RU2845845C2 - External anti-inflammatory drug based on compound obtained by coupling reaction, method for production thereof and use thereof - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to an anti-inflammatory compound or a pharmaceutically acceptable salt thereof, having a structure represented by general formula (I): AYB (I), where A is a group after dehydrogenation of an amino compound selected from the group consisting of any of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib, B is a group formed by dehydroxylation of a carboxy-containing compound of carboxylic acid B₁, or a group formed by dehydrogenation of hydroxy-containing compound B₂; and wherein when carboxylic acid B₁ is dehydroxylated to form a group, group Y is a direct bond or -(CH₂)-O-; when hydroxy-containing compound B₂ is dehydrated to form a group, group Y is -(CH₂)-, wherein the group formed by dehydroxylation of the carboxy-containing compound of carboxylic acid B₁ is a group after dehydroxylation of any of the carboxylic acid groups selected from the group consisting of the following groups: ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, ethodolac, actarite, indometacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid, wherein the group formed by dehydrogenation of the hydroxy-containing compound B₂, is a group obtained after dehydrogenation of a hydroxyl-containing compound of one of the following specific compounds:

methods for production and use thereof to produce external anti-inflammatory drugs means.

EFFECT: obtaining novel compounds which have special properties in form of a strong transdermal action, controlled drug release, high efficacy and can be used to produce external anti-inflammatory drugs.

14 cl, 5 dwg, 5 tbl, 149 ex

Description

Field of technology

The present invention relates to an external anti-inflammatory drug, and in particular to a drug based on a compound synthesized through a coupling reaction, and its use.

State of the art

The JAK-STAT signaling pathway is a newly discovered cytokine-stimulated signaling pathway involved in cell proliferation, differentiation, apoptosis, immune regulation, and other important biological processes. Many cytokines and growth factors, including IL (interleukins), GM-CSF (granulocyte/macrophage colony-stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PDGF (platelet-derived factor), and IFN (interferons), among others, signal through the JAK-STAT signaling pathway. The JAK-STAT signaling pathway consists of three components: a receptor tyrosine kinase-associated protein (JAK), and a transcription factor (STAT). When a ligand binds to a receptor tyrosine kinase, the JAK associated with it is activated. The activated JAK further activates the corresponding STAT protein. The activated STAT protein enters the nucleus, binds to the target gene, and regulates the transcription of that gene. The JAK family includes JAK1, JAK2, JAK3, and TYK2. These kinases control seven different STATs, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. It is by controlling these STATs that cytokines and growth factors can control cell proliferation, differentiation, apoptosis, and immune regulation. Many diseases arise due to mutations in JAKs and STATs. These diseases can be effectively treated by modulating and selectively inhibiting certain JAKs.

Although JAK-STAT is a relatively simple signaling pathway, it is involved in many cellular functions. Currently, dozens of JAK inhibitors are commercially available and under investigation. The vast majority of JAK inhibitor programs aim to maximize efficacy and minimize side effects by selectively inhibiting one component of the JAK-STAT signaling pathway. However, systemic administration often fails to overcome the trade-off between efficacy and side effects. Local administration of JAK inhibitors can improve efficacy while reducing systemic side effects. Many of the JAK inhibitors under investigation also exhibit organ selectivity, ultimately helping to maximize the efficacy/risk ratio.

Another object of the present invention is to maximize the therapeutic effect of dermal administration and minimize systemic toxicity by local (dermal) administration in combination with optimization of the compound structure. There is a clear understanding of the causes and mechanisms of treatment of many skin diseases, including psoriasis, vitiligo, focal alopecia, etc. In addition, the regulatory and control mechanisms of various JAK-STAT inhibitors of JAK currently available on the market and undergoing research are well understood. The goals of selective dermal administration can also be achieved by changing the chemical structure of currently known JAK inhibitors, improving their penetration through the protective layer of the skin. Compared with the development of a skin-selective drug delivery formulation based on a completely new compound, a product containing a known compound with an optimized structure is characterized by a relatively short development cycle, a low risk of inefficiency, a low probability of developing unknown toxicity and a low cost of development. Optimization of the structure of a compound by increasing the skin penetration ability of the compound can change the physical and chemical properties of the compound by adding non-functional groups to the known structure of the compound, which enhances its ability to penetrate the protective layer of the skin. This technology is also known as prodrug technology. It is widely used in drug research and development.

Brief description of the invention

The present invention addresses the technical problem that existing known JAK inhibitors are also characterized by high doses and side effects, and optimizes the structure of known JAK-active compounds, effectively providing the possibility of their administration selectively with respect to the skin, thereby increasing their effectiveness in skin diseases and reducing the systemic dose and side effects. Thus, structural optimization and selective administration of known JAK inhibitors are achieved by combining them with other low-molecular compounds.

In particular, the present invention proposes the following technical solutions:

1. Depending on the structure of various JAK inhibitor compounds, specific linkers and low molecular weight attachments are selected to allow the final compound (prodrug) to more effectively penetrate the protective layer of the skin.

2. The chemical bond between the linker and the JAK inhibitor is unstable in human skin, resulting in hydrolysis and release of the active substances known as JAK inhibitors.

3. The bond between the linker and the attached low molecular weight compound is also unstable, which leads to the release of the attached low molecular weight compound.

4. It is known that the linker itself is a simple chemical structure that is not toxic.

5. The chemical structure of the attached low molecular weight compounds, their pharmacology and toxicology are known.

In particular, the present invention provides the following technical solutions. In one aspect, the present invention provides an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, having a structure represented in the general formula (I):

where A is a group after dehydrogenation of an amino compound having inhibitory activity against JAK;

Y represents a direct bond or -(CH ₂ )-O- or -(CH ₂ )-;

B is a group formed by dehydroxylation of a carboxylic acid compound _B1 , or a group formed by dehydrogenation of a hydroxy compound Br; wherein when the carboxylic acid Bi is dehydroxylated to form a group, the Y group is a direct bond or -(CH2)-0-; when the hydroxy compound _B2 is dehydrogenated to form a group (i.e. B is _B2 ), the Y group is -( _CH2 )-.

In a specific embodiment, the anti-inflammatory compound or stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof described above has a structure as represented in general formulae (II) or (IIa):

where R ₁ is selected from pyrazolyl or pyrrolyl, unsubstituted or substituted by groups R _a ; or -N(CH ₃ )-Cy, R _1a is a pyrrole ring substituted by a halogen-substituted C ₁ -C ₆ -alkylaminoacyl group and/or a C ₁ -C ₆ -alkyl group;

C _y is a five- or six-membered carbocyclic ring or a five- or six-membered nitrogen-containing heterocyclic ring, unsubstituted or substituted by a group R _b ; each of the groups of _Ra and R _b independently represent groups containing 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 C ₁ -C ₆ alkyl-substituted amino group and a four-, five- or six-membered nitrogen-containing heterocyclic group or a nitrogen-containing heterocyclic group substituted by C ₁ -C ₆ alkyl; each of the groups R _a and R _b is preferably independently a group that consists of one acyl or dithioacyl group and at least one group selected from the group consisting of a piano, amino or C ₁ -C ₆ alkyl-substituted amino group and a four-, five- or six-membered nitrogen-containing heterocyclyl or a nitrogen-containing heterocyclyl group substituted by C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ alkyl is substituted by a halogen atom. Thus, each of the groups R _a and R _b herein is independently preferably a group that contains at least one acyl or dithioacyl-containing group and at least one group containing a nitrogen atom; R ₂ in both general formulae (II) and (IIa) is -B, i.e. a group formed by dehydroxylation of a carboxy-containing compound B ₁ , which is a carboxylic acid, and is selected from R ₄ -Ar-R ₃ -CO-,

wherein R ₃ is selected from C ₁ -C ₆ -alkylene; -NH-, R ₅ NH- or C ₁ -C ₆ -alkylene substituted by a C ₁ -C ₆ alkoxyamide group; or a direct bond, i.e. the Ar group is directly bonded to -CO-; R ₃ is preferably methyl substituted or unsubstituted methylene, -C ₂ H ₄ - or a direct bond; R ₅ is C ₁ -C ₆ -alkylene; said C ₁ -C ₆ -alkylene optionally being substituted by a halogen atom (the halogen atom is preferably one or two or more atoms selected from the group consisting of fluorine, chlorine or bromine atoms);

Ar is an aromatic ring group, preferably selected from a benzene ring; a naphthalene ring or an aryl heterocyclic ring; a benzene ring, a naphthalene ring or an aryl heterocyclic ring or an aryl fused heterocyclic ring (in this case, the aryl heterocyclic ring is preferably a nitrogen-containing or oxygen-containing benzoheterocyclic ring, for example, a benzopyrrole ring), substituted with one or more groups selected from a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ acyl group or a C ₁ -C ₆ alkoxy group; In a more preferred case, Ar is an aryl heterocyclic ring containing a nitrogen atom; and

R ₄ is a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl containing a C ₁ -C ₆ cycloalkanoyl, a C ₁ -C ₆ alkylamido or aryl fused heterocyclic amido group, a C ₁ -C ₆ carbonyloxy group, a halo-substituted benzoyl, a C ₁ -C ₆ alkyl- or halogen-substituted or unsubstituted phenoxy group, a C ₁ -C ₆ alkyl- or halogen-substituted or unsubstituted phenyl or aryl fused heterocyclic ring, a C ₁ -C ₆ alkyl- or halogen-substituted or unsubstituted phenylamino group, or R4 may be absent; wherein the C ₁ -C ₆ alkoxy group may also form a bridging ring with Ar.

In a particular embodiment, there is provided an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, as described above in the present invention, wherein Cy is a substituted cyclohexyl or substituted piperidinyl group, the substituted cyclohexyl group is preferably a cyclohexyl group substituted with an amino group and a dithio group, and the substituted piperidinyl group is a piperidinyl group substituted with an acyl group or a dithio group, and -CN.

The compound or its stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate according to the present invention is preferably a composite compound obtained by a condensation reaction of an amino compound A with a carboxylic acid compound B ₁ .

Preferably, there is provided a compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof as described above in the present invention, wherein A- is a group obtained after dehydrogenation of an amino compound selected from the group consisting of any of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:

A preferably represents a group formed after dehydrogenation of tofacitinib, ruxolitinib and baricitinib.

In a preferred case, an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention is provided, wherein -B ₁ is a group after dehydroxylation of a carboxylic acid group selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylhaicin, aspirin, indobufen, mefenamic acid and tolfenamic acid:

More preferably, an anti-inflammatory compound or a stereoisomer, tautomer, N-oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the present invention is provided, wherein said compound is a composite compound obtained by a condensation reaction of an amino compound A selected from the group consisting of tofacitinib, baricitinib, upadacitinib, oclacitinib and ruxolitinib with a carboxylic acid compound B ₁ selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin; the amino compound is preferably tofacitinib, ruxolitinib and baricitinib.

More preferably, an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention is provided, said compound being any of the following specific compounds:

More preferably, an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention is provided, said compound being any of the following specific compounds:

Furthermore, preferably an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention is provided, said compound being one of the following specific compounds:

In yet another scheme according to the present invention, there is provided an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, having a structure presented in the general formula (III):

where R ₁ has the same meaning as R ₁ in the general formula (II); R _1a has the same meaning as R ₁ a in the formula (IIa);

R2' in both formula (III) and formula (IIIa) is YB, B is B ₁ in formula (II) or (IIa), or B is B ₂ ; wherein the group -B ₁ is a group formed by dehydroxylation of a carboxylic acid compound B ₁ , and Y- is (CH ₂ )-O-; the group -B ₂ is a group formed by dehydrogenation of a hydroxyl-containing compound B ₂ , and Y- is -(CH ₂ )-; the group -B ₁ has the same meaning as the group R ₂ in formula (II) or in formula (IIa); group - B ₂ represents R _c -CO-NH-R _d , where R _c represents 4-hydroxybenzothiazine-3-yl dioxide represented by the following structural formula (a) (wherein the phenyl ring may be substituted with a halogen atom or C ₁ -C ₆ alkyl), or 4-hydroxy-Re substituted thienothiazine-3-yl dioxide represented by the following structural formula (b), where -CO-NH-R _d is attached at the 3-position of the thiazine ring,

wherein R _a is thiazole, isothiazole, oxazole, isoxazole or pyridine or a group thereof substituted by C ₁ -C ₆ alkyl or a halogen atom, preferably thiazole or isoxazole substituted by a methyl group; and unsubstituted pyridyl; R _e is C ₁ -C ₆ alkyl or a halogen atom (the halogen atom is preferably one or two or more atoms selected from the group consisting of fluorine, chlorine or bromine atoms); the arrow next to Re in formula (b) indicates that its position in the thiophene ring may be any carbon-bonded hydrogen atom capable of being substituted.

More specifically, there is provided an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention, wherein -B ₁ is a group obtained after dehydroxylation of a carboxylic acid group selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:

-B ₂ is a group obtained after dehydrogenation of a hydroxyl-containing compound of one of the following specific compounds:

Furthermore, more specifically, there is provided an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention, obtained by a method comprising the steps of:

2) the interaction of compound A- _CH2 -OH with acyl chloride B or directly with compound B;

wherein the compound A- _CH2 -OH is preferably obtained by the following step 1): reaction of the amino compound A to form the compound A- _CH2 -OH.

More specifically, there is provided an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof as described above, wherein A- is a group obtained after dehydrogenation of an amino compound selected from the group consisting of any of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:

A preferably represents a group formed after dehydrogenation of tofacitinib, ruxolitinib and baricitinib.

In some embodiments, A is preferably a group formed by any one of baricitinib, oclacitinib, or upadacitinib.

Furthermore, more specifically, an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof as described above is provided, wherein said compound is any of the following specific compounds:

On the other hand, the present invention also provides a method for producing an anti-inflammatory compound or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof according to the present invention, comprising the steps of:

subjecting A and B to a condensation reaction accompanied by loss of water in the presence of a catalyst and an organic solvent.

For the production method according to the present invention, the catalyst is preferably one or two or more of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N-carbonyldiimidazole), DMTMM (4-(4,6-dimethoxytriazine)-4-methylmorpholine hydrochloride), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HCTU (6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazole-1-hydroxytripyrrolidinophosphonium hexafluorophosphate) and NPC; the organic solvent is preferably one or two or more solvents selected from the group consisting of DCM (dichloromethane), DMF (dimethylformamide), petroleum ether, acetone, chloroform, ethyl acetate, acetonitrile and THF (tetrahydrofuran), more preferably dichloromethane and/or dimethylformamide; furthermore, the reaction is preferably carried out in the presence of a basic substance, said basic substance being preferably one or two or more substances selected from the group consisting of DMAP (dimethylaminopyridine), triethylamine, DIPEA (N,N-diisopropylethylamine) and hydroxides or salts of sodium, potassium, lithium and ammonium. The method for producing an anti-inflammatory compound or its stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate according to the present invention preferably includes the steps in which A- _CH2OH and B are subjected to a condensation reaction with loss of water.

Preferably, a method for producing an anti-inflammatory compound or its stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate according to the present invention is provided, obtained by a method comprising the steps of:

2) the interaction of compound A- _CH2 -OH with acyl chloride B or directly with compound B;

wherein the compound A- _CH2 -OH is preferably obtained in the following step 1): reacting an amine-containing compound A to form a compound A- _CH2 -OH. More preferably, for the production process according to the present invention, wherein step 1) comprises: a) adding (2-(chloromethoxy)ethyl)trimethylsilane to A in the presence of a catalyst and a solvent to form A- _{CH2O -C2H4 -} Si( _CH3 ) ₃ ; and b) obtaining A-CH2OH from A- _CH2O - _C2H4 -Si( _CH3 ) ₃ in the presence of a catalyst and _a solvent, step 2) comprises: reacting A- _CH2OH with the acid chloride obtained from compound _B1 or directly with compound Br to form A- _CH2O -B;

wherein preferably in step b) the reaction is carried out in the presence of TFA (trifluoroacetic acid) as a catalyst and DCM (dichloromethane) as a solvent; or in step 2) A- _CH2OH is reacted with the acid chloride obtained from compound _B1 in the presence of _Et3N (triethylamine) as a catalyst and DCM (dichloromethane) as a solvent, or is reacted with compound _B2 in the presence of PPH3 (triphenylphosphine) and DIAD (diisopropyl azodicarboxylate) as a catalyst and THF (tetrahydrofuran) as a solvent.

In addition, the present invention provides a medicinal use, i.e., it provides the use of said anti-inflammatory compound or its stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate in the preparation of anti-inflammatory drugs or medicinal compositions (preferably external medicinal compositions).

In addition, the present invention also provides an anti-inflammatory drug or drug composition (preferably external drug compositions) containing said anti-inflammatory compound or its stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate described above.

It has been found that by synthesizing the above compounds, the compounds according to the present invention have a dissolution rate of 0.04% to 50% per day, which increases the transdermal potential of known JAK inhibitors.

Brief description of the drawings

Fig. 1 is a graph of the PASI evaluation of the ointment prepared from CPD-029 according to the present invention by application to the skin for the treatment of psoriasis in a mouse model test;

Fig. 2 is a graph of the PASI evaluation of the ointment prepared from CPD-028 according to the present invention by application to the skin for the treatment of psoriasis in a mouse model test;

Fig. 3 is a graph of the PASI evaluation of the ointment prepared from CPD-027 according to the present invention by application to the skin for the treatment of psoriasis in a mouse model test;

Fig. 4 is a graph of the PASI evaluation of the ointment prepared from CPD-017 according to the present invention by application to the skin for the treatment of psoriasis in a mouse model test; and

Fig. 5 is a graph of the PASI evaluation of the ointment prepared from CPD-002 according to the present invention by application to the skin for the treatment of psoriasis in a mouse model test.

Detailed description of the invention

As a result of intensive studies, the present inventors unexpectedly found that a combination of an anti-inflammatory pharmaceutical compound containing a carboxylic acid group or a hydroxyl group with a JAK inhibitor compound to form a composite compound containing an acyloxy group and/or a methoxy group has a significant therapeutic effect and a special effect of controlled-release pharmaceutical activity.

