3.8Hz,3H),2.99(d, J=2.0Hz,3H),2.41-2.33(m,1H),1.90-1.69(m,1H),1.63-1.56(m,1H),1.00(d,J=7.1Hz,3H).

[0569] (Example 147) 2-methyl-4-((4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide

[0570] [ka]

[0571] Synthesis of 2-methyl-4-((4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(pyridine-2-yl)-2H-benzo[e][1,2]thiadin-3-carboxamide 1,1-dioxide (piroxicam, 122 mg, 0.368 mmol) and triphenylphosphine (PPh3, 214 mg, 0.817 mmol) were added to tetrahydrofuran (3 mL) and stirred. Once the temperature dropped to -10°C, diisopropyl azodicarboxylic acid (DIAD, 124 mg, 0.613 mmol) was added dropwise to the mixture. After stirring at -10°C for 20 minutes and allowing it to rise naturally to room temperature, 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (150 mg, 0.409 mmol) was added and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared, the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.012 g of a yellow solid with a yield of 4.8%. MS(m / z):[M+H] + C 31 H 36 The calculated value for N8O6S2 is 681.22, and the measured value is 681.2.1 ¹H NMR (400MHz, chloroform-d)δ 15.31 (s, 1H), 8.59 (d, J=6.6Hz, 1H), 8.39 (d, J=9.1Hz, 1H), 8.32 (s, 1H), 8.10 (dd, J=7.7, 1.4Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=7.6, 1.4Hz, 1H), 7.77-7.61 (m, 3H), 6.85-6.65 (m, 2H), 6.55 (d, J= 3.8Hz,1H),5.40-5.31(m,2H),4.69(s,1H),3.19(s,3H),3.10(s,3H),2.95(d,J=6.2Hz,2H),2. 82(d,J=5.3Hz,3H),2.19-2.11(m,2H),2.02-1.94(m,1H),1.90-1.65(m,4H),1.37-1.27(m,2H).

[0572] (Example 148) 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-thieno[3,2-e][1,2]thiadin-3-carboxamide 1,1-dioxide

[0573] [ka]

[0574] Synthesis of 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidine-3-yl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methoxy)-2-methyl-N-(pyridine-2-yl)-2H-thieno[3,2-e][1,2]thiadin-3-carboxamide 1,1-dioxide Under nitrogen protection, 4-hydroxy-2-methyl-N-(pyridine-2-yl)-2H-thieno[3,2-e][1,2]thiadin-3-carboxamide 1,1-dioxide (tenoxicam, 75 mg, 0.224 mmol) and triphenylphosphine (PPh3, 196 mg, 0.748 mmol) are added to tetrahydrofuran (2 mL), stirred, and when cooled to -10°C, the mixture contains azodicarboxylic acid diiso Propylene glycol (DIAD, 75 mg, 0.374 mmol) was added dropwise, and the mixture was stirred at -10°C for 20 minutes. After allowing it to rise naturally to room temperature, 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)azetidine-3-yl)acetonitrile (100 mg, 0.249 mmol) was added and the mixture was continued to stir. The reaction was monitored by TLC. After the starting materials had completely disappeared, the solvent was evaporated under reduced pressure to obtain the crude product. Further separation by silica gel column chromatography (dichloromethane:acetonitrile = 20:1~9:1) yielded the target compound, which was 0.008 g of a yellow solid with a yield of 4.9%. MS(m / z):[M+H] + C 30 H 28 N 10 The calculated value for O6S3 was 721.14, and the measured value was 721.2. 1 H NMR(400MHz,chloroform-d)δ 13.45(s,1H),8.65(s,1H),8.46(s,1H),8.25(s,1H),8.18-8.08(m,2H) ,7.65-7.56(m,2H),7.44-7.31(m,2H),6.90(ddd,J=7.3,4.9,1.0Hz,1H ),6.60(d,J=3.7Hz,1H),6.17(s,2H),4.56(d,J=9.2Hz,2H),4.18(d,J= 9.2Hz,2H),3.35(s,2H),3.12-2.99(m,5H),1.35(td,J=7.5,3.8Hz,3H).

[0575] (Example 149) 2-methyl-4-((4-(methyl((trans)-4-((N-methylsulfamoyl...