The anti-inflammatory compound or its stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate provided in the present invention has a structure represented in the general formula (I):

where A is a group after dehydrogenation of an amino compound having inhibitory activity against JAK;

Y represents a direct bond or -(CH ₂ )-O-;

B is a group formed by dehydroxylation of the carboxylic acid compound B ₁ with anti-inflammatory action, or a group formed by dehydrogenation of the hydroxy-containing compound B ₂ .

In other words, the compounds of general formula (I) proposed in the present invention actually include two main classes. The first main class refers to the case where A is a direct bond and its structural formula corresponds to the formula shown in (II) or (IIa).

where R ₁ is selected from pyrazolyl or -N(CH ₃ )-Cy, unsubstituted or substituted by the Ra group;

R _1a represents a pyrrole ring substituted with a halogen-substituted C ₁ -C ₆ -alkylaminoacyl group and/or a C ₁ -C ₆ -alkyl group;

Cy is a five- or six-membered carbocyclic ring or a five- or six-membered nitrogen-containing heterocyclic ring, unsubstituted or substituted by a group R _b ; each of the groups _Ra and R _b independently represents at least one or two groups containing an acyl group, a dithioyl group, a cyano group, an amino group or a C ₁ -C ₆ alkyl-substituted amino group, each of the groups _Ra and R _b preferably independently represents one of an acyl or dithioacyl group and at least one group selected from a cyano group, an amino group or a C ₁ -C ₆ alkyl-substituted amino group, wherein C ₁ -C ₆ alkyl may be substituted by a halogen atom;

R ₂ in both general formulae (II) and (IIa) represents -B, i.e. a group formed by dehydroxylation of a carboxy-containing compound B ₁ , which is a carboxylic acid, and is selected from R4-Ar-R ₃ -CO-,

wherein R ₃ is selected from C ₁ -C ₄ alkylene; -NH-, R5NH- or C ₁ -C ₆ alkylene substituted by a C ₁ -C ₆ alkoxyamide group; or a direct bond, i.e. the Ar group is directly bonded to -CO-; R ₃ is preferably methyl substituted or unsubstituted methylene, -C ₂ H ₄ - or a direct bond; R ₅ is C ₁ -C ₆ alkylene; wherein said C ₁ -C ₆ alkylene may be substituted by a halogen atom (preferably the halogen atom is selected from one or two or more of fluorine, chlorine or bromine atoms);

Ar is an aromatic ring group, preferably selected from a benzene ring; a naphthalene ring or an aryl heterocyclic ring; and a benzene ring, a naphthalene ring or an aryl heterocyclic ring or an aryl fused heterocyclic ring (in this case, the aryl heterocyclic ring is preferably a nitrogen- or oxygen-containing benzoheterocyclic ring, for example, a benzopyrrole ring) substituted with a group selected from a halogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a _C1 - _C6 acyl group or a _C1 - _C6 alkoxy group; More preferably, Ar is an aryl heterocyclic ring containing a nitrogen atom; and R ₆ represents a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ cycloalkanoyl-containing C ₁ -C ₆ alkyl;

or R ₆ is C ₁ -C ₆ alkyl or an aromatic fused ring or an aromatic fused heterocyclic ring containing acyl and/or amino groups, for example, a C ₁ -C ₆ alkylamido group or an aryl fused heterocyclic amido group, a C ₁ -C ₆ carbonyloxy group, a halogenated benzoyl group, a C ₁ -C ₆ alkyl- or halogenated or unsubstituted phenoxy group, a C ₁ -C ₆ alkyl- or halogenated or unsubstituted phenyl or aryl fused heterocyclic ring, a C ₁ -C ₆ alkyl- or halogenated or unsubstituted phenylamino group, or R ₆ may be absent; wherein the C ₁ -C ₆ alkoxy group may also form a bridging ring with Ar.

The above terms in the present invention, as well as all "C ₁ -C ₆ " mentioned below, refer to a carbon number of 1-6. For example, "C ₁ -C ₆ alkyl" refers to an alkyl group having 1-6 carbon atoms. Similarly, the terms "C ₁ -C ₆ alkoxy group" and "C ₁ -C ₆ acyl" mentioned herein refer to alkoxy groups having 1-6 carbon atoms and groups having 1-6 carbon atoms containing -C=O, respectively. "C ₁ -C ₆ alkylamide group" refers to an alkyl group containing amide groups having 1-6 carbon atoms. "C ₁ -C ₆ carboacyloxy group" refers to an alkyl group or ring o of an alkyl group containing an acyloxy group -CO-O, having 1-6 carbon atoms. " _C1 - _C6 cycloalkanolyl group" refers to a cyclic alkyl group containing a -C=O group and having 1 to 6 carbon atoms. The term " _C1 - _C6 alkyl group containing a _C1 - _C6 cycloalkanoyl group" refers to a situation where the hydrogen atoms at the carbon atoms are substituted with _C1 - _C6 cycloalkanoyl groups in the alkyl group having 1 to 6 carbon atoms, i.e. " _C1 - _C6 alkyl group containing a _C1 - _C6 cycloalkanoyl group" is equivalent to "a _C1 - _C6 alkyl group substituted with a _C1 - _C6 cycloalkanoyl group". "C ₁ -C ₆ " in the present invention may, in particular, be "C ₁ -C ₆ ", "C1-C5", "C1-C4", "C1-C3" or "C1-C2", and may also be C1, i.e. only one carbon atom.

The first general compound described above is a compound A-B (particularly AB ₁ ) formed by dehydrogenating an amino compound A having JAK inhibitory activity and dehydroxylating a carboxylic acid compound B ₁ . The compound of general formula (I) provided in the present invention includes a second main class of compound having the structural formula and structure shown in general formula (III):

where R ₁ has the same meaning as R ₁ in the general formula (II); R _1a has the same meaning as R ₁ a in the formula (IIa);

R ₂ ' in both the general formula (III) and the general formula (IIIa) are -YB, where Y is -(CH ₂ )-O-, and B is -B ₁ in the general formula (II) or (IIa), i.e. a group -B1 formed by dehydroxylation of a carboxylic acid compound B ₁ ; or B is -B ₂ , the group -B ₂ is R _c -CO-NH-R _d , where R _c is 4-hydroxybenzothiazine-3-dioxide represented by the following structural formula (a), wherein the phenyl ring may be substituted with a halogen atom or C ₁ -C ₄ alkyl, or 4-hydroxy-Re-substituted thienothiazine-3-dioxide represented by the following structural formula (b), wherein -CO-NH-R _d is attached to the 3-position of the thiazine ring,

wherein R _d is thiazole, isothiazole, oxazole, isoxazole or pyridine or a group thereof substituted by C ₁ -C ₆ alkyl or a halogen atom, preferably thiazole or isoxazole substituted by a methyl group; and unsubstituted pyridyl; R _e is C ₁ -C ₆ alkyl or a halogen atom (the halogen atom is preferably selected from one or two atoms or more of fluorine, chlorine or bromine atoms); the arrow next to R _e in formula (b) indicates that its substitution position on the thiophene ring may be any hydrogen atom bonded to a carbon atom capable of undergoing substitution.

The second main compound according to the present invention is obtained using A- _CH2OH , subjected to a condensation reaction with B, accompanied by a loss of water. In particular, the preparation of the second main class of compound includes the following steps:

2) the reaction of compound A- _CH2 -OH with acyl chloride B or directly with compound B; wherein compound A- _CH2 -OH is obtained in step 1): reaction of A with the formation of compound A- _CH2 -OH.

The concept of the compound of the general formula (I) according to the present invention also actually includes its various stereoisomers, tautomers, N-oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates, which can be obtained by those skilled in the art according to the generally known information, in other words, these compounds and the various stereoisomers, tautomers, N-oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates and the like, which can be modified by those skilled in the art according to the generally known information, can be used in the present invention to achieve the specific effects of the compounds according to the present invention, such as effective transdermal characteristics, controlled drug release and high efficiency, and,

therefore, all of them fall within the scope of the present invention.

Examples

The following is an example illustrating a method for preparing a compound according to the present invention and evaluating its characteristics.

The NMR and mass spectrometer models used in Examples 1-149 below are described below, respectively:

Nuclear Magnetic Resonance Spectrometer: Bruker 400M Nuclear Magnetic Resonance Instrument; Liquid Chromatography/Mass Spectrometry Instrument: Agilent InfinityLab LC/MSD iQ

Table 1 below presents the structural formula and name of the target compound obtained in each example.

Example 1

3-((3R,4R)-3-((7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol) and 2-(4-isobutylphenyl)propanoic acid (ibuprofen, 412 mg, 2 mmol) were dissolved in dichloromethane (20 mL). 4-Dimethylaminopyridine (DMAP, 134 mg, 1.1 mmol) and dicyclohexylcarbodiimide (DCC, 412 mg, 2 mmol) were added in an ice bath, followed by stirring under reflux for 16 h. After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to _give the title compound as _a white solid, 0.292 g, 58% yield. MS (m/z): [M+H] ⁺ calculated for _C29H36N6O2 , _501.65 ; found, 501.2. ^1H NMR (400 MHz, chloroform-d) δ 8.39 (d, J=7.3 Hz, 1H), 7.68 (dd, J=15.2, 4.2 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.08 - 7.03 (m, 2H), 6.61 (t, J=4.2 Hz, 1H), 6.13 (tt, J=7.3, 3.5 Hz, 1H), 5.09 (s, 1H), 4.09 - 3.70 (m, 2H), 3.66 - 3.44 (m, 4H), 3.33 (d, J=16.4 Hz, 3H), 2.39 (d, J=7.2 Hz, 3H), 1.88 - 1.70 (m, 2H), 1.67 - 1.60 (m, 4H), 1.15 - 1.03 (m, 3H), 0.86 (d, J=6.6 Hz, 6H).

Example 2

3-((3R,4R)-3-((7-((S)-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-((S)-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-l-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol) and S)-(+)-2-(4-isobutylphenyl)propanoic acid ((S)-(+)-ibuprofen, 309 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). 4-Dimethylaminopyridine (DMAP, 134 mg, 1.1 mmol) and dicyclohexylcarbodiimide (DCC, 412 mg, 2 mmol) were added in an ice bath, followed by stirring under reflux for 16 h. After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography ₍ petroleum ether/ethyl acetate = 5:1 to 2:1) to give the title compound as a _white solid, 0.24 g, 48% yield. MS (m/z): [M+H] ⁺ calculated for _C29H36N6O2 , _501.65 ; found, 501.2. ¹ H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=4.6 Hz, 1H), 7.68 (dd, J=4.3, 2.8 Hz, 1H), 7.29 (dd, J=8.2, 2.6 Hz, 2H), 7.06 (d, J=7.9 Hz, 2H), 6.88 (d, J=4.2 Hz, 1H), 6.09 (qd, J=6.7, 3.0 Hz, 1H), 4.85 (s, 1H), 4.18 3.59 (m, 5H), 3.41 (q, J=5.3, 4.9 Hz, 1H), 3.24 (d, J=2.4 Hz, 3H), 2.36 (d, J=7.2 Hz, 3H), 1.87 - 1.65 (m, 2H), 1.63 - 1.48 (m, 4H), 1.00 (dd, J=7.2, 2.6 Hz, 3H), 0.81 (d, J=6.6 Hz, 6H).

Example 3

(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-(S)-2-(4-isobutylphenyl)propanoate

First step: synthesis of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[23-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-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) under nitrogen protection. After stirring at room temperature for half an hour, (2-(chloromethoxy)ethyl)trimethylsilane (4.8 g, 28.81 mmol) was added and stirring was continued at room temperature overnight. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by column chromatography on silica gel _to give the title compound as a white solid, 9 g, 71% yield. MS (m/z): [M+ _H ] ⁺ calculated for _C22H34N6O2Si , _443.25 ; found, 443.2. Second step: synthesis of 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2.3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

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]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (5 g, 11.3 mmol) in dichloromethane (100 mL) under nitrogen protection in an ice-water bath. After half an hour, the ice-water bath was removed, the temperature was raised to room temperature and stirring was continued for 24 hours. To the above reaction solution, saturated sodium bicarbonate solution was added at 0 °C to adjust the pH to 8. Then, the mixture was poured into a separatory funnel and separated. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title product in an amount of 3.5 g, 90% yield. MS (m/z): [M+H] ⁺ calculated for C ₁₇ H ₂₂ N ₆ O ₂ , 343.18; found, 343.1. Third step: synthesis of (4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(4-isobutylphenyl)propanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-(1]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (6.63 g, 19.4 mmol), (S)-2-(4-isobutylphenyl)propanoyl chloride (8.72 g, 38.8 mmol) and triethylamine (3.93 g, 38.8 mmol) were dissolved in dichloromethane (100 mL). After stirring at room temperature for 24 h, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by column chromatography on silica gel (petroleum ether/ethyl acetate = 2:1 to 1:1) to give the title compound, 4.05 g, 39.4% yield. MS (m/z): _[ M ₊ H] ⁺ calculated for _C30H38N6O3 , 531.67; found, 531.2. ¹ H NMR (400 MHz, _CDCl3 ) δ 8.32 (d, J=7.4 Hz, 1H), 7.11 (dd, _J =12.7, 5.5 Hz, 3H), 7.03 (d, J=7.6 Hz, 2H), 6.51 (s, 1H), 6.18 (dd, J=10.4, 4.0 Hz, 1H), 6.14 - 6.06 (m, 1H), 5.13 (s, 1H), 4.06 (dd, J=13.2, 3.8 Hz, 1H), 3.81 (dd, J=18.3, 10.5 Hz, 1H), 3.69 (k, J=7.1 Hz, 1H), 3.61 (t, J=11.8 Hz, 1H), 3.55 - 3.47 (m, 2H), 3.37 (d, J=17.9 Hz, 3H), 2.58 - 2.46 (m, 1H), 2.42 (d, J=7.1 Hz, 2H), 2.05 - 1.91 (m, 1H), 1.83 (td, J=13.0, 6.2 Hz, 2H), 1.45 (d, J=7.1 Hz, 3H), 1.28 (s, 1H), 1.09 (dd, J=12.9, 7.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 6H).

Example 4

3-((3R,4R)-3-((7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a yellow solid, 0.1 g, 18.6% yield. MS (m/z): [M+H] ⁺ calcd for _C31H33N7O2 , _536.65 ; found, 536.2. ¹ H NMR (400 MHz, DMSO) δ 8.60 (d, J=16.4 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.35 (dt, J=17.9, 8.5 Hz, 2H), 7.06 (d, J=6.2 Hz, 2H), 6.98 (s, 1H), 6.87 (t, J=12.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.73 (t, J=7.4 Hz, 1H), 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=5.3 Hz, 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=6.9 Hz, 3H).

Example 5

3-((3R,4R)-3-((7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-l-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-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 (EBCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) _to give the title compound as _a yellow solid, 0.12 g, 35.9% yield. MS (m/z): [M+H] ⁺ calcd for _C30H30ClN7O2 , _557.07 ; found, 557.2. ¹ H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J=17.2 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.46 (ddd, J=8.6, 7.1, 1.6 Hz, 1H), 7.43-7.34 (m, 2H), 7.07 (tk, J=7.0, 4.8, 3.6 Hz, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 6.84 (d, J=4.1 Hz, 1H), 4.84 (s, 1H), 4.19-3.90 (m, 3H), 3.74 (dtd, J=34.8, 14.2, 13.1, 7.4 Hz, 2H), 3.50-3.39 (m, 1H), 3.29-3.21 (m, 3H), 2.46-2.32 (m, 1H), 2.06 (d, J=8.5 Hz, 3H), 1.92-1.66 (m, 1H), 1.64-1.51 (m, 1H), 1.03 (d, J=7.1 Hz, 3H).

Example 6

3-((3R,4R)-3-((7-((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-l-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-l-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to give the title compound as a _white solid, 0.7 g, 66.8% yield. MS (m/z): [M+H] ⁺ calculated for _C30H32N6O3 , _525.63 ; found, _525.3 . ¹ H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.81 - 7.69 (m, 4H), 7.50 (dd, J=7.0, 5.3 Hz, 1H), 7.24 (s, 1H), 7.12 (dd, J=8.9, 2.3 Hz, 1H), 6.88 (d, J=3.7 Hz, 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=13.3 Hz, 1H), 1.83 -1.49 (m, 5H), 0.99 (d, J=7.1 Hz, 3H)

Example 7

3-((3R,4R)-3-((7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2) to give the title compound as a _white solid, 0.73 g, 66.6% yield. MS (m/z): [M+H] ⁺ calculated for _C32H33N6O3 , _549.65 ; found, _549.3 . ¹ H NMR (400 MHz, DMSO) δ 8.33 (d, J=7.4 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.76-7.63 (m, 5H), 7.61 (d, J=7.8 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J=7.7Hr, 1H), 6.94 (d, J=3.8 Hz, 1H), 6.16 (q, J=6.8 Hz, 1H), 4.85 (s, 1H), 4.14 - 3.90 (m, 3H), 3.83 - 3.60 (m, 2H), 3.46 - 3.39 (m, 1H), 3.26 (s, 3H), 2.44 - 2.29 (m, 1H), 1.90 - 1.68 (m, 1H), 1.67-1.51 (m, 4H), 1.02 (t, J=9.4 Hz, 3H).

Example 8

3-((3R,4R)-3-((7-(2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-(2-(2-fluoro-[1,D-diphenyl]-4-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)(methyl)amino)-4-methylpiperidin- 1-yl)-3-oxopropanenitrile 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-(1]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2-fluoro-4-diphenyl)propanoic acid (flurbiprofen, 537 mg, 2.2 mmol) and 1-(3-dimethylamino) hydrochloride (propyl)-3-ethylcarbodiimide (EDCI, 576 mg, 3 mmol) was dissolved in dichloromethane (20 mL) and stirred at room temperature for 24 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to give the title compound as _{a white} solid, 0.73 g, 67.8% yield. MS (m/z): [M+H] ⁺ calculated for _C31H31FN6O2 , _539.63 ; found, 539.2. ^1H NMR (400 MHz, DMSO) δ 8.41 (dd, J=5.7, 1.3 Hz, 1H), 7.72 (d, J=4.2 Hz, 1H), 7.54 - 7.43 (m, 5H), 7.41 - 7.27 (m, 3H), 6.93 (s, 1H), 6.16 (k, J=6.7 Hz, 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).