Claims

1. The structure is as shown in general formula (I), A-Y-B(I) In the formula, A is a group obtained by removing a hydrogen atom from an amine compound having JAK inhibitory activity. Y is a direct connection, B is a carboxylic acid compound B containing a carboxyl group. １ It is a group formed by dehydration and acidification, Here, the structure of A-Y-B is as shown in general formula (II) or general formula (IIa), 【Chemistry 1】 In the formula, R １ is an unsubstituted or R ａ substituted pyrazolyl group or pyrrolyl group, or -N(CH ３ ), -Cy, R １ａ is a halogen-substituted C １ -C ６ alkylamine acyl group substituted and / or C １ -C ６ represents a pyrrole ring substituted by an alkyl group, Cy is unsubstituted or R ｂ A five-membered or six-membered carbon ring, a five-membered or six-membered nitrogen-containing heterocycle, and the R ａ and R ｂ Each of these is independently an acyl group, a sulfonyl group, a cyano group, an amino group, or C １ ~C ６ Alkyl-substituted amino groups, 4-membered, 5-membered, or 6-membered nitrogen-containing heterocyclic groups, and C １ ~C ６ It contains at least one or two groups selected from the group consisting of nitrogen-containing heterocyclic groups substituted with alkyl groups, R in general formula (II) and general formula (IIa) ２ Both are -B, i.e., carboxylic acid compound B １ Group B is formed by the elimination of a hydroxyl group from the original group. １ And R ４ -Ar-R ３ Selected from CO- Here, R ３ C １ ~C ６ Alkylene group, -NH-, R ５ NH- and C １ ~C ６ C substituted with an alkoxyamide group １ ~C ６ A group selected from the group consisting of alkylene groups, or directly connected, i.e., the Ar group is directly connected to -CO-, R ５ C １ ~C ６ It is an alkylene group, where the C １ ~C ６ The alkylene group may be substituted with a halogen. Ar is an aromatic ring group, R ４ is halogen, C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ C containing a cycloalkanoyl group １ ~C ６ Alkyl alkyl group, C １ ~C ６ Alkanamide group or aromatic condensed heterocyclic amide group, C １ ~C ６ Carbonyloxy group, halogen-substituted benzoyl group, C １ ~C ６ A phenoxy group substituted with an alkyl group or halogen, or unsubstituted, C １ ~C ６ A phenyl group or aromatic condensed heterocycle substituted with an alkyl group or halogen, or an unsubstituted phenyl group or aromatic condensed heterocycle, C １ ~C ６ A phenylamine group substituted with an alkyl group or halogen, or unsubstituted, or R ４ It is not necessary, and here, C １ ~C ６ A compound in which an alkoxy group may form a crosslinking ring with Ar, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

3. The aforementioned R ａ and R ｂ However, each independently comprises one of an acyl group and a sulfonyl group, and a cyano group, an amino group, or C. １ ~C ６ Alkyl-substituted amino groups, 4-membered, 5-membered, or 6-membered nitrogen-containing heterocyclic groups, and C １ ~C ６ A group composed of at least one group selected from the group consisting of nitrogen-containing heterocyclic groups substituted with alkyl groups, where the C １ ~C ６ The alkyl group may be substituted with a halogen. The compound described in claim 1, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

4. R ３ This refers to a methyl-substituted or unsubstituted methylene group, -C ２ H ４ -, or direct connection, Ar is a benzene ring, a naphthalene ring, or an aromatic heterocycle, and a halogen, C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Acyl group or C １ ~C ６ A benzene ring, naphthalene ring, or aromatic heterocycle or aromatic condensed heterocycle is selected from those substituted with one or more groups selected from alkoxy groups, where the aromatic heterocycle is a benzo-containing nitrogen or oxygen-containing heterocycle. The halogen is selected from fluorine, chlorine, and bromine, one or more of them. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

5. A- is a group obtained by removing a hydrogen atom from any amine compound selected from the following group of compounds: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib, and delgocitinib. 【Chemistry 2】 The compound described in claim 1, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

6. -B １ The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the group is one of the following carboxylic acid substances, namely ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid, and tolfenamic acid, from which a hydroxyl group has been removed. 【Transformation 3】