Example 9

3-((3R,4R)-3-((7-(2-(2-(2-(2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-l-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-(2-(2-(2-(2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-l-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1: ₂ ) to give the title compound as a _white solid, 0.25 g, 21.2% yield. MS (m/z): [M+H] ⁺ calculated for _{C30H29Cl2N7O2} , _590.51 ; found, _590.2 . ¹ H NMR (400 MHz, DMSO) δ 8.41 (d, J=5.9 Hz, 1H), 7.75 (d, J=4.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.35 (d, J=12.7 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.07 (t, J=7.7 Hz, 1H), 6.96 (d, J=3.8 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 6.22 (d, J=8.0 Hz, 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=7.1 Hz, 3H).

Example 10

3-((3R,4R)-4-methyl-3-(methyl(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 781 mg, 2.5 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography ₍ petroleum ether/ethyl acetate = 5:1 to 1:2) to give the title compound as a _white solid, 1.1 g, 82% yield. MS (m/z): [M+H] ⁺ calculated for _{C31H32N6O3 537.64} ; found, 537.3. ^1H NMR (400 MHz, Chloroform-d) δ 8.30 (dd, J=10.4, 4.8 Hz, 1H), 7.77 - 7.61 (m, 1H), 7.36 - 7.16 (m, 5H), 7.10 (t, J=7.4 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.83 (dt, J=7.7, 2.0 Hz, 1H), 6.62 (t, J=4.2 Hz, 1H), 6.10 (cd, J=7.0, 4.5 Hz, 1H), 5.09 (ddk, 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=15.6 Hz, 3H), 2.48 (ddt, J=17.9, 12.9, 5.9 Hz, 1H), 1.93 (dddd, J=17.4, 12.6, 7.5, 3.9 Hz, 1H), 1.81 -1.68 (m, 1H), 1.66 - 1.58 (m, 3H), 1.08 (dd, J=12.6, 7.1 Hz, 3H).

Example 11

3-((3R,4R)-4-methyl-3-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-4-methyl-3-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 624 mg, 2 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to give the title compound as a _white solid, 0.48 g, 44.4% yield. MS (m/z): [M+H] ⁺ calculated for _C31H36N6O3 , _541.67 ; found, _541.3 . ¹ H NMR (400 MHz, DMSO) δ 8.38 (dd, J=6.2, 1.5 Hz, 1H), 7.80 - 7.60 (m, 1H), 7.32 (dd, J=17.9, 16.2 Hz, 2H), 7.10 (d, J=7.9 Hz, 2H), 6.89 (d, J=4.3 Hz, 1H), 6.19 - 5.98 (m, 1H), 4.84 (s, 1H), 4.17 - 3.98 (m, 2H), 3.96 - 3.57 (m, 3H), 3.40 (t, J=5.9 Hz, 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).

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-yl)-3-oxopropanenitrile

Synthesis of 3-((3R,4R)-3-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[23-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 156 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 (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 a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 2:3) to _give the title compound as _a white solid, 0.16 g, 49.1% yield. MS (m/z): [M+H] ⁺ calculated for _C35H34ClN7O4 , _653.15 ; found, 653.3. ¹ H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=6.4 Hz, 1H), 7.77 - 7.61 (m, 5H), 7.11 (t, J=2.8 Hz, 1H), 6.97 (t, J=6.7 Hz, 2H), 6.71 (dd, J=9.1, 2.5 Hz, 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=7.1 Hz, 3H).

Example 13

N-(4-(2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

Synthesis of N-(4-(2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 156 mg, 0.5 mmol), 2-(4-acetamidophenyl)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1: ₆ ) to give the title compound as a _white solid, 0.118 g, 48.6% yield. MS (m/z): [M+H] ⁺ calculated for _C26H29N7O3 , _488.56 ; found, 488.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 8.39 (d, J=5.8 Hz, 1H), 7.70 (d, J=4.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.94 (d, J=4.4 Hz, 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), 2.39 (k, J=6.2 Hz, 1H), 2.03 (s, 3H), 1.88 - 1.46 (m, 2H), 1.02 (d, J=7.0 Hz, 3H).

Example 14

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-methylpyridin-yl)-3-oxopropanenitrile

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-l-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 156 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[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 24 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to _give the title compound as _a white solid, 0.11 g, 37.8% yield. MS (m/z): [M+H] ⁺ calculated for _C33H39N7O3 , _582.72 ; found, 582.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 8.29 (s, 1H), 7.67 (td, J=4.5, 2.2 Hz, 1H), 7.23 (dd, J=7.5, 2.0 Hz, 1H), 6.98 - 6.81 (m, 3H), 4.84 (s, 1H), 4.67 (ddd, J=14.7, 8.6, 6.3 Hz, 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 (k, J=7.5 Hz, 2H), 2.60 (dt, J=9.4, 4.7 Hz, 2H), 2.45 - 2.30 (m, 1H), 2.16 (kk, J=6.9, 4.5, 3.9 Hz, 2H), 1.83 (s, 2H), 1.26 (td, J=7.6, 3.1 Hz, 3H), 1.01 (dt, J=7.2, 2.8 Hz, 3H), 0.69 (td, J=7.1, 3.4 Hz, 3H).

Example 15

2-(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-carbonyl)phenylacetate

Synthesis of 2-(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-carbonyl)phenylacetate

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to give the title compound as a white solid, 0.06 g, 12.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₅ H ₂₆ N ₆ O ₄ , 475.52; found, 475.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (d, J=6.8 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.58 (d, J=4.1 Hz, 1H), 7.43 -7.36 (m, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.98 (t, J=5.0 Hz, 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 (dk, J=12.0, 6.7, 5.6 Hz, 1H), 1.92 (d, J=1.7 Hz, 3H), 1.88 - 1.66 (m, 1H), 1.58 (p, J=8.0, 7.0 Hz, 1H), 1.01 (d, J=7.1 Hz, 3H).

Example 16

tert-Butyl ((S)-2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

Synthesis of tert-butyl ((S)-2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography ( _petroleum ether _/ ethyl acetate = 1:1 to 1:2) to give the title compound as a white solid, 0.3 g, yield 55%. MS (m/z): [M+H] ⁺ calcd for _C29H35N7O4 , _546.64 ; found, 546.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (d, J=4.7 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.70 (d, J=4.1 Hz, 1H), 7.48 (t, J=7.4 Hz, 3H), 7.35-7.21 (m, 3H), 7.02-6.83 (m, 1H), 4.86 (s, 1H), 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).

Example 17

(S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Synthesis of (S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-l-yl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 488 mg, 4 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2) to _give the title compound as a _white solid, 0.5 g, 44.7% yield. MS (m/z): _[ M+H] ⁺ calcd for _C29H33N7O3S , 560.69; found, 560.2. ¹ H NMR (400 MHz, chloroform-d) δ 8.96 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.03 (d, J=4.2 Hz, 1H), 7.47 - 7.34 (m, 2H), 7.06 (d, J=7.9 Hz, 2H), 6.81 (d, J=4.1 Hz, 1H), 6.06 (q, J=6.9 Hz, 1H), 4.62 (d, J=9.2 Hz, 2H), 4.34 - 4.16 (m, 2H), 3.40 (s, 2H), 3.08 (q, J=7.4 Hz, 2H), 2.39 (d, J=7.2 Hz, 2H), 1.80 (dp, J=13.5, 6.8 Hz, 1H), 1.68 (d, J=6.9 Hz, 3H), 1.41 (t, J=7.4 Hz, 3H), 0.95 - 0.82 (m, 6H).

Example 18

(S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(6-methoxynaphthalen-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Synthesis of (S)-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(6-methoxynaphthalin-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-l-yl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 305 mg, 2.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to _give the title compound as _a white solid, 0.25 g, 42.9% yield. MS (m/z): _[ M+H] ⁺ calcd for _C30H29N7O4S , 584.67; found, 584.2. ¹ H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.49 (s, 1H), 8.18 (d, J=4.2 Hz, 1H), 7.85 (s, 1H), 7.80 - 7.74 (m, 2H), 7.58 - 7.54 (m, 1H), 7.40 (d, J=4.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H), 7.12 (dd, J=9.0, 2.4 Hz, 1H), 6.12 (q, J=6.8 Hz, 1H), 4.58 (d, J=9.2 Hz, 2H), 4.23 (d, J=9.2 Hz, 2H), 3.83 (s, 3H), 3.68 (s, 2H), 3.23 (k, J=7.3 Hz, 2H), 1.68 (d, J=6.9 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H).

Example 19

2-(3-(4-(7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

Synthesis of 2-(3-(4-(7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 244 mg, 2 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to ₁ :2) to give the title compound as _a white solid, 0.2 g, 32.9% yield. MS (m/z): [M+H] ⁺ calculated for _C32H29N7O4S , _608.69 ; found, 608.3. ¹ H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.93 (s, 1H), 8.51 (s, 1H), 8.17 (d, J=4.2 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.70 - 7.58 (m, 4H), 7.52 (t, J=7.6 Hz, 3H), 7.43 (d, J=4.2 Hz, 1H), 6.06 (k, J=6.8 Hz, 1H), 4.59 (d, J=9.1 Hz, 2H), 4.24 (d, J=9.1 Hz, 2H), 3.68 (s, 2H), 3.23 (k, J=7.3 Hz, 2H), 1.63 (d, J=6.9 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H).

Example 20

2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 610 mg, 5 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to ₁ :2) to give the title compound as _a white solid, 0.3 g, 25.1% yield. MS (m/z): [M+H] ⁺ calculated for _C31H28FN7O3S , _598.67 ; found, 598.2. ¹ H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 9.02 (s, 1H), 8.53 (s, 1H), 8.20 (d, J=4.2 Hz, 1H), 7.54-7.35 (m, 9H), 6.08 (k, J=7.0 Hz, 1H), 4.61 (d, J=9.2 Hz, 2H), 4.25 (d, J=9.2 Hz, 2H), 3.70 (s, 2H), 3.24 (k, J=7.4 Hz, 2H), 1.66 (d, J=7.0 Hz, 3H), 1.25 (t, J=7.3 Hz, 3H).

Example 21

2-(1-(Ethylsulfonyl)-3-(4-(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as a white solid, _0.11 g, 74.5% yield. MS (m/z): [M+H] ⁺ calculated for _C31H29N7O4S , _596.68 ; found, 596.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 8.86 (s, 1H), 8.50 (s, 1H), 8.12 (d, J=4.2 Hz, 1H), 7.40 (d, J=4.2 Hz, 1H), 7.37-7.25 (m, 3H), 7.21-7.10 (m, 2H), 7.07 (t, J=2.1 Hz, 1H), 6.95-6.89 (m, 2H), 6.86-6.78 (m, 1H), 5.94 (d, J=6.9 Hz, 1H), 4.60 (d, J=9.1 Hz, 2H), 4.24 (d, J=9.1 Hz, 2H), 3.68 (s, 2H), 3.23 (k, J=7.3 Hz, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.24 (t, J=; 7.4 Hz, 3H).

Example 22

2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 3:4) to _give the title compound as _a white solid, 0.13 g, 43.4% yield. MS (m/z): _[ M+H] ⁺ calcd for _C31H33N7O4S , 600.71; found, 600.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J=3.4 Hz, 2H), 8.50 (s, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.40 (d, J=4.2 Hz, 1H), 7.34 (d, J=7.9 Hz, 2H), 7.12 (d, J=1.9 Hz, 2H), 5.98 (q, J=6.9 Hz, 1H), 4.59 (d, J=9.1 Hz, 2H), 4.24 (d, J=9.1 Hz, 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, 8.5 Hz, 1H), 2.03 (ddd, J=18.6, 10.1, 8.6 Hz, 1H), 1.95-1.74 (m, 2H), 1.70-1.61 (m, 1H), 1.58 (d, J=6.9 Hz, 3H), 1.42 (dd, J=10.6, 6.9 Hz, 1H), 1.24 (dd, J=8.7, 6.1 Hz, 3H).

Example 23

2-(3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

Synthesis of 2-(3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:5) to _give the title compound as _{a white} solid, 0.18 g, 50.6% yield. MS (m/z): [M+H] ⁺ calcd for _{C35H31ClN8O5S} , 712.19; found, 711.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J=2.4 Hz, 2H), 8.56 (s, 1H), 8.17 (d, J=4.2 Hz, 1H), 7.77-7.61 (m, 4H), 7.47 (d, J=4.2 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.72 (dd, J=9.0, 2.6 Hz, 1H), 5.04 (s, 2H), 4.64 (d, J=9.1 Hz, 2H), 4.28 (d, J=9.1 Hz, 2H), 3.71 (d, J=6.8 Hz, 5H), 3.25 (k, J=7.3 Hz, 2H), 2.27 (s, 3H), 1.26 (t, J=7.3 Hz, 3H).

Example 24

N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

Synthesis of N-(4-(2-(4-(l-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl)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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2) to _give the title compound as _a white solid, 0.03 g, 10% yield. MS (m/z): _[ M+H] ⁺ calcd for _C26H26N8O4S , 547.61; found, 547.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 9.01 (d, J=10.0 Hz, 2H), 8.53 (s, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 2H), 7.44 (d, J=4.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 4.87 (s, 2H), 4.62 (d, J=9.0 Hz, 2H), 4.26 (d, J=9.1 Hz, 2H), 3.71 (s, 2H), 3.25 (q, J=7.3 Hz, 2H), 2.04 (s, 3H), 1.26 (t, J=7.4 Hz, 3H).

Example 25

2-(3-(4-(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)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

Synthesis of 2-(3-(4-(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)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as _a white solid, 0.18 g, 56% yield. MS (m/z): _[ M+H] ⁺ calcd for _C33H36N8O4S , 641.76; found, 641.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 9.04 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 8.15 (d, J=4.2 Hz, 1H), 7.44 (d, J=4.2 Hz, 1H), 7.27 (dd, J=7.4, 1.6 Hz, 1H), 7.00-6.88 (m, 2H), 4.71-4.56 (m, 3H), 4.29 (d, J=9.1 Hz, 2H), 4.22 (d, J=14.5 Hz, 1H), 3.91 (ddd, J=11.7, 7.1, 4.9 Hz, 1H), 3.83-3.76 (m, 1H), 3.74 (s, 2H), 3.27 (k, J=7.3 Hz, 2H), 2.89 (k, J=7.5 Hz, 2H), 2.64 (dt, J=6.8, 4.2 Hz, 2H), 2.21 (k, J=7.2 Hz, 2H), 1.29 (td, J=7.4, 4.3 Hz, 6H), 0.76 (t, J=7.3 Hz, 3H).

Example 26

tert-Butyl (S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

Synthesis of tert-butyl (N)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2) to _give the title compound as a white solid, _0.12 g, 19.8% yield. MS (m/z): [M+H] ⁺ calculated for _C29H32N8O5S , _605.69 ; found, 605.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (d, J=3.7 Hz, 2H), 8.51 (s, 1H), 8.18 (d, J=4.1 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.61-7.37 (m, 4H), 7.36-7.23 (m, 3H), 4.60 (d, J=9.1 Hz, 2H), 4.24 (d, J=9.1 Hz, 2H), 3.69 (s, 2H), 3.23 (k, J=7.3 Hz, 2H), 1.40 (s, 9H), 1.24 (t, J=7.4 Hz, 3H).

Example 27

l-((1S,4R)-4-((7-((S)-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((1R,4R)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 338 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 122 mg, 1 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to _give the title compound as _a white solid, 0.14 g, 26.6% yield. MS (m/z): _[ M+H] ⁺ calcd for _C28H39N5O3S , 526.71; found, 526.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.66 (d, J=4.2 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.06 (d, J=7.8 Hz, 2H), 6.93-6.79 (m, 2H), 6.10 (q, J=6.9 Hz, 1H), 4.63 (s, 1H), 3.14 (s, 3H), 2.94 (d, J=6.2 Hz, 2H), 2.59 (d, J=5.0 Hz, 3H), 2.35 (d, J=7.2 Hz, 2H), 2.04 (d, J=13.1 Hz, 2H), 1.88-1.74 (m, 2H), 1.74-1.63 (m, 4H), 1.52 (d, J=7.0 Hz, 3H), 1.27-1.21 (m, 2H), 0.81 (d, J=6.6 Hz, 6H).

Example 28

(R)-3-cyclopentyl-3-(4-(7-(S)-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-ciuopentylpropane (ruxolitinib, 306 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 3:1) to _give the title compound as a _white solid, 0.42 g, 85% yield. MS (m/z): [M+H] ⁺ calcd for _C30H34N6O4 , _495.64 ; found, 495.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.11 (d, J=4.2 Hz, 1H), 7.36-7.27 (m, 3H), 7.07 (d, J=8.0 Hz, 2H), 6.00 (q, J=6.9 Hz, 1H), 4.53 (td, J=9.6, 4.3 Hz, 1H), 3.23 (cd, J=17.1, 6.9 Hz, 2H), 2.47-2.38 (m, 1H), 2.34 (d, J=7.1 Hz, 2H), 1.77 (ddd, J=21.2, 12.6, 7.2 Hz, 2H), 1.66-1.47 (m, 5H), 1.47-1.11 (m, 5H), 0.88-0.76 (m, 6H).

Example 29

3-((3R,4R)-4-methyl-3-(methyl(7-(2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic acid (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:5) to _give the title compound as _a white solid, 0.27 g, 45.8% yield. MS (m/z): [M+H] ⁺ calcd for _C34H35N7O3 , _590.70 ; found, 590.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52-8.37 (m, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.74 (dd, J=22.3, 5.9 Hz, 2H), 7.66 (d, J=7.1 Hz, 2H), 7.57-7.50 (m, 1H), 7.50-7.44 (m, 2H), 6.90 (d, J=4.6 Hz, 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=6.3 Hz, 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=7.1 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).

Example 30

2-2-(1-(Ethylsulfonyl)-3-(4-(7-(2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-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)butanoic acid (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as _a white solid, 0.46 g, 70.9% yield. MS (m/z): _[ M+H] ⁺ calcd for _C34H32N8O4S , 649.74; found, 649.3. ¹ H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.98 (s, 1H), 8.50 (s, 1H), 8.16 (d, J=3.9 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.73 (t, J=14.0 Hz, 1H), 7.69-7.58 (m, 2H), 7.52 (d, J=8.4 Hz, 3H), 7.40 (d, J=3.9 Hz, 1H), 5.85 (t, J=7.2 Hz, 1H), 4.96 (s, 2H), 4.59 (d, J=9.0 Hz, 2H), 4.24 (d, J=9.0 Hz, 2H), 3.68 (s, 2H), 3.22 (dd, J=14.5, 7.2 Hz, 2H), 2.26 (dt, J=13.8, 7.1 Hz, 1H), 1.94 (dd, J=13.6, 7.2 Hz, 1H), 1.23 (dd, J=14.8, 7.6 Hz, 3H), 0.94 (t, J=7.1 Hz, 3H).

Example 31

(R)-3-cyclopentyl-3-(4-(7-((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl))-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-ciuopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to _give the title compound as a _white solid, 0.16 g, 61.7% yield. MS (m/z): [M+H] ⁺ calcd for _C31H30N6O2 , _519.62 ; found, 519.3. ¹ H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.85 (s, 1H), 8.39 (s, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.84 (s, 1H), 7.81-7.73 (m, 2H), 7.55 (dd, J=8.6, 1.5 Hz, 1H), 7.30 (d, J=4.2 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.13 (q, J=6.8 Hz, 1H), 4.53 (td, J=9.6, 4.2 Hz, 1H), 3.83 (s, 3H), 3.29-3.14 (m, 2H), 2.47-2.34 (m, 1H), 1.81 (td, J=11.7, 7.3 Hz, 1H), 1.68 (d, J=6.9 Hz, 3H), 1.63-1.38 (m, 4H), 1.38-1.21 (m, 3H).

Example 32

(3R)-3-(4-(7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to _give the title compound as _a white solid, 0.18 g, 66.4% yield. MS (m/z): [M+H] ⁺ calculated for _C33H30N6O2 , _543.64 ; found, 543.2. ^1H NMR (400 MHz, DMSO) δ 8.89(d, J=6.4 Hz, 2H), 8.41 (s, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.82 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.70-7.59 (m, 4H), 7.53 (t, J=7.6 Hz, 3H), 7.33 (d, J=4.1 Hz, 1H), 6.08 (k, J=6.8 Hz, 1H), 4.55 (td, J=9.6, 4.2 Hz, 1H), 3.29-3.16 (m, 2H), 2.42 (dt, J=17.0, 8.5 Hz, 1H), 1.82 (td, J=11.6, 7.3 Hz, 1H), 1.70-1.39 (m, 7H), 1.39-1.20 (m, 3H).

Example 33

(3R)-3-cyclopentyl-3-(4-(7-(2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2) to give the title compound as _a white solid, 0.17 g, 63.9% yield. MS (m/z): [M+H] ⁺ calculated for _C32H29FN6O , _533.62 ; found, 533.2. ¹ H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.15 (d, J=4.1 Hz, 1H), 7.52-7.29 (m, 9H), 6.08 (k, J=6.7 Hz, 1H), 4.54 (td, J=9.4, 4.0 Hz, 1H), 3.28-3.15 (m, 2H), 2.43 (dd, J=16.9, 8.4 Hz, 1H), 1.87-1.76 (m, 1H), 1.70-1.38 (m, 7H), 1.38-1.20 (m, 3H).

Example 34

(3R)-3-cyclopentyl-3-(4-(7-(2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-ciuopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic 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 16 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as _a white solid, 0.17 g, 58.3% yield. MS (m/z): [M+H] ⁺ calcd for _C35H33N7O2 , _584.70 ; found, 584.3. ¹ H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.86 (s, 1H), 8.39 (s, 1H), 8.13 (d, J=4.2 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.70-7.59 (m, 2H), 7.52 (t, J=7.0 Hz, 3H), 7.30 (d, J=3.9 Hz, 1H), 5.86 (t, J=7.4 Hz, 1H), 4.96 (s, 2H), 4.53 (td, J=9.5, 4.2 Hz, 1H), 3.28-3.14 (m, 2H), 2.41 (dt, J=17.2, 8.5 Hz, 1H), 2.25 (td, J=14.2, 7.2 Hz, 1H), 1.97-1.88 (m, 1H), 1.80 (dt, J=11.9, 5.8 Hz, 1H), 1.65-1.39 (m, 3H), 1.36-1.21 (m, 4H), 0.94 (t, J=7.3 Hz, 3H).

Example 35

N-methyl-1-((trans)-4-(methyl(7-(2-(4-(l-oxoisoindolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide

(R)-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic acid (indobufen, 230 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as _a white solid, 0.22 g, 59.7% yield. MS (m/z): _[ M+H] ⁺ calcd for _C33H38N6O4S , 615.77; found, 615.3. ¹ H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.83 (d, J=8.3 Hz, 2H), 7.76 (d, J=7.4 Hz, 1H), 7.67 (dd, J=9.6, 5.5 Hz, 3H), 7.59-7.42 (m, 3H), 6.92-6.73 (m, 2H), 5.97 (t, J=7.1 Hz, 1H), 4.96 (s, 2H), 4.64 (s, 1H), 3.14 (s, 3H), 2.94 (d, J=5.8 Hz, 2H), 2.57 (t, J=9.7 Hz, 3H), 2.26-2.13 (m, 1H), 2.03 (d, J=12.0 Hz, 2H), 1.97-1.77 (m, 2H), 1.68 (s, 4H), 1.37-1.13 (m, 2H), 0.90 (dd, J=18.8, 11.8 Hz, 3H).

Example 36

1-((Trans)-4-((7-(2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to ₁ :2) to give the title compound as _a white solid, 0.22 g, 65.1% yield. MS (m/z): [M+H] ⁺ calculated for _C30H34FN5O3S , _564.69 ; found, 564.3. ¹ H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 7.70 (d, J=4.2 Hz, 1H), 7.52-7.41 (m, 5H), 7.35 (dt, J=19.2, 7.4 Hz, 3H), 6.92-6.82 (m, 2H), 6.17 (k, J=6.8 Hz, 1H), 4.64 (s, 1H), 3.16 (s, 3H), 2.94 (d, J=6.2 Hz, 2H), 2.59 (d, J=4.9 Hz, 3H), 2.04 (d, J=12.5 Hz, 2H), 1.85 (s, 1H), 1.65 (d, J=26.0 Hz, 4H), 1.59 (d, J=7.0 Hz, 3H), 1.37-1.19 (m, 2H).

Example 37

1-((Trans)-4-((7-(2-(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)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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-tetrahydropyran[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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 3:1 to 1:1) to _give the title compound as _a white solid, 0.23 g, 63.2% yield. MS (m/z): _[ M+H] ⁺ calcd for _C32H42N6O4S , 607.79; found, 607.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.47 (s, 1H), 8.27 (s, 1H), 7.64 (d, J=4.2 Hz, 1H), 7.22 (dd, J=7.4, 1.6 Hz, 1H), 6.98-6.78 (m, 4H), 4.66 (d, J=14.6 Hz, 2H), 4.03 (d, J=7.5 Hz, 1H), 3.89 (s, 1H), 3.76 (dt, J=10.7, 4.4 Hz, 1H), 3.16 (s, 3H), 2.94 (d, J=6.2 Hz, 2H), 2.84 (k, J=7.5 Hz, 2H), 2.59 (t, J=3.8 Hz, 5H), 2.15 (tt, J=7.2, 4.6 Hz, 2H), 2.09-2.01 (m, 2H), 1.85 (t, J=7.5 Hz, 1H), 1.69 (s, 4H), 1.35 1.21 (m, 5H), 0.68 (t, J=7.3 Hz, 3H).

Example 38

1-((Trans)-4-((7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(metal)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 73 mg, 0.6 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to ₁ :1) to give the title compound as _a white solid, 0.17 g, 49.4% yield. MS (m/z): [M+H] ⁺ calcd for _C31H35N5O4S , _574.71 ; found, 574.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 7.78 (t, J=1.9 Hz, 1H), 7.74-7.57 (m, 6H), 7.52 (dt, J=11.6, 7.7 Hz, 3H), 6.86 (t, J=4.9 Hz, 2H), 6.16 (k, J=6.9 Hz, 1H), 4.64 (s, 1H), 3.15 (s, 3H), 2.95 (d, J=6.2 Hz, 2H), 2.59 (d, J=5.0 Hz, 3H), 2.04 (d, J=13.0 Hz, 2H), 1.84 (dk, J=13.3, 6.8 Hz, 1H), 1.68 (d, J=8.5 Hz, 4H), 1.58 (d, J=7.0 Hz, 3H), 1.28 (s, 2H).

Example 39

1-((Trans)-4-((7-((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as a white solid, _0.23 g, 69.8% yield. MS (m/z): [M+H] ⁺ calcd for _C29H35N5O4S , _550.69 ; found, 550.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.74 (t, J=8.9 Hz, 2H), 7.68 (d, J=4.1 Hz, 1H), 7.50 (dd, J=8.5, 1.3 Hz, 1H), 7.23 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.9, 2.4 Hz, 1H), 6.87 (k, J=4.5 Hz, 1H), 6.79 (d, J=3.0 Hz, 1H), 6.21 (k, J=6.8 Hz, 1H), 4.61 (s, 1H), 3.83 (s, 3H), 3.10 (s, 3H), 2.93 (d, J=6.2 Hz, 2H), 2.59 (d, J=4.8 Hz, 3H), 2.06-1.98 (m, 2H), 1.83 (s, 1H), 1.63 (t, J=9.3 Hz, 7H), 1.36-1.15 (m, 2H).

Example 40

2-(3-(4-(7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as _{a white} solid, 0.22 g, 35.7% yield. MS (m/z): [M+H] ⁺ calcd for _{C30H27ClN8O3S} , 616.11; found, 616.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 7.83 (d, J=4.1 Hz, 1H), 7.50 (dd, J=8.3, 6.5 Hz, 2H), 7.37 (d, J=4.1 Hz, 1H), 7.09-7.04 (m, 3H), 7.00-6.90 (m, 2H), 4.61 (d, J=9.1 Hz, 2H), 4.25 (d, J=9.1 Hz, 2H), 3.70 (s, 2H), 3.24 (k, J=7.3 Hz, 2H), 2.01 (s, 3H), 1.25 (t, J=7.4 Hz, 3H).

Example 41

1-((Trans)-4-((7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as a _yellow solid, 0.2 g, 57.4% yield. MS (m/z): [M+H] ⁺ calculated for _{C29H33ClN6O3S} , _581.20 ; found, 581.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 8.08 (s, 1H), 7.45 (dd, J=11.4, 4.2 Hz, 1H), 7.41-7.22 (m, 2H), 7.14-7.01 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.93-6.75 (m, 3H), 4.63 (s, 1H), 3.17 (s, 3H), 2.95 (d, J=6.1 Hz, 2H), 2.60 (d, J=4.9 Hz, 3H), 2.13-2.01 (s, 5H), 1.89 (d, J=22.2 Hz, 1H), 1.78-1.62 (m, 4H), 1.36-1.24 (m, 2H).

Example 42

1-((Trans)-4-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

Synthesis of 1-((trans)-4-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a yellow solid _, 0.14 g, 41.4% yield. MS (m/z): [M+H] ⁺ calcd for _{C34H37ClN6O5S} , 677.22; found, 677.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.76-7.60 (m, 5H), 7.11 (d, J=2.6 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 6.89 (dt, J=9.9, 4.5 Hz, 2H), 6.71 (dd, J=9.0, 2.6 Hz, 1H), 4.99 (s, 2H), 4.69 (s, 1H), 3.69 (s, 3H), 3.20 (s, 3H), 2.96 (d, J=6.2 Hz, 2H), 2.59 (d, J=4.9 Hz, 3H), 2.24 (s, 3H), 2.06 (d, J=12.6 Hz, 2H), 1.87 (dt, J=15.5, 5.8 Hz, 1H), 1.72 (dt, J=8.5, 5.0 Hz, 4H), 1.41-1.27 (m, 2H).

Example 43

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

Synthesis of 1-((trans)-4-((7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to ₁ :1) to give the title compound as _a yellow solid, 0.17 g, 60.7% yield. MS (m/z): [M+H] ⁺ calculated for _C30H36N6O3S , _561.26 ; found, 561.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.12 (s, 1H), 7.48 (d, J=4.0 Hz, 1H), 7.43-7.28 (m, 2H), 7.13-6.96 (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=6.2 Hz, 2H), 2.59 (d, J=4.9 Hz, 3H), 2.27 (d, J=9.8 Hz, 3H), 2.07 (d, J=21.6 Hz, 5H), 1.92-1.82 (m, 1H), 1.72 (g, J=3.3 Hz, 4H), 1.37-1.26 (m, 2H).

Example 44

N-methyl-1-((trans)-4-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide

Synthesis of N-methyl-1-((trans)-4-(methyl(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a white solid, 0.2 g, 70.7% yield. MS (m/z): _[ M+H] ⁺ calcd for _C30H39N5O4S , 566.27; found, 566.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.65 (d, J=4.2 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 6.95-6.79 (m, 2H), 6.09 (k, J=6.9 Hz, 1H), 4.63 (s, 1H), 3.14 (s, 3H), 2.98-2.87 (m, 3H), 2.58 (d, J=2.6 Hz, 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=7.0 Hz, 3H), 1.46-1.38 (m, 1H), 1.35-1.22 (m, 2H).

Example 45

(3R)-3-cyclopentyl-3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Synthesis of (3R)-3-cyclopentyl-3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetal)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-ciuopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as _a white solid, 0.28 g, 81.5% yield. MS (m/z): [M+H] ⁺ calcd for _C34H37N7O2 , _576.30 ; found, 576.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 8.88 (d, J=3.1 Hz, 2H), 8.42 (s, 1H), 8.09 (d, J=4.2 Hz, 1H), 7.30 (d, J=4.3 Hz, 1H), 7.24 (dd, J=7.4, 1.5 Hz, 1H), 6.96-6.87 (m, 2H), 4.66-4.51 (m, 2H), 4.19 (dd, J=14.5, 1.7 Hz, 1H), 3.88 (ddd, J=11.8, 7.2, 5.0 Hz, 1H), 3.76 (dt, J=11.1, 4.6 Hz, 1H), 3.30-3.15 (m, 2H), 2.86 (k, J=7.5 Hz, 2H), 2.64-2.56 (m, 2H), 2.44 (k, J=8.4 Hz, 1H), 2.18 (k, J=7.2 Hz, 2H), 1.89-1.78 (m, 1H), 1.70-1.41 (m, 4H), 1.41-1.22 (m, 6H), 0.73 (t, J=7.3 Hz, 3H).

Example 46

tert-Butyl ((S)-2-(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

Synthesis of tert-butyl ((S)-2-(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to give the title compound as a _white solid, 0.027 g _, 9.4% yield. MS (m/z): [M+H] ⁺ calculated for _C28H38N6O5S , _571.26 ; found, 571.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.68 (d, J=4.1 Hz, 1H), 7.56-7.45 (m, 3H), 7.29 (d, J=7.7 Hz, 3H), 6.86 (d, J=4.9 Hz, 2H), 4.63 (s, 1H), 3.14 (s, 3H), 2.94 (d, J=6.2 Hz, 2H), 2.58 (d, J=5.0 Hz, 3H), 2.03 (d, J=12.7 Hz, 2H), 1.90-1.79 (m, 1H), 1.67 (d, J=8.0 Hz, 4H), 1.39 (s, 9H), 1.32-1.21 (m, 2H).

Example 47

2-(3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

Synthesis of 2-(3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (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 hydrochloride 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 289 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to give the title compound as a _yellow solid, _0.25 g, 42% _yield . MS (m/z): [M+H] ⁺ calculated for _C31H30N8O3S , 595.22; found, 595.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 7.90 (d, J=4.1 Hz, 1H), 7.42 (ddd, J=12.4, 6.6, 3.0 Hz, 3H), 7.08-6.99 (m, 2H), 6.94 (dd, J=5.6, 3.2 Hz, 1H), 6.91-6.75 (m, 2H), 4.62 (d, J=9.1 Hz, 2H), 4.26 (d, J=9.1 Hz, 2H), 3.71 (s, 2H), 3.24 (k, J=7.3 Hz, 2H), 2.23 (s, 3H), 1.97 (s, 3H), 1.25 (t, J=7.5 Hz, 3H).

Example 48

4-(((3R,4R)-1-(2-anoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(6-methoxynaphtha lin-2-yl)propanoate

Synthesis of 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(6-methoxynaphthalen-2-yl)propanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propanoic 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 temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to ₁ :1) to give the title compound as _a white solid, 0.107 g, 38.6% yield. MS (m/z): [M+H] ⁺ calculated for _C31H34N6O4 , _555.26 ; found, 555.3. ^1H NMR (400 MHz, chloroform-d) δ 8.31 (d, J=4.1 Hz, 1H), 7.69-7.49 (m, 3H), 7.32 (dt, J=8.6, 2.5 Hz, 1H), 7.20-7.02 (m, 3H), 6.47 (d, J=3.8 Hz, 1H), 6.22-6.06 (m, 2H), 5.10 (d, J=8.2 Hz, 1H), 4.06 (dd, J=13.4, 4.5 Hz, 1H), 3.91 (s, 3H), 3.88-3.66 (m, 2H), 3.66-3.44 (m, 4H), 3.34 (d, J=11.5 Hz, 3H), 2.49 (dt, J=20.2, 6.2 Hz, 1H), 1.99-1.83 (m, 1H), 1.81-1.65 (m, 1H), 1.54 (d, J=7.1 Hz, 3H), 1.08 (dd, J=9.5, 7.0 Hz, 3H).

Example 49

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(3-benzoylphenyl)propanoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(3-benzoylphenyl)propanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl)propanoic 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a white solid, 0.153 g, 52.9% yield. MS (m/z): [M+H] ⁺ calcd for _C33H34N6O4 , _579.26 ; found, 579.3. ¹ H NMR (400 MHz, chloroform-c) δ 8.29 (d, J=4.5 Hz, 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, 2.1 Hz, 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, 4.9 Hz, 3H), 2.56-2.41 (m, 1H), 2.00-1.85 (m, 1H), 1.80-1.71 (m, 1H), 1.50 (d, J=7.2 Hz, 3H), 1.07 (dd, J=10.5, 7.1 Hz, 3H).

Example 50

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1,1-diphenyl]-4-yl)propanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to give the title compound as _{a white} solid, 0.083 g, 29.2% yield. MS (m/z): [M+H] ⁺ calcd for _C32H33FN6O3 , _569.26 ; found, 569.3. ^1H NMR (400 MHz, chloroform-d) δ 8.31 (d, J=2.2 Hz, 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 (k, J=3.3 Hz, 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, 2.6 Hz, 3H), 1.10-1.00 (m, 3H).

Example 51

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

Synthesis of (4-((3R,4R)-1-(2-cyanoacetyl)-4-methylnsp1eridin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

3-((3R,4R-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2,6-dichloroanilino)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 completion of the reaction, the reaction solution diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to give the title compound as a white solid, 0.106 g, 34.2% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₁ Cl ₂ N ₇ O ₃ , 620.19; found, 620.3. ¹ H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 8.1, 1.8 Hz, 2H), 7.18 (dd, J=7.5, 1.7 Hz, 1H), 7.12 (dd, J=9.3, 5.7 Hz, 2H), 6.96 (dt, J=15.1, 7.8 Hz, 2H), 6.64 (d, J=9.4 Hz, 1H), 6.53 (dk, J=7.6, 3.3 Hz, 2H), 6.23 (d, J=3.9 Hz, 2H), 5.13 (s, 1H), 4.10-3.56 (m, 6H), 3.52 (t, J=7.6 Hz, 2H), 3.39 (s, 1H), 3.34 (s, 2H), 2.50 (ddd, J=19.4, 9.7, 4.0 Hz, 1H), 1.99-1.83 (m, 1H), 1.76 (dk, J=17.7, 3.9, 3.2 Hz, 1H), 1.09 (dd, J=13.9, 7.1 Hz, 3H).

Example 52

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(3-phenoxyphenyl)propanoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(3-phenoxyphenyl)propanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as a _white solid, 0.13 g, 45.9% yield. MS (m/z): [M+H] ⁺ calcd for _C32H34N6O4 , _567.26 ; found, 567.3. ¹ H NMR (400 MHz, chloroform-d) δ 8.32 (d, J=6.6 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.20 (td, J=7.9, 2.2 Hz, 1H), 7.13-7.05 (m, 2H), 6.96 (J, J=7.2 Hz, 3H), 6.92-6.87 (m, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.51 (t, J=3.1 Hz, 1H), 6.21-6.07 (m, 2H), 5.11 (dp, J=9.4, 4.8, 4.4 Hz, 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, 6.1 Hz, 1H), 1.94 (dt, J=9.4, 4.6 Hz, 1H), 1.80-1.66 (m, 1H), 1.45 (d, J=1.2 Hz, 3H), 1.08 (dd, J=12.3, 7.1 Hz, 3H).

Example 53

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a white solid, 0.08 g, 28% yield. MS (m/z): [M+H] ⁺ calcd for _C32H38N6O4 , _571.30 ; found, 571.3. ¹ H NMR (400 MHz, chloroform-d) δ 8.34-8.27 (m, 1H), 7.11 (tt, J=9.3, 7.5, 3.4 Hz, 3H), 7.04 (dt, J=8.3, 2.9 Hz, 2H), 6.51 (s, 1H), 6.17 (dd, J=10.5, 4.6 Hz, 1H), 6.10 (dt, J=10.6, 2.8 Hz, 1H), 5.12 (qd, J=8.6, 5.0 Hz, 1H), 4.11 3.57 (m, 5H), 3.50 (q, J=9.1, 7.3 Hz, 3H), 3.40 (d, J=2.2 Hz, 1H), 3.14-3.02 (m, 1H), 2.49 (dd, J=23.3, 11.0, 4.9 Hz, 2H), 2.33 (dd, J=17.7, 8.4 Hz, 2H), 2.16-2.01 (m, 2H), 1.95 (tdd, J=11.1, 5.8, 2.8 Hz, 2H), 1.83-1.60 (m, 3H), 1.58-1.47 (m, 1H), 1.44 (dd, J=7.2, 1.8 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H).

Example 54

(3R)-3-cyclopentyl-3-(4-(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Synthesis of (3R)-3-cyclopentyl-3-(4-(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(3-phenoxyphenyl)propanoic 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 3:1) to _give the title compound as _a white solid, 0.2 g, 62.8% yield. MS (m/z): [M+H] ⁺ calculated for _C32H30N6O2 , _531.24 ; found, 531.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (d, J = 13.5 Hz, 2H), 8.41 (s, 1H), 8.09 (d, J = 4.2 Hz, 1H), 7.40-7.26 (m, 4H), 7.20-7.09 (m, 2H), 7.07 (t, J = 2.1 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 6.84 (dd, J = 8.1, 2.5 Hz, 1H), 5.96 (q, J = 6.9 Hz, 1H), 4.54 (td, J = 9.6, 4.2 Hz, 1H), 3.29-3.15 (m, 2H), 2.42 (p, J=8.5 Hz, 1H), 1.82 (dtd, J=12.1, 7.4,3.8 Hz, 1H), 1.66-1.40 (m, 7H), 1.37-1.18 (m, 3H).

Example 55

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl l)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (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 temperature for 18 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to give the title compound as _a light _yellow solid, 0.036 g, 10.5% yield. MS (m/z): [M+H] ⁺ calculated for _C36H36ClN7O5 , _682.25 ; found, 682.3. ^1H NMR (400 MHz, chloroform-d) δ 8.32 (s, 1H), 7.68-7.59 (m, 2H), 7.51-7.43 (m, 2H), 7.09 (d, J=3.8 Hz, 1H), 6.91-6.78 (m, 2H), 6.65 (dd, J=9.0, 2.4 Hz, 1H), 6.50 (dd, J=8.2, 3.8 Hz, 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=10.3 Hz, 3H), 2.03-1.85 (m, 1H), 1.81-1.73 (m, 1H), 1.09 (dd, Y=11.4, 7.1 Hz, 3H).

Example 56

(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpieridin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-acetoxybenzoate

Synthesis of (4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]piperimidin-7-yl)methyl 2-acetoxybenzoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a light yellow solid, 0.178 g, 70.6% yield. MS (m/z): [M+H] ⁺ calcd for _C26H28N6O5 , _505.21 ; found, 505.3. ¹ H NMR (400 MHz, chloroform-d) δ 8.34 (d, J=6.5 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.60-7.50 (m, 1H), 7.31-7.18 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.57 (d, J=3.8 Hz, 1H), 6.37 (d, J=2.6 Hz, 2H), 5.12 (tt, J=8.3, 4.6 Hz, 1H), 4.25-3.98 (m, 1H), 3.80 (ddt, J=13.2, 8.8, 4.7 Hz, 1H), 3.62-3.50 (m, 3H), 3.37 (d, J=15.2 Hz, 3H), 2.49 (dp, J=24.6, 6.0 Hz, 1H), 2.25 (dt, J=12.7 Hz, 3H), 1.93 (dtt, J=17.8, 9.0, 4.5 Hz, 2H), 1.74 (dtt, J=17.9, 7.6, 3.5 Hz, 1H), 1.08 (dd, J=13.2, 7.0 Hz, 3H).

Example 57

(R)-3-(4-(7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[23-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

Synthesis of (R)-3-(4-(7-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:1) to _give the title compound as a yellow solid, 0.26 g, 47.3% yield. MS (m/z): [M+H] ⁺ calculated for _C31H28ClN7O , _550.20 ; found, 550.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (s, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 7.80 (d, J=4.1 Hz, 1H), 7.49 (t, J=1.1 Hz, 2H), 7.27 (d, J=4.1 Hz, 1H), 7.12-7.00 (m, 3H), 7.00-6.91 (m, 2H), 4.55 (td, J=9.6, 4.2 Hz, 1H), 3.29-3.17 (m, 2H), 2.43 (p, J=8.5 Hz, 1H), 2.02 (s, 3H), 1.83 (dtd, J=11.9, 7.3, 3.9 Hz, 1H), 1.69-1.42 (m, 4H), 1.41-1.27 (m, 2H), 1.23 (td, J=9.4, 8.7, 2.9 Hz, 1H).

Example 58

N-(4-(2-(4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

Synthesis of N-(4-(2-(4-(methyl((trans)-4-((N-metholsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to ₀ :1) to give the title compound as _a white solid, 0.017 g, 6.6% yield. MS (m/z): [M+H] ⁺ calculated for _C25H32N6O4S , _513.22 ; found, 513.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 8.37 (s, 1H), 7.68 (d, J=4.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.88 (d, J=4.9 Hz, 2H), 4.81 (s, 2H), 4.67 (s, 1H), 3.18 (s, 3H), 2.95 (d, J=6.2 Hz, 2H), 2.59 (d, J=4.9 Hz, 3H), 2.03 (s, 5H), 1.94-1.80 (m, 1H), 1.70 (dd, J=8.6, 3.4 Hz, 4H), 1.37-1.26 (m, 2H).

Example 59

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl)acetic acid (actarit, 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to _give the title compound as _a white solid, 0.154 g, yield 59.5%. MS (m/z): [M+H] ⁺ calcd for _C27H31N7O4 , _518.24 ; found, 518.3. ¹ H NMR (400 MHz, chloroform-d) δ 8.33 (d, J=4.2 Hz, 1H), 7.71 (d, J=29.0 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.10 (dt, J=13.1, 4.8 Hz, 3H), 6.51 (dd, J=8.4, 3.9 Hz, 1H), 6.16 (s, 2H), 5.10 (tt, J=9.2, 4.4 Hz, 1H), 4.10-3.75 (m, 2H), 3.63-3.44 (m, 6H), 3.36 (d, J=18.1 Hz, 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=7.5 Hz, 3H).

Example 60

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3--d]pyrimidin-7-yl)(S)-2-(4-isobutylphenyl)propanoate

First step: synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]-4-yl)-1H-pyrazol-1-yl)-3-yl)azetidin)-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 7420 mg, 20 mmol) and N,N-diisopropylethylamine (3.12 g, 24 mmol) were dissolved in dichloromethane (200 mL) under nitrogen protection. After stirring at room temperature for half an hour, (2-(chloromethoxy)ethyl)trimethylsilane (4 g, 24 mmol) was added and stirring was continued at room temperature overnight. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further isolated by silica gel column chromatography to give the title compound as a white solid, 5 g, 49% yield. MS (m/z): [M+H] ⁺ calcd for C ₂₂ H ₃₁ N ₇ O ₃ SSi, 502.20; found, 502.3. Step 2: Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

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]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (5 g, 11.3 mmol) in dichloromethane (100 mL) under nitrogen atmosphere in an ice bath. After half an hour, the ice-water bath was removed, the temperature was raised to room temperature and stirring was continued for 24 hours. To the above reaction solution, saturated sodium bicarbonate solution was added at 0 °C to adjust pH to 8. Then, the mixture was poured into a separatory funnel and separated. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title product in an amount of 3.5 g, 90% yield. MS (m/z): [M+H] ⁺ calculated for C ₁₇ H ₁₉ N ₇ O ₃ S, 402.13; found, 402.3.

Step 3: Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(S)-2-(4-isobutylphenyl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _a white solid, 0.025 g, 8.4% yield. MS (m/z): _[ M+H] ⁺ calcd for _C30H35N7O4S , 590.25, found, 590.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.77 (s, 1H), 8.48 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 7.16 (d, J=3.8 Hz, 1H), 7.06 (d, J=7.8 Hz, 2H), 6.96 (d, J=7.8 Hz, 2H), 6.25 (d, J=3.2 Hz, 2H), 4.60 (d, J=9.1 Hz, 2H), 4.25 (d, J=9.1 Hz, 2H), 3.76 (q, J=7.0 Hz, 1H), 3.69 (s, 2H), 3.24 (q, J=7.3 Hz, 2H), 2.32 (d, J=7.1 Hz, 2H), 1.71 (hept, J=6.7 Hz, 1H), 1.34 (d, J=7.1 Hz, 3H), 1.26 (d, J=7.4 Hz, 3H), 0.77 (d, J=6.5 Hz, 6H).

Example 61

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(S)-2-(6-methoxynaphthalen-2-yl)propanoate

Synthesis of methyl (4-(1-(3-(cyanometal)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(S)-2-(6-methoxynaphthalen-2-yl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (401 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to _give the title compound as _a white solid, 0.31 g, 50.5% yield. MS (m/z): _[ M+H] ⁺ calcd for _C31H31N7O5S , 614.21; found, 614.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 7.72 (d, J=3.8 Hz, 1H), 7.65 (dd, J=10.9, 8.8 Hz, 2H), 7.56 (d, J=1.9 Hz, 1H), 7.29 (dd, J=8.5, 1.9 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.16 (d, J=3.8 Hz, 1H), 7.08 (dd, J=8.9, 2.6 Hz, 1H), 6.28 (s, 2H), 4.61 (d, J=9.1 Hz, 2H), 4.26 (d, J=9.1 Hz, 2H), 3.94 (k, J=7.0 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.24 (k, J=7.3 Hz, 2H), 1.44 (d, J=1.1 Hz, 3H), 1.26 (t, J=7.4 Hz, 3H).

Example 62

4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-benzoylphenyl)propanoate

Synthesis of 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-benzoylphenyl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (401 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to _give the title compound as _a white solid, 0.43 g, 67.5% yield. MS (m/z): _[ M+H] ⁺ calcd for _C33H31N7O5S , 638.21; found, 638.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.75 (s, 1H), 8.48 (s, 1H), 7.71 (d, J=3.8 Hz, 1H), 7.69-7.62 (m, 3H), 7.59 (t, J=1.8 Hz, 1H), 7.57-7.49 (m, 4H), 7.43 (t, J=7.6 Hz, 1H), 7.17 (d, J=3.8 Hz, 1H), 6.28 (d, J=4.4 Hz, 2H), 4.62 (d, J=9.1 Hz, 2H), 4.27 (d, J=9.1 Hz, 2H), 3.99 (k, J=7.1 Hz, 1H), 3.71 (s, 2H), 3.25 (k, J=7.3 Hz, 2H), 1.41 (d, J=7.1 Hz, 3H), 1.26 (t, J=7.3 Hz, 3H).

Example 63

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, _0.18 g, 58.9% yield. MS (m/z): [M+H] ⁺ calcd for _C34H41N7O4 , _612.32 ; found, _612.3 . ¹ H NMR (400 MHz, chloroform-d) δ 8.97 (d, J=13.6 Hz, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.10-7.02 (m, 2H), 7.00 (d, J=7.3 Hz, 1H), 6.51 (d, J=4.1 Hz, 1H), 6.17 (dtd, J=15.9, 10.7, 4.1 Hz, 2H), 5.10 (dp, J=14.0, 4.6 Hz, 1H), 4.09-3.70 (m, 5H), 3.60-3.47 (m, 3H), 3.35 (d, J=14.9 Hz, 3H), 3.02 (d, J=16.2 Hz, 1H), 2.87 (ddd, J=16.8, 12.9, 5.8 Hz, 3H), 2.68 (dt, J=15.4, 4.3 Hz, 1H), 2.56-2.41 (m, 1H), 2.07 (dt, J=14.3, 6.8 Hz, 1H), 1.98 (s, 2H), 1.90 (d, J=24.6 Hz, 3H), 1.79-1.65 (m, 1H), 1.37 (ddd, J=10.0, 6.5, 2.4 Hz, 3H), 1.06 (dt, J=13.8, 6.3 Hz, 3H), 0.74 (t, J=7.3 Hz, 3N).

Example 64

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a white} solid, 0.148 g, 51.4% yield. MS (m/z): [M+H] ⁺ calcd for _C30H37N7O5 , _576.29 ; found, 576.3. ¹ H NMR (400 MHz, chloroform-d) δ 8.28 (d, J=9.3 Hz, 1H), 7.25 (d, J=6.9 Hz, 5H), 7.07 (dd, J=16.0, 3.9 Hz, 1H), 6.51 (dd, J=7.1, 3.7 Hz, 1H), 6.23-6.14 (m, 2H), 5.49 (d, J=7.5 Hz, 1H), 5.29 (d, J=7.5 Hz, 1H), 5.11 (dt, J=9.7, 4.5 Hz, 1H), 4.13-3.76 (m, 2H), 3.63-3.46 (m, 4H), 3.36 (d, J=17.3 Hz, 3H), 2.49 (tt, J=13.9, 6.0 Hz, 1H), 1.87 (dd, J=9.5, 4.6 Hz, 1H), 1.82-1.67 (m, 1H), 1.39 (s, 9H), 1.08 (dd, J=13.5, 7.1 Hz, 3H).

Example 65

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-(1-oxoisoindol-2-yl))phenyl)butanoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-(1-oxoisoindol-2-yl))phenyl)butanoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (20 mg, 0.058 mmol), 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: ₁ to 50:1) to give the title compound as _a white solid, 0.012 g, 33.4% yield. MS (m/z): [M+H] ⁺ calculated for _C35H37N7O4 , _620.29 ; found, 620.3. ^1H NMR (400 MHz, chloroform-d) δ 8.30 (d, J=8.7 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.80-7.69 (m, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 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, 10.9 Hz, 2H), 5.08 (s, 1H), 4.82 (s, 2H), 4.05 (d, J=13.5 Hz, 1H), 3.92-3.66 (m, 2H), 3.53 (k, J=6.6, 5.1 Hz, 3H), 3.37-3.27 (m, 3H), 2.54-2.40 (m, 1H), 2.07 (dk, J=14.1, 7.3 Hz, 2H), 1.93 (s, 1H), 1.76 (t, J=19.7, 8.8 Hz, 2H), 1.06 (s, 3H), 0.82 (s, 3H).

Example 66

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-((3-chloro-2 chietylphenyl)amino)benzoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to give the title compound as a yellow solid, 0.145 g, 42.7% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₂ ClN ₇ O ₃ , 586.23; found, 586.3. ^1H NMR (400 MHz, chloroform-d) δ 9.20 (s, 1H), 8.37 (d, J = 7.1 Hz, 1H), 7.95 (dd, J = 8.2, 1.7 Hz, 1H), 7.30-7.17 (m, 4H), 7.12 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.60-6.55 (m, 1H), 6.42 (d, J = 3.3 Hz, 2H), 5.13 (k, J = 6.0, 5.5 Hz, 1H), 4.12-3.75 (m, 2H), 3.64-3.56 (m, 1H), 3.53-3.46 (m, 2H), 3.38 (d, J = 16.8 Hz, 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, 7.0 Hz, 3H).

Example 67

(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-((2,3-dimethylphenyl)amino)benzoate

Synthesis of (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylgosheridin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-((2,3-dimethylphenyl)amino)benzoate

3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a yellow} solid, 0.012 g, 45.6% yield. MS (m/z): [M+H] ⁺ calcd for _C32H35N7O3 , _566.28 ; found, 566.3. ¹ H NMR (400 MHz, chloroform-d) δ 9.14 (s, 1H), 8.37 (d, J = 7.1 Hz, 1H), 7.93 (dd, J = 8.1, 1.7 Hz, 1H), 7.29 (dd, J = 15.0, 3.7 Hz, 1H), 7.25-7.16 (m, 1H), 7.16-7.06 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H), 6.63-6.53 (m, 2H), 6.41 (d, J = 3.0 Hz, 2H), 5.12 (dt, J = 9.7, 4.7 Hz, 1H), 4.05 (dd, J = 13.2, 4.4 Hz, 1H), 3.78 (dd, J = 15.8, 13.2, 8.1 Hz, 1H), 3.58 (td, J = 11.3, 10.3, 5.0 Hz, 1H), 3.54-3.47 (m, 2H), 3.37 (d, J = 15.3 Hz, 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, 3.6 Hz, 1H), 1.07 (dd, J = 13.3, 7.0 Hz, 3H).

Example 68

N-methyl-1-((trans)-4-(methyl(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide

Synthesis of N-methyl-1-((trans)-4-(methyl(7-(2-(3-phenoxyphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 5:3) to _give the title compound as a white solid, _0.18 g, 64.1% yield. MS (m/z): [M+H] ⁺ calcd for _C30H35N5O4S , _562.24 ; found, 562.4. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.26 (s, 1H), 7.65 (d, J = 4.2 Hz, 1H), 7.40-7.33 (m, 2H), 7.29 (t, J = 7.9 Hz, 1H), 7.18-7.11 (m, 2H), 7.05 (t, J = 2.1 Hz, 1H), 6.98-6.90 (m, 2H), 6.90-6.78 (m, 3H), 6.06 (k, J = 6.9 Hz, 1H), 4.64 (s, 1H), 3.15 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.60 (d, J = 5.0 Hz, 3H), 2.10-2.02 (m, 2H), 1.92-1.77 (m, 1H), 1.70 (tt, J = 8.2, 3.1 Hz, 4H), 1.53 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 12.9 Hz, 2H).

Example 69

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as _{a white} solid, 0.27 g, 86.1% yield. MS (m/z): [M+H] ⁺ calcd for _C32H30FN7O4S , 628.21; found, 628.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.95 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.75 (d, J = 3.8 Hz, 1H), 7.50-7.41 (m, 4H), 7.40-7.32 (m, 2H), 7.19 (d, J = 3.8 Hz, 1H), 7.17-7.08 (m, 2H), 6.37-6.24 (m, 2H), 4.60 (d, J = 9.1 Hz, 2H), 4.25 (d, J = 9.1 Hz, 2H), 3.93 (k, J = 7.0 Hz, 1H), 3.69 (s, 2H), 3.23 (k, J = 7.3 Hz, 2H), 1.40 (d, J = 7.1 Hz, 3H), 1.25 (%J = 1.2 Hz, 3H).

Example 70

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(2,6-dichloroanilino)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:2) to give the title compound as _{a white} solid, 0.07 g, 20.6% yield. MS (m/z): _{[ M} +H] ⁺ calcd for _{C31H28Cl2N8O4S} , 679.13; found, 679.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 7.76 (d, J = 3.8 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.24-7.12 (m, 3H), 7.04 (td, J = 7.7, 1.6 Hz, 1H), 6.92 (s, 1H), 6.81 (td, J = 7.4, 1.2 Hz, 1H), 6.32 (s, 2H), 6.22 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 9.1 Hz, 2H), 4.26 (d, J = 9.1 Hz, 2H), 3.86 (s, 2H), 3.70 (s, 2H), 3.24 (k, J = 7.4 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H).

Example 71

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(3-phenoxyphenyl)propanoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(3-phenoxyphenyl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as _a white solid, 0.22 g, 70.4% yield. MS (m/z): _[ M+H] ⁺ calcd for _C32H31N7O5S , 626.21; found, 626.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.96 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.71 (d, J = 3.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.24 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 3.8 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.1, 2.5 Hz, 1H), 6.27 (d, J = 4.3 Hz, 2H), 4.61 (d, J = 9.1 Hz, 2H), 4.26 (d, J = 9.1 Hz, 2H), 3.84 (q, J = 7.1 Hz, 1H), 3.70 (s, 2H), 3.24 (q, J = 7.3 Hz, 2H), 1.35 (d, J = 7.1 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H).

Example 72

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as _a white solid, 0.26 g, 82.6% yield. MS (m/z): _[ M+H] ⁺ calcd for _C32H35N7O5S , 630.24; found, 630.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.78 (d, J = 1.6 Hz, 1H), 8.49 (s, 1H), 7.71 (d, J = 3.8 Hz, 1H), 7.17 (d, J = 3.8 Hz, 1H), 7.04 (ddd, J = 25.3, 8.1, 2.3 Hz, 4H), 6.26 (d, J = 4.2 Hz, 2H), 4.60 (d, J = 9.1 Hz, 2H), 4.25 (d, J = 9.1 Hz, 2H), 3.77 (q, J = 7.1 Hz, 1H), 3.69 (s, 2H), 3.24 (q, J = 7.3 Hz, 2H), 2.87 (dd, J = 13.3, 3.7 Hz, 1H), 2.40-2.15 (m, 3H), 2.04 (dd, J = 10.2, 8.5 Hz, 1H), 1.80 (d, J = 12.9 Hz, 2H), 1.70-156 (m, 1H), 1.44-1.31 (m, 4H), 1.28-1.23 (m, 3H).

Example 73

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

Synthesis of methyl (4-(1-(3-(cyanometal)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as _a yellow solid _, 0.26 g, 75.6% yield. MS (m/z): [M+H] ⁺ calcd for _{C36H33ClN8O6S} , 741.19; found, 741.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.98 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 7.76 (d, J = 3.8 Hz, 1H), 7.63 (s, 4H), 7.21 (d, J = 3.8 Hz, 1H), 6.96-6.87 (m, 2H), 6.68 (dd, J = 9.0, 2.5 Hz, 1H), 6.31 (s, 2H), 4.63 (d, J = 9.2 Hz, 2H), 4.27 (d, J = 9.1 Hz, 2H), 3.83 (s, 2H), 3.72 (s, 2H), 3.67 (s, 3H), 3.25 (k, J = 7.4 Hz, 2H), 2.14 (s, 3H), 1.27 (t, J = 7.3 Hz, 3H).

Example 74

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to give the title compound as _a white solid, 0.23 g, 72.5% yield. MS (m/z): [M+H] ⁺ calcd for _C30H34N8OS , _635.23 ; found, 635.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.97 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.41-7.16 (m, 6H), 6.42-6.24 (m, 2H), 5.20 (d, J = 7.8 Hz, 1H), 4.63 (d, J = 9.1 Hz, 2H), 4.27 (d, J = 9.2 Hz, 2H), 3.71 (s, 2H), 3.25 (k, J = 7.3 Hz, 2H), 1.38-1.21 (m, 12H).

Example 75

(R)-3-cyclopentyl-3-(4-(7-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Synthesis of (R)-3-cyclopentyl-3-(4-(7-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(2,6-dichloroanilino)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 5:1) to _give the title compound as _a white solid, 0.11 g, 31.4% yield. MS (m/z): [M+H] ⁺ calcd for _C31H27Cl2N7O , _584.17 ; found, 584.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.99 (s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.17 (d, J = 4.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.41-7.29 (m, 2H), 7.21 (dd, J = 17.2, 9.1 Hz, 2H), 7.15-7.02 (m, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 5.01 (s, 2H), 4.56 (td, J = 9.7, 4.2 Hz, 1H), 3.31-3.17 (m, 2H), 2.45 (k, J = 8.5 Hz, 1H), 1.83 (dtd, J = 12.2, 7.5, 3.9 Hz, 1H), 1.68-1.41 (m, 4H), 1.39-1.21 (m, 3H).

Example 76

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound as a white solid, 0.28 g, 82.5% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₅ H ₃₄ N ₈ O ₅ S, 679.24; found, 679.2. ^1H NMR (400 MHz, 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 = 3.8 Hz, 1H), 6.32 (k, J = 10.8 Hz, 2H), 5.00 (s, 2H), 4.63 (d, J = 9.1 Hz, 2H), 4.28 (d, J = 9.1 Hz, 2H), 3.72 (s, 2H), 3.63 (t, J = 7.6 Hz, 1H), 3.28 (k, J = 7.3 Hz, 2H), 2.04-1.97 (m, 1H), 1.76 (dt, J = 13.6, 7.0 Hz, 1H), 1.32-1.28 (m, 3H), 0.82 (t, J = 7.3 Hz, 3H).

Example 77

(3R)-3-cyclopentyl-3-(4-(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Synthesis of (3R)-3-cyclopentyl-3-(4-(7-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-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]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to _give the title compound as _a light yellow solid, 0.26 g, 81.1% yield. MS (m/z): [M+H] ⁺ calculated for _C32H34N6O2 , _535.27 ; found, 535.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.11 (d, J = 4.2 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 4.2 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.00 (q, J = 6.8 Hz, 1H), 4.55 (td, J = 9.6, 4.2 Hz, 1H), 3.31-3.15 (m, 2H), 2.90 (dd, J = 13.2, 3.4 Hz, 1H), 2.38 (tdd, J = 20.0, 14.0, 5.9 Hz, 3H), 2.20 (ddd, J = 18.1, 8.2, 2.8 Hz, 1H), 2.05 (dd, J = 10.1, 8.6 Hz, 1H), 1.92-1.75 (m, 3H), 1.68-1.50 (m, 7H), 1.48-1.22 (m, 5H)

Example 78

(R)-N-(4-(2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

Synthesis of (R)-N-(4-(2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(4-acetamidophenyl)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 2:3) to give the title compound as a light yellow solid, 0.18 g, 62.3% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₇ H ₂₇ N ₇ O ₂ , 482.22; found, 482.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.90 (s, 1H), 8.97 (s, 1H), 8.90 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 4.2 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 16.1, 6.1 Hz, 3H), 4.87 (s, 2H), 4.55 (td, J = 9.6, 4.1 Hz, 1H), 3.30-3.17 (m, 2H), 2.43 (p, J = 8.5 Hz, 1H), 2.04 (s, 3H), 1.83 (dhept, J = 12.4, 4.1, 3.7 Hz, 1H), 1.67-1.41 (m, 4H), 1.39-1.16 (m, 3H).

Example 79

(R)-3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

Synthesis of (R)-3-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to give the title compound as _a light _yellow solid, 0.3 g, yield 77.5%. MS (m/z): [M+H] ⁺ calcd for _C36H32ClN7O3 , _646.23 ; found, 646.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.03 (s, 1H), 8.93 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 4.2 Hz, 1H), 7.76-7.63 (m, 4H), 7.38 (d, J = 4.2 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 6.73 (dd, J = 9.1, 2.6 Hz, 1H), 5.05 (s, 2H), 4.58 (td, J = 9.6, 4.3 Hz, 1H), 3.71 (s, 3H), 3.31-3.19 (m, 2H), 2.46 (k, J = 8.2 Hz, 1H), 2.28 (s, 3H), 1.90-1.80 (m, 1H), 1.68-1.31 (m, 7H).

Example 80

tert-Butyl ((S)-2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

Synthesis of tert-butal-((S)-2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to give the title compound as a yellow solid, 0.26 g, yield 55.6%. MS (m/z): [M+H] ⁺ calculated for C ₃₀ H ₃₃ N ₇ O ₃ , 540.26; found, 540.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.87 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 4.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.31 (td, J = 11.8, 10.6, 5.4 Hz, 4H), 4.54 (td, J = 9.6, 4.3 Hz, 1H), 3.29-3.12 (m, 2H), 2.43 (g, J = 8.5 Hz, 1H), 1.82 (dtd, J = 11.9, 7.4, 4.2 Hz, 1H), 1.65-1.50 (m, 3H), 1.46-1.23 (m, 13H).

Example 81

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((3-chloro-2-methylphenyl)amino)benzoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((3-chloro-2-methylphenyl)amino)benzoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) _to give the title compound as _a yellow solid, 0.26 g, yield 80.7%. MS (m/z): _[ M+H] ⁺ calcd for _{C31H29ClN8O4S} , 645.17; found, 645.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.12 (s, 1H), 8.98 (s, 1H), 8.84 (s, 1H), 8.52 (s, 1H), 7.93 (d, J = 3.8 Hz, 1H), 7.79 (dd, J = 8.4, 1.7 Hz, 1H), 7.37 (td,7 = 7.6, 7.1, 1.7 Hz, 1H), 7.33-7.21 (m, 4H), 6.78-6.70 (m, 2H), 6.55 (s, 2H), 4.62 (d, J = 9.1 Hz, 2H), 4.26 (d, J = 9.1 Hz, 2H), 3.71 (s, 2H), 3.24 (k, J = 7.3 Hz, 2H), 2.24 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H).

Example 82

(R)-3-cyanopentyl-3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Synthesis of (R)-3-cyclopentyl-3-(4-(7-(2-((2,3-dimethylphenyl)amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-ciutopentylpropane (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 4:1 to 3:1) to _give the title compound as a yellow solid, 0.08 g, 25.2% yield. MS (m/z): [M+H] ⁺ calcd for _C32H31N7O , _530.26 ; found, 530.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 8.73 (s, 1H), 8.44 (d, J = 13.9 Hz, 2H), 7.87 (d, J = 4.0 Hz, 1H), 7.42 (ddd, J = 7.7, 4.5, 2.8 Hz, 2H), 7.29 (d, J = 4.1 Hz, 1H), 7.08-7.01 (m, 2H), 6.94 (dd, J = 6.2, 2.6 Hz, 1H), 6.87-6.75 (m, 2H), 4.56 (td, J = 9.7, 4.2 Hz, 1H), 3.29-3.15 (m, 2H), 2.45 (k, J = 8.4 Hz, 1H), 2.22 (s, 3H), 1.98 (s, 3H), 1.83 (dtd, J = 12.3, 7.4, 3.8 Hz, 1H), 1.55 (tdt, J = 32.5, 29.7, 18.3, 6.6 Hz, 4H), 1.39-1.22 (m, 3H).

Example 83

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((2,3-dimethylphenyl)amino)benzoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((2,3-dimethylphenyl)amino)benzoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as _{a yellow} solid, 0.27 g, yield 86.5%. MS (m/z): [M+H] ⁺ calcd for _C32H32N8O4S , 625.23; found, 625.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.06 (s, 1H), 8.98 (s, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 7.94 (d, J = 3.8 Hz, 1H), 7.76 (dd, J = 8.1, 1.7 Hz, 1H), 7.32 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 7.27 (d, J = 3.8 Hz, 1H), 7.18 7.05 (m, 3H), 6.70-6.59 (m, 2H), 6.55 (s, 2H), 4.61 (d, J = 9.1 Hz, 2H), 4.25 (d, J = 9.1 Hz, 2H), 3.70 (s, 2H), 3.24 (k, J = 7.3 Hz, 2H), 2.30 (s, 3H), 2.09 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H).

Example 84

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-acetamidophenyl)acetate

Synthesis of methyl (4-(1-(3-(cyanometal)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-acetamidophenyl)acetate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 2-(4-acetamidophenyl)acetic acid (actarit, 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound as a white solid, 0.22 g, 76.3% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₇ H ₂₈ N ₈ O ₅ S, 577.19; found, 577.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.89 (s, 1H), 8.98 (s, 1H), 8.84 (s, 1H), 8.52 (s, 1H), 7.78 (d, J = 3.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 31.5, 5.9 Hz, 3H), 6.29 (s, 2H), 4.63 (d, J = 9.1 Hz, 2H), 4.27 (d, J = 9.1 Hz, 2H), 3.69 (d, J = 20.8 Hz, 4H), 3.26 (k, J = 7.3 Hz, 2H), 2.04 (s, 3H), 1.27 (t, J = 7.4 Hz, 3H).

Example 85

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate

Synthesis of methyl (4-(1-(3-(cyanometal)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 31 mg, 0.25 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1 to 1:2) to _give the title compound as _a white solid, 0.17 g, 50.7% yield. MS (m/z): _[ M+H] ⁺ calcd for _C34H38N8O5S , 671.27; found, 671.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 7.61 (d, J = 3.8 Hz, 1H), 7.20-7.10 (m, 2H), 6.93-6.81 (m, 2H), 6.27-6.12 (m, 2H), 4.63 (d, J = 9.1 Hz, 2H), 4.27 (d, J = 9.1 Hz, 2H), 3.88-3.76 (m, 2H), 3.72 (s, 2H), 3.25 (q, J = 7.3 Hz, 2H), 3.06 (d, J = 13.6 Hz, 1H), 2.86 (d, J = 13.6 Hz, 1H), 2.81-2.75 (m, 2H), 2.61-2.48 (m, 2H), 2.01-1.80 (m, 2H), 1.30-1.21 (m, 6H), 0.58 (t, J = 7.3 Hz, 3H).

Example 86

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(4-isobutylphenyl)propanoate

First step: Synthesis of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-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) under nitrogen atmosphere. After stirring at room temperature for half an hour, (2-(chloromethoxy)ethyl)trimethylsilane (0.65 g, 3.92 mmol) was added in an ice-water bath and stirring was continued at room temperature for 3 hours. The reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography ₍ dichloromethane/methanol = 150:1 to 50:1) to give the title compound, 1.4 g, 98.5% yield. MS (m/z): [M+H] ⁺ calcd for _C23H32N6OSi , _437.24 ; found, 437.3.

Step 2: Synthesis of (R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

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]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (1.4 g, 3.2 mmol) in dichloromethane (90 mL) under nitrogen atmosphere in an ice-water bath. After half an hour, the ice-water bath was removed. The temperature was raised to room temperature and stirring was continued for another 2 hours. To the above reaction solution, saturated sodium bicarbonate solution was added at 0 °C to adjust the pH to 8. Then, the mixture was poured into a separatory funnel for separation. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 100:1 to 30:1) to give the title product, 0.36 g, 33.4% yield. MS (m/z): [M+H] ⁺ calcd for C ₁₈ H ₂₀ N ₆ O, 337.17; found, 337.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.95-8.80 (m, 2H), 8.49 (s, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.15 (d, J = 3.7 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 5.72 (d, J = 7.3 Hz, 2H), 4.64 (dtd, J = 9.6, 4.2 Hz, 1H), 3.42-3.26 (m, 2H), 2.53 (k, J = 8.5 Hz, 1H), 1.92 (dtd, J = 11.8, 7.5, 4.2 Hz, 1H), 1.76-1.50 (m, 4N), 1.50-1.23 (m, 3N).

Step 3: Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(4-isobutylphenyl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (120 mg, 0.36 mmol), 4-dimethylaminopyridine (DMAP, 44 mg, 0.36 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.106 g, 56.1% yield. MS (m/z): [M+H] ⁺ calcd for C ₃₁ H ₃₆ N ₆ O ₂ , 525.29; found, 525.3. ¹ H NMR (400 MHz, chloroform-d ) δ 8.85 (s, 1H), 8.31 (d, J = 10.9 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H), 6.72 (d, J = 3.8 Hz, 1H), 6.30-6.18 (m, 2H), 4.28 (ddd, J = 10.1, 8.6, 4.0 Hz, 1H), 3.71 (q, J = 7.1 Hz, 1H), 3.14 (dd, J = 17.0, 8.6 Hz, 1H), 2.97 (dd, J = 17.0, 4.0 Hz, 1H), 2.61 (ddd, J = 16.8, 8.2, 4.6 Hz, 1H), 2.40 (d, J = 7.1 Hz, 2H), 2.00-1.93 (m, 1H), 1.85-1.53 (m, 6H), 1.47 (d, J = 7.2 Hz, 3H), 1.37-1.23 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H).

Example 87

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(6-methoxynaphthalen-2-yl)propanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(6-methoxynaphthalin-2-yl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (140 mg, 0.42 mmol), 4-dimethylaminopyridine (DMAP, 51 mg, 0.42 mmol), (S)--(+)-2-(6-methoxy-2-naphthyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give _the title compound as a _white solid, 0.146 g, 63.4% yield. MS (m/z): [M+H] ⁺ calcd for _C32H32N6O3 , _549.25 ; found, 549.3. ¹ H NMR (400 MHz, chloroform-d ) δ 8.83 (s, 1H), 8.29 (d, J = 7.0 Hz, 2H), 7.60 (t, J = 8.6 Hz, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 3.8 Hz, 1H), 7.29 (dd, J = 6.6, 1.9 Hz, 1H), 7.14-7.03 (m, 2H), 6.68 (d, J = 3.8 Hz, 1H), 6.24 (d, J = 2.4 Hz, 2H), 4.27 (ddd, J = 10.1, 8.6, 4.0 Hz, 1H), 3.89 (s, 3H), 3.14 (dd, J = 17.0, 8.6 Hz, 1H), 2.96 (dd, J = 17.0, 4.0 Hz, 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, 6.5 Hz, 2H).

Example 88

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(4-isobutylphenyl)propanoate

Step One: Synthesis of N-methyl-1-((trans)-4-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 1687 mg, 5 mmol) and N,N-diisopropylethylamine (780 mg, 6 mmol) were added in dichloromethane (50 mL) under nitrogen atmosphere. After stirring at room temperature for half an hour, (2-(chloromethoxy)ethyl)trimethylsilane (1 g, 6 mmol) was added in an ice-water bath. Stirring was continued at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound as an oily solid, 2 g, 85.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₁ H ₃₇ N ₅ O ₃ SSi, 468.24; found, 468.2.

Step 2: Synthesis of 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(metal)amino)cyclohexyl)-N-methylmethanesulfonamide

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]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (2 g, 4.29 mmol) in dichloromethane (60 mL) under nitrogen atmosphere in an ice-water bath. After half an hour, the ice-water bath was removed, the temperature was raised to room temperature and stirring was continued for 24 hours. To the above reaction solution, saturated sodium bicarbonate solution was added at 0 °C to adjust the pH to 8. Then, the mixture was poured into a separatory funnel for separation. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 0:1) to give the title product, 0.9 g, 98.5% yield. MS (m/z): [M+H] ⁺ calcd for C ₁₆ H ₂₅ N ₅ O ₃ S, 368.17; found, 368.2.

Step 3: Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-(S)-2-(4-isobutylphenyl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (150 mg, 0.41 mmol), 4-dimethylaminopyridine (DMAP, 50 mg, 0.41 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:2) to give the title compound as a white solid, 0.086 g, 37.7% yield. MS (m/z): [M+H] ⁺ calcd for C ₂₉ H ₄₁ N ₅ O ₄ S, 556.29; found, 556.3. ¹ H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.11 (d, J = 7.7 Hz, 2H), 7.08-6.94 (m, 3H), 6.48 (d, J = 3.8 Hz, 1H), 6.22-6.04 (m, 2H), 4.75 (s, 1H), 4.31 (q, J = 5.3 Hz, 1H), 3.68 (q, J = 7.2 Hz, 1H), 3.20 (s, 3H), 2.96 (d, J = 6.2 Hz, 2H), 2.82 (d, J = 5.1 Hz, 3H), 2.41 (d, J = 7.1 Hz, 2H), 2.24-2.13 (m, 2H), 2.06-1.95 (m, 1H), 1.84 (ddd, J = 22.7, 13.2, 5.3 Hz, 3H), 1.76-1.62 (m, 2H), 1.44 (d, J = 7.3 Hz, 3H), 1.36 (d, J = 12.4, 9.1 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H).

Example 89

(4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(6-methoxynaphthalen-2-yl)propanoate

Synthesis of (4-(methyl((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(6-methoxynaphthalen-2-yl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-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)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:2) to _give the title compound as _a white solid, 0.056 g, 23.5% yield. MS (m/z): _[ M+H] ⁺ calcd for _C30H37N5O5S , 580.25; found, 580.3. ^1H NMR (400 MHz, 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=3.8 Hz, 1H), 6.14 (k, J= 10.6 Hz, 2H), 4.72 (s, 1H), 4.24 (k, J = 5.4 Hz, 1H), 3.97-3.78 (m, 4H), 3.17 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.82 (d, J = 5.3 Hz, 3H), 2.16 (d, J = 13.1 Hz, 2H), 1.99 (s, 1H), 1.85 (d, J = 11.1 Hz, 2H), 1.74-1.60 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H), 1.36 (td, J = 13.7, 5.9 Hz, 2H).

Example 90

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-benzoylphenyl)propanoate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(3-benzoylphenyl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2) to _give the title compound as _a white solid, 0.16 g, 44.2% yield. MS (m/z): [M+H] ⁺ calcd for _C32H37N5O5S , _604.25 ; found, 604.4. ^1H NMR (400 MHz, DMSO- _d6 )5 8.12(s, 1H), 7.71-7.65 (m, 3H), 7.61-7.51 (m, 5H), 7.46 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 3.8 Hz, 1H), 6.88 (k, J = 4.9 Hz, 1H), 6.60 (d, J = 3.7 Hz, 1H), 6.14 (s, 2H), 4.63 (s, 1H), 3.95 (k, J = 7.1 Hz, 1H), 3.13 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.59 (d, J = 5.0 Hz, 3H), 2.09-2.01 (m, 2H), 1.81 (s, 1H), 1.72-1.62 (m, 4H), 1.39 (d, J = 7.1 Hz, 3H), 1.35-1.26 (m, 2H).

Example 91

(4-(methyl-((trans)-4-((N-methylsulfamoyl)metal)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1: ₂ ) to give the title compound as a _white solid, 0.14 g, 38.8% yield. MS (m/z): _[ M+H] ⁺ calcd for _C29H40N6O6S , 601.27; found, 601.4. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.21 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.39-7.25 (m, 6H), 6.94 (k, J = 5.0 Hz, 1H), 6.67 (d, J = 3.8 Hz, 1H), 6.27-6.16 (m, 2H), 5.22 (d, J = 7.9 Hz, 1H), 4.71 (s, 1H), 3.21 (s, 3H), 3.01 (d, J = 6.2 Hz, 2H), 2.64 (d, J = 5.0 Hz, 3H), 2.10 (d, J = 12.7 Hz, 2H), 1.95-1.85 (m, 1H), 1.73 (d, J = 7.5 Hz, 4H), 1.41 (s, 11H).

Example 92

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

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(2,6-dichloroanilino)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to _give the title compound as _{a white} solid, 0.14 g, 36.2% yield. MS (m/z): [M+H] ⁺ calcd for _{C30H34Cl2N6O4S} , _645.17 ; found, 645.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 3.8 Hz, 1H), 7.24-7.12 (m, 2H), 7.05 (td, J = 7.7, 1.6 Hz, 1H), 6.95 (s, 1H), 6.87 (q, J = 4.9 Hz, 1H), 6.82 (td, J = 7.4, 1.2 Hz, 1H), 6.64 (d, J = 3.8 Hz, 1H), 6.23 (dd, J = 8.0, 1.2 Hz, 1H), 6.19 (s, 2H), 4.66 (s, 1H), 3.82 (s, 2H), 3.16 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.59 (d, J = 5.0 Hz, 3H), 2.05 (d, J = 12.1 Hz, 2H), 1.82 (s, 1H), 1.75-1.65 (m, 4H), 1.30 (k, J = 7.9, 7.2 Hz, 2H).

Example 93

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(4-acetamidophenyl)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 16 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 0:1) to _give the title compound as a white solid, _0.016 g, 49.2% yield. MS (m/z): [M+H] ⁺ calcd for _C26H34N6O5S , _543.23 ; found, 543.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.89 (s, 1H), 8.19 (s, 1H), 7.54-7.39 (m, 2H), 7.29 (d, J = 3.8 Hz, 1H), 7.19-7.09 (m, 2H), 6.87 (k, J = 4.9 Hz, 1H), 6.65 (d, J = 3.7 Hz, 1H), 6.14 (s, 2H), 4.67 (s, 1H), 3.61 (s, 2H), 3.17 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.59 (d, J = 5.0 Hz, 3H), 2.03 (s, 5H), 1.84 (s, 1H), 1.70 (k, J = 6.7 Hz, 4H), 1.37-1.27 (m, 2H).

Example 94

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-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-tetrahydropyran[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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 0:1) to _give the title compound as _a white solid, 0.14 g, 36.6% yield. MS (m/z): _[ M+H] ⁺ calcd for _C33H44N6O5S , 637.31; found, 637.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.42 (s, 1H), 8.18 (s, 1H), 7.20 (dd, J = 7.6, 1.4 Hz, 1H), 7.13 (d, J = 3.8 Hz, 1H), 6.94-6.84 (m, 3H), 6.56 (d, J = 3.8 Hz, 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 = 7.3 Hz, 3H).

Example 95

2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 1113 mg, 3 mmol), 4-dimethylaminopyridine (DMAP, 36.6 mg, 0.3 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to ₁ :2) to give the title compound as a white solid, _0.12 g, 71.5% yield. MS (m/z): [M+H] ⁺ calcd for _C29H33N7O3S , _560.69 ; found, 560.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J = 4.2 Hz, 2H), 8.50 (s, 1H), 8.14 (d, J = 4.2 Hz, 1H), 7.40 (d, J = 4.2 Hz, 1H), 7.37-7.29 (m, 2H), 7.08 (d, J = 7.9 Hz, 2H), 5.99 (q, J = 6.9 Hz, 1H), 4.59 (d, J = 9.1 Hz, 2H), 4.24 (d, J = 9.1 Hz, 2H), 3.68 (s, 2H), 3.23 (q, J = 7.3 Hz, 2H), 2.35 (d, J = 7.2 Hz, 2H), 1.76 (hept, J = 6.7 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H), 0.80 (d, J = 6.6 Hz, 6H).

Example 96

l-((trans)-4-((7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

Synthesis of 1-((trans)-4-((7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide

N-methyl-1-((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (oclacitinib, 150 mg, 0.44 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.044 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 4:1 to ₂ :1) to _give the title compound as a white solid, 0.07 g, 30% yield. MS (m/z): [M+H] ⁺ calcd for _C28H39N5O3S , _526.28 ; found, 526.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.36 (s, 1H), 7.66 (d, J = 4.2 Hz, 1H), 7.33-7.26 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.95-6.81 (m, 2H), 6.10 (k, J = 6.9 Hz, 1H), 4.66 (s, 1H), 3.15 (s, 3H), 2.94 (d, J = 6.2 Hz, 2H), 2.58 (d, J = 5.0 Hz, 3H), 2.36 (d, J = 7.1 Hz, 2H), 2.10-1.96 (m, 2H), 1.91-1.60 (m, 6H), 1.52 (d, J = 7.0 Hz, 3H), 1.35-1.22 (m, 2H), 0.82 (d, J = 6.7 Hz, 6H).

Example 97

4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylgosheridin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

Synthesis of 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylgaseridin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (piroxicam, 66 mg, 0.2 mmol) and triphenylphosphine (PPH ₃ , 79 mg, 0.3 mmol) were added to tetrahydrofuran (0.4 mL) and stirred under nitrogen atmosphere. After cooling to -10°C, diisopropyl azodicarboxylate (DIAD, 53 mg, 0.26 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature naturally. 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (68 mg, 0.2 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.005 g, 3.8% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₂ H ₃₃ N ₉ O ₅ S, 656.23, found, 656.2. ^1H NMR (400 MHz, chloroform-d) δ 15.22 (d, J = 17.7 Hz, 1H), 8.52 (t, J = 8.4 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.23 (d, J = 3.1 Hz, 1H), 8.07-7.91 (m, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.71-7.55 (m, 3H), 6.70-6.58 (m, 2H), 6.51 (dd, J = 9.8, 3.8 Hz, 1H), 4.95 (s, 1H), 4.06 (dd, J = 13.0, 4.4 Hz, 1H), 3.85-3.67 (m, 1H), 3.66-3.55 (m, 1H), 3.54-3.36 (m, 4H), 3.27 (d, J = 18.4 Hz, 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 = 7.7H, 3H).

Example 98

(R)-3-cyclopentyl-3-(4-(7-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Synthesis of (R)-3-cyclopentyl-3-(4-(7-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl)-3-ciutopentylpropane (ruxolitinib, 50 mg, 0.163 mmol), 4-dimethylaminopyridine (DMAP, 2 mg, 0.016 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 4:1 to 3:1) to _give the title compound as _a white solid, 0.05 g, 61% yield. MS (m/z): [M+H] ⁺ calculated for _C30H34N6O4 , _495.64 ; found, 495.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.97 (s, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.39 (d, J = 11.3 Hz, 1H), 8.12 (d, J = 4.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.09 (dd, J = 7.9, 5.8 Hz, 2H), 6.00 (k, J = 6.9 Hz, 1H), 4.54 (td, J = 9.6, 4.6 Hz, 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).

Example 99

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-benzoylphenyl)propanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-benzoylphenyl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl)propanoic 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a white} solid, 0.143 g, 50% yield. MS (m/z): [M+H] ⁺ calcd for _C34H32N6O3 , _573.25 ; found, 573.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (d, J = 0.7 Hz, 1H), 8.72 (s, 1H), 8.38 (s, 1H), 7.69 (d, J = 3.8 Hz, 1H), 7.68-7.62 (m, 3H), 7.58 (d, J = 1.8 Hz, 1H), 7.57-7.49 (m, 4H), 7.44 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 3.8 Hz, 1H), 6.33-6.22 (m, 2H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.99 (k, J = 7.0 Hz, 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).

Example 100

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a white} solid, 0.15 g, 53.3% yield. MS (m/z): [M+H] ⁺ calcd for _C33H31FN6O2 , _563.25 ; found, 563.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.73 (d, J = 3.7 Hz, 1H), 7.50-7.31 (m, 6H), 7.17-7.07 (m, 3H), 6.35-6.24 (m, 2H), 4.54 (td, J = 9.7, 4.2 Hz, 1H), 3.92 (k, J = 7.1 Hz, 1H), 3.33-3.14 (m, 2H), 2.42 (t, J = 8.5 Hz, 1H), 1.82 (dtd, J = 12.0, 7.6, 4.5 Hz, 1H), 1.64-1.48 (m, 3H), 1.48-1.11 (m, 7H).

Example 101

(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2,6-dichloroanilino)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered.

The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.12 g, 39.1% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₂ H ₂₉ Cl ₂ N ₇ O ₂ , 614.18; found, 614.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86-8.73 (m, 2H), 8.40 (s, 1H), 7.81-7.68 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.26-6.94 (m, 4H), 6.81 (td, J = 7.4, 1.1 Hz, 1H), 6.31 (s, 2H), 6.21 (d, J = 8.1 Hz, 1H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.87 (d, J = 14.3 Hz, 2H), 3.24 (cd, J = 17.2, 6.9 Hz, 2H), 2.43 (g, J = 8.3 Hz, 1H), 1.82 (kt, J = 7.5, 5.4, 4.1 Hz, 1H), 1.67-1.40 (m, 4H), 1.40-1.13 (m, 3H).

Example 102

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-phenoxyphenyl)propanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-phenoxyphenyl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give _the title compound as a _white solid, 0.133 g, 457.5% yield. MS (m/z): [M+H] ⁺ calcd for _C33H32N6O3 , _561.25 ; found, 561.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.74 (s, 1H), 8.40 (s, 1H), 7.67 (d, J = 3.8 Hz, 1H), 7.33 (dd, J = 8.5, 7.3 Hz, 2H), 7.24 (t, J = 7.9 Hz, 1H), 7.14-7.05 (m, 2H), 6.97 (dt, J = 7.7, 1.2 Hz, 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, 4.2 Hz, 1H), 3.83 (k, J = 7.0 Hz, 1H), 3.28 (dd, J = 17.2, 9.6 Hz, 1H), 3.19 (dd, J = 17.2, 4.2 Hz, 1H), 2.42 (g, J = 8.6 Hz, 1H), 1.82 (dtd, J = 11.9, 7.5, 4.4 Hz, 1H), 1.66-1.43 (m, 4H), 1.43-1.12 (m, 6H).

Example 103

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give _the title compound as a _white solid, 0.125 g, 44.3% yield. MS (m/z): [M+H] ⁺ calcd for _C33H36N6O3 , _565.28 ; found, 565.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.82 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.39 (s, 1H), 7.68 (d, J = 3.8 Hz, 1H), 7.11-6.96 (m, 5H), 6.28-6.19 (m, 2H), 4.54 (td, J = 9.6, 4.2 Hz, 1H), 3.76 (k, J = 7.0 Hz, 1H), 3.23 (cd, J = 17.1, 6.9 Hz, 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).

Example 104

(R)-2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

Synthesis of (R)-2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a light yellow solid, 0.176 g, 52.1% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₇ H ₃₄ ClN ₇ O ₄ , 676.24; found, 676.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.84 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.71 (d, J = 3.8 Hz, 1H), 7.62 (s, 4H), 7.10 (d, J = 3.8 Hz, 1H), 6.95-6.85 (m, 2H), 6.66 (dd, J = 9.0, 2.5 Hz, 1H), 6.29 (s, 2H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.82 (s, 2H), 3.65 (s, 3H), 3.32-3.15 (m, 2H), 2.42 (p, J = 8.5 Hz, 1H), 2.13 (s, 3H), 1.89-1.76 (m, 1H), 1.59 (dddd, J = 26.4, 12.6, 7.1, 4.5 Hz, 3H), 1.41-1.12 (m, 4H).

Example 105

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (20 mg, 0.058 mmol), 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.152 g, 49.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₆ H ₃₅ N ₇ O ₃ , 614.28; found, 614.4. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (s, 1H), 8.38 (s, 1H), 7.79 (t, J = 8.5 Hz, 3H), 7.74-7.67 (m, 2H), 7.67-7.62 (m, 1H), 7.54 (td, J = 7.2, 1.5 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 3.7 Hz, 1H), 6.35-6.21 (m, 2H), 4.96 (s, 2H), 4.53 (td, J = 9.6, 4.2 Hz, 1H), 3.58 (t, J = 7.6 Hz, 1H), 3.23 (cd, J = 17.2, 6.9 Hz, 2H), 2.42 (g, J = 8.4 Hz, 1H), 2.07-1.88 (m, 1H), 1.81 (dtd, J = 12.1, 7.6, 4.4 Hz, 1H), 1.76-1.40 (m, 5H), 1.40-1.11 (m, 4H), 0.77 (t, J = 7.3 Hz, 3H).

Example 106

(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoate

Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give _the title compound as _a yellow solid, 0.147 g, 52.6% yield. MS (m/z): [M+H] ⁺ calcd for _C33H33N7O2 , _560.27 ; found, 560.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.08 (s, 1H), 8.84 (d, J = 18.4 Hz, 2H), 8.42 (s, 1H), 7.91 (d, J = 3.8 Hz, 1H), 7.75 (dd, J = 8.1, 1.6 Hz, 1H), 7.32 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 7.20-7.00 (m, 4H), 6.69-6.59 (m, 2H), 6.54 (s, 2H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.24 (cd, J = 17.2, 6.9 Hz, 2H), 2.43 (k, J = 8.4 Hz, 1H), 2.29 (s, 3H), 2.08 (s, 3H), 1.82 (dtd, J = 12.0, 7.4, 3.9 Hz, 1H), 1.65-1.50 (m, 3H), 1.49-1.12 (m, 4H).

Example 107

(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoate

Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (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 (0.20 ml) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a yellow solid, 0.161 g, 55.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₂ H ₃₀ ClN ₇ O ₂ , 580.21; found, 580.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.83 (d, J = 18.6 Hz, 2H), 8.42 (s, 1H), 7.90 (d, J = 3.8 Hz, 1H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (ddd, J = 8.8, 7.1, 1.7 Hz, 1H), 7.32-7.21 (m, 3H), 7.17 (d, J = 3.8 Hz, 1H), 6.78-6.68 (m, 2H), 6.54 (s, 2H), 4.55 (td, J = 9.6, 4.2 Hz, 1H), 3.33-3.15 (m, 2H), 2.43 (k, J = 8.4 Hz, 1H), 2.24 (s, 3H), 1.82 (dtd,7 = 11.9, 7.4, 4.2 Hz, 1H), 1.59 (ddd, J = 23.3, 7.9, 5.7 Hz, 2H), 1.47-1.12 (m, 5H).

Example 108

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-isobutylphenyl)propanoate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-isobutylphenyl)propanoate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.145 g, 55.3% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₆ N ₆ O ₂ , 525.29, found, 525.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (s, 1H), 8.74 (s, 1H), 8.39 (s, 1H), 7.68 (d, J = 3.8 Hz, 1H), 7.12-7.02 (m, 3H), 6.95 (d, J = 7.9 Hz, 2H), 6.25 (k, J = 10.7 Hz, 2H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.76 (k, J = 7.0 Hz, 1H), 3.30-3.15 (m, 2H), 2.43 (k, J = 8.5 Hz, 1H), 2.32 (d, J = 7.1 Hz, 2H), 1.89-1.77 (m, 1H), 1.70 (hept, J = 6.8 Hz, 1H), 1.64-1.48 (m, 3H), 1.41-1.13 (m, 7H), 0.76 (dd, J = 6.6, 1.0 Hz, 6H).

Example 109

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.153 g, 50.5% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₅ H ₃₉ N ₇ O ₃ , 606.31; found, 606.3. ^1H 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, 1.5 Hz, 1H), 7.15 (dd, J = 7.3, 1.5 Hz, 1H), 7.01 (d, J = 3.7 Hz, 1H), 6.90-6.79 (m, 2H), 6.19 (d, J = 1.4 Hz, 2H), 4.56 (td, J = 9.7, 4.2 Hz, 1H), 3.82 (td, J = 11.1, 5.4 Hz, 2H), 3.31-3.15 (m, 2H), 3.05 (d, J = 13.6 Hz, 1H), 2.88-2.69 (m, 3H), 2.60 (ddd, J = 15.0, 8.1, 5.3 Hz, 1H), 2.44 (k, J = 8.4 Hz, 1H), 2.07-1.76 (m, 3H), 1.68-1.41 (m, 4H), 1.41-1.14 (m, 7H), 0.57 (%J = 7.2 Hz, 3H).

Example 110

(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate

Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl)acetic acid (actarit, 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.133 g, 52% yield. MS (m/z): [M+H] ⁺ calcd for C ₂₈ H ₂₉ N ₇ O ₃ , 512.23; found, 512.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.91 (s, 1H), 8.83 (d, J = 20.0 Hz, 2H), 8.41 (s, 1H), 7.75 (d, J = 3.7 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.18-7.10 (m, 3H), 6.27 (s, 2H), 4.55 (td, J = 9.6, 4.2 Hz, 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).

Example 111

(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate

(R)-3-cyclopentyl-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered.

The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a white solid, 0.153 g, 53.7% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₅ N ₇ O ₄ , 570.28; found, 570.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.84 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 3.7 Hz, 1H), 7.40-7.19 (m, 5H), 7.09 (d, J = 3.8 Hz, 1H), 6.37-6.22 (m, 2H), 5.19 (d, J = 7.8 Hz, 1H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.29-3.15 (m, 2H), 2.45-2.34 (m, 1H), 1.88-1.77 (m, 1H), 1.67-1.40 (m, 4H), 1.39-1.11 (m, 12H).

Example 112

Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-isobutylphenyl)propanoate

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-isobutylphenyl)propanoate

2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (143 mg, 0.356 mmol), 4-dimethylaminopyridine (DMAP, 44 mg, 0.356 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give _the title compound as a _white solid, 0.191 g, 91% yield. MS (m/z): _[ M+H] ⁺ calcd for _C30H35N7O4S , 590.25, found, 590.3. ¹ H NMR (400 MHz, chloroform-d) δ 8.85 (s, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 7.44 (d, J=3.8 Hz, 1H), 7.09 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.1 Hz, 2H), 6.71 (d, J=3.8 Hz, 1H), 6.27-6.17 (m, 2H), 4.63 (d, J=9.2 Hz, 2H), 4.29 - 4.22 (m, 2H), 3.70 (q, J=7.1 Hz, 1H), 3.40 (s, 2H), 3.08 (q, J=7.4 Hz, 2H), 2.38 (d, J=7.2 Hz, 2H), 1.79 (dg, J=13.5, 6.7 Hz, 1H), 1.48 - 1.38 (m, 6H), 0.85 (d, J=6.6 Hz, 6H).

Example 113

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1,1,-diphenyl]-4-yl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-b]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-T-methylmethanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a white} solid, 0.072 g, 24.2% yield. MS (m/z): [ _M +H] ⁺ calcd for _C31H36FN5O4S , 594.25; found, 594.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 7.54 - 7.44 (m, 4H), 7.42 - 7.35 (m, 2H), 7.29 (d, J=3.7 Hz, 1H), 7.12 (d, J=9.9 Hz, 2H), 6.90 (q, J=5.0 Hz, 1H), 6.63 (d, J=3.7 Hz, 1H), 6.17 (d, J=2.1 Hz, 2H), 4.64 (s, 1H), 3.89 (q, J=7.1 Hz, 1H), 3.15 (s, 3H), 2.95 (d, J=6.2 Hz, 2H), 2.59 (d, J=5.0 Hz, 3H), 2.07 - 1.99 (m, 2H), 1.84 (dt, J=11.8, 6.9 Hz, 1H), 1.75 - 1.61 (m, 4H), 1.39 (d, J=7.1 Hz, 3H), 1.36-1.21 (m, 2H).

Example 114

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(3-phenoxyphenyl)propanoate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(3-phenoxyphenyl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a white} solid, 0.118 g, 39.9% yield. MS (m/z): [M+H] ⁺ calcd for _C31H37N5O5S , _592.25 ; found, 592.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.42 (dd, J=8.5, 7.3 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.07-6.85 (m, 6H), 6.68 (d, J=3.7 Hz, 1H), 6.19 (s, 2H), 4.71 (s, 1H), 3.86 (k, J=7.1 Hz, 1H), 3.21 (s, 3H), 3.01 (d, J=6.2 Hz, 2H), 2.64 (d, J=5.0 Hz, 3H), 2.10 (d, J=12.9 Hz, 2H), 1.97 - 1.82 (m, 1H), 1.73 (t, J=5.3 Hz, 4H), 1.42 - 1.27 (m, 5H).

Example 115

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-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]propanoic 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 dimethylformide (0.3 mL) and stirred at room temperature for 18 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give _the title compound as a _white solid, 0.073 g, 24.5% yield. MS (m/z): [M+H] ⁺ calcd for _C31H41N5O5S , _596.28 ; found, 596.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J=1.9 Hz, 1H), 7.25 (d, J=3.7 Hz, 1H), 7.07 (cd, J=8.3, 2.9 Hz, 4H), 6.89 (k, J=4.9 Hz, 1H), 6.62 (d, J=3.8 Hz, 1H), 6.12 (d, J=1.6 Hz, 2H), 4.65 (s, 1H), 3.74 (k, J=7.0 Hz, 1H), 3.16 (s, 3H), 3.00 - 2.80 (m, 3H), 2.59 (d, J=5.0 Hz, 3H), 2.45 - 2.16 (m, 3H), 2.05 (dddd, J=14.5, 10.1, 8.5, 1.7 Hz, 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).

Example 116

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-b]pyrimidin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as a light yellow solid, 0.136 g, 38.5% yield. MS (m/z): [M+H] ⁺ calcd for C+35H39ClN6O6S, 707.23; found, 707.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.64 (s, 4H), 7.28 (d, J=3.7 Hz, 1H), 7.01 - 6.83 (m, 3H), 6.70 (dd, J=9.0, 2.6 Hz, 1H), 6.64 (d, J=3.8 Hz, 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=6.2 Hz, 2H), 2.60 (d, J=4.9 Hz, 3H), 2.14 (s, 3H), 2.06 (d, J=12.8 Hz, 2H), 1.96 - 1.80 (m, 1H), 1.77 - 1.63 (m, 4H), 1.31 (p, J=4.9, 4.3 Hz, 2H).

Example 117

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-(4-(1-)oxoisoindolin-2-yl)phenyl)butanoate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-(1-)oxoisoindolin-2-yl)phenyl)butanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (20 mg, 0.058 mmol), 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic 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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150:1 to 50:1) to give the title compound as _{a white} solid, 0.156 g, 48.4% yield. MS (m/z): _[ M+H] ⁺ calcd for _C34H40N6O5S , 645.28; found, 645.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.86 - 7.75 (m, 3H), 7.68 (dd, J=6.3, 1.2 Hz, 2H), 7.55 (dd, J=8.1, 6.3, 2.0 Hz, 1H), 7.34 - 7.24 (m, 3H), 6.88 (k, J=5.0 Hz, 1H), 6.62 (d, J=3.8 Hz, 1H), 6.22 - 6.08 (m, 2H), 4.99 (s, 2H), 4.64 (s, 1H), 3.55 (t, J=7.6 Hz, 1H), 3.14 (s, 3H), 2.94 (d, J=6.2 Hz, 2H), 2.59 (d, J=5.0 Hz, 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=7.3 Hz, 3H). Example 118

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-2-((2,3-dimethylphenyl)amino)benzoate

Synthesis of (4-(methyl-((trans)-4-(((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((2,3-dimethylphenyl)amino)benzoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol=150:1 to 50:1) to give _the title compound as _a yellow solid, 0.096 g, 32.5% yield. MS (m/z): _[ M+H] ⁺ calcd for _C31H38N6O4S , 591.27; found, 591.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.21 (s, 1H), 7.73 (dd, J=8.1, 1.6 Hz, 1H), 7.47 (dd, J=8.8, 3.9 Hz, 1H), 7.32(ddd,J=8.6, 7.0, 1.7 Hz, 1H), 7.19-7.03 (m, 3H), 6.90 (k, J=4.9 Hz, 1H), 6.66 (ddd,J=20.2, 9.1, 4.5 Hz, 3H), 6.41 (s, 2H), 4.68 (s, 1H), 3.22 - 3.13 (m, 3H), 2.95 (d, J=6.2 Hz, 2H), 2.59 (d, J=4.9 Hz, 3H), 2.29 (s, 2H), 2.06 (d, J=14.3 Hz, 5H), 1.92 - 1.79 (m, 1H), 1.70 (g, J=3.4 Hz, 4H), 1.38-1.19 (m, 2H).

Example 119

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-isobutylphenyl)propanoate

Synthesis of (4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(4-isobutylphenyl)propanoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (201 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol=150:1 to 50:1) to give the title compound as a white solid, 0.142 g, 51.1% yield. MS (m/z): [M+H]++calculated for C-29H41N5O4S, 556.29, found, 556.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (s, 1H), 7.24 (d, J=3.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.89 (q, J=5.0 Hz, 1H), 6.61 (d, J=3.7 Hz, 1H), 6.12 (s, 2H), 4.66 (s, 1H), 3.73 (q, J=7.0 Hz, 1H), 3.15 (s, 3H), 2.95 (d, J=6.2 Hz, 2H), 2.59 (d, J=5.0 Hz, 3H), 2.37 (d, J=7.1 Hz, 2H), 2.05 (d, J=12.9 Hz, 2H), 1.91-1.80 (m, 1H), 1.79 - 1.64 (m, 5H), 1.37 - 1.25 (m, 5H), 0.82 (d, J=6.6 Hz, 6H).

Example 120

(4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-((3-chloro-2-methylphenyl)amino)benzoate

Synthesis of (4-(methyl-((trans)-4-(((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2-(((3-chloro-2-methylphenyl)amino)benzoate

1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography ₍ dichloromethane/methanol=150:1 to 50:1) to give the title compound as _a yellow solid, 0.137 g, 44.9% yield. MS (m/z): _[ M+H] ⁺ calcd for _{C30H35ClN6O4S} , 611.21; found, 611.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18(s, 1H), 8.26 (s, 1H), 7.81 (dd, J=8.2, 1.5 Hz, 1H), 7.51 (d, J=3.7 Hz, 1H), 7.43 (td, J=7.7, 7.1, 