7. The compound according to claim 1, which is any of the following specific compounds, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】

8. The compound according to claim 7, which is any of the following specific compounds, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. 【Chemistry 10】

9. The compound according to claim 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, which is one of the following specific compounds. 【Chemistry 11】 【Chemistry 12】

10. The structure is as shown in general formula (I), A-Y-B(I) In the formula, A is a group obtained by removing a hydrogen atom from an amine compound having JAK inhibitory activity. Y is - (CH ２ )-O-, B is a carboxylic acid compound B containing a carboxyl group. １ It is a group formed by dehydration and acidification, Here, A- is a group obtained by removing a hydrogen atom from any amine compound selected from the following group of compounds: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib, and delgocitinib. 【Chemistry 13】 -B １ However, it is a group obtained by removing any hydroxyl group selected from the following group of carboxylic acid substances: ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid, and tolfenamic acid. 【Chemistry 14】 Here, the structure shown in general formula (I) is obtained by removing hydrogen from tofacitinib, and -B １ The following cases are not included: when ibuprofen or (S)-(+)-ibuprofen has had its hydroxyl group removed; when A- is ruxolitinib with hydrogen removed and -B1 is ibuprofen or (S)-(+)-ibuprofen with its hydroxyl group removed; and when A- is upadacitinib with hydrogen removed and -B1 is ibuprofen or (S)-(+)-ibuprofen with its hydroxyl group removed. Compounds, or their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

11. The compound according to claim 10, which is any of the following specific compounds, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】

12. The structure is as shown in general formula (I), A-Y-B(I) In the formula, A is a group obtained by removing a hydrogen atom from an amine compound having JAK inhibitory activity. Y is - (CH ２ ) - and B is a hydroxyl group-containing compound B ２ It is a group formed by the dehydrogenation of Here, the structure of A-Y-B is as shown in general formula (III) or general formula (IIIa), 【Chemistry 26】 wherein R １ is an unsubstituted or R ａ -substituted pyrazolyl or pyrrolyl group, or -N(CH ３ ), and R １ａ is a halogen-substituted C １ -C ６ alkylamine acyl group-substituted and / or C １ -C ６ represents a pyrrole ring substituted by an alkyl group, Cy is an unsubstituted or R ｂ -substituted 5- or 6-membered carbocyclic ring or 5- or 6-membered nitrogen-containing heterocyclic ring, and the R ａ and R ｂ each independently contain at least one or two groups selected from the group consisting of an acyl group, a sulfonyl group, a cyano group, an amino group, or a C １ -C ６ alkyl-substituted amino group, a 4-, 5- or 6-membered nitrogen-containing heterocyclic group, and a nitrogen-containing heterocyclic group substituted by a C １ -C ６ alkyl group, R in general formula (III) and general formula (IIIa) ２ ' is Y-B in all cases, and B is B ２ And here, the base-B ２ This is a hydroxyl group-containing compound B ２ It is a group formed by the dehydrogenation of, in this case Y- is -(CH ２ ) - and the above base - B ２ R ｃ -CO-NH-R ｄ And here, R ｃ This is either 4-hydroxybenzothiaidinedioxide-3-yl shown in the following structural formula (a) or 4-hydroxy-R shown in the following structural formula (b). ｅ This is a substituted thienothiazine dioxide-3-yl, where -CO-NH-R is located at the 3-position of the thiazine ring. ｄ It is connected, 【Chemistry 27】 Here, R ｄ This includes thiazole, isothiazole, oxazole, isoxazole, or pyridine, or those which are C １ ~C ６ A group substituted with an alkyl group or halogen, R ｅ C １ ~C ６ It is an alkyl group or halogen, and R in formula (b) ｅ The arrow next to it indicates that the substitution position in the thiophene ring can be any hydrogen atom connected to a carbon that can be substituted. Compounds, or their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

13. Cy is a substituted cyclohexyl group or a substituted piperidinyl group, the substituted cyclohexyl group is a substituted cyclohexyl group containing an amino group and a sulfonyl group, and the substituted piperidinyl group is a substituted piperidinyl group containing an acyl group or a sulfonyl group and -CN. The compound according to claim 12, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

14. The aforementioned R ａ and R ｂ However, each independently comprises one of an acyl group and a sulfonyl group, and a cyano group, an amino group, or C. １ ~C ６ Alkyl-substituted amino groups, 4-membered, 5-membered, or 6-membered nitrogen-containing heterocyclic groups, and C １ ~C ６ A group composed of at least one group selected from the group consisting of nitrogen-containing heterocyclic groups substituted with alkyl groups, where the C １ ~C ６ The alkyl group may be substituted with a halogen. The compound according to claim 12, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

15. R ｄ This is a thiazole, isoxazole, or unsubstituted pyridinyl group substituted with a methyl group, and the halogen is selected from the group consisting of fluorine, chlorine, and bromine, with one or more selected from that group. A compound according to any one of claims 12 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

16. In structural formula (a), the benzene ring is a halogen or C １ ~C ６ It may be substituted with an alkyl group, A compound according to any one of claims 12 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

17. -B ２ However, it is a group obtained by removing hydrogen from one of the following specific compounds containing a hydroxyl group, 【Chemistry 28】 The compound according to claim 12, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

18. A- is a group obtained by removing a hydrogen atom from any amine compound selected from the following group of compounds: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib, and delgocitinib. 【Chemistry 29】 The compound according to claim 12, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

19. It is one of the following specific compounds: The compound according to claim 12, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates. 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】

20. A method for producing a compound according to any one of claims 1 to 3, 5 to 9, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, comprising the step of obtaining a compound according to any one of claims 1 to 3, 5 to 9, by carrying out a condensation reaction in which A and B lose water in the presence of a catalyst and an organic solvent.

21. The catalyst is one or more of the following: EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N-carbonyldiimidazole), DMTMM (4-(4,6-dimethoxytriazine)-4-methylmorpholinium chloride), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HCTU (6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), and NPC. The manufacturing method according to claim 20.

22. The condensation reaction is carried out in the presence of a basic substance, where the basic substance is selected from one or more of DMAP (dimethylaminopyridine), triethylamine, DIPEA (N,N-diisopropylethylamine), and hydroxides or salts of sodium, potassium, lithium, and ammonium. The manufacturing method according to claim 21.

23. A-CH ２ A method for producing a compound according to any one of claims 10 to 14, 17 to 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, comprising the step of obtaining it by a condensation reaction using OH to lose B and water.

24. 2) Compound A-CH ２ It is obtained by a manufacturing method that includes the step of directly reacting -OH with the chloride acylide of B or compound B, Here, the compound A-CH ２ -OH is formed from amine compound A to compound A-CH ２ A method for producing a compound according to any one of claims 10 to 14, 17 to 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, prepared by step 1) forming an -OH group.

25. Step 1) is, (2-(chloromethoxy)ethyl)trimethylsilane is added to A and then A-CH is added in the presence of a catalyst and solvent. ２ O-C ２ H ４ -Si(CH ３ ) ３ a) to generate A-CH ２ O-C ２ H ４ -Si(CH ３ ) ３ From A-CH in the presence of a catalyst and solvent ２ Step 2) includes b) forming an OH group, and A-CH ２ OH is compound B １ Acyl chloride or compound B formed from ２ And it reacts directly to A-CH ２ The purpose is to form O-B. The manufacturing method according to claim 24.

26. In step b), the reaction takes place in the presence of TFA (trifluoroacetic acid) as a catalyst and DCM (dichloromethane) as a solvent, and in step 2), Et as a catalyst ３ A-CH in the presence of N (triethylamine) and DCM (dichloromethane) as a solvent ２ OH is compound B １ It reacts with acyl chloride formed from or as a catalyst with PPh ３ A-CH4 in the presence of (triphenylphosphine) and DIAD (diisopropyl azodicarboxylate) and THF (tetrahydrofuran) as a solvent. ２ OH is compound B ２ And they reacted, The manufacturing method according to claim 25.

27. Use of a compound according to any one of claims 1 to 3, 5 to 14, or 17 to 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, for the manufacture of an anti-inflammatory drug preparation or pharmaceutical composition.

28. An anti-inflammatory drug preparation or pharmaceutical composition containing a compound according to any one of claims 1 to 3, 5 to 14, or 17 to 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

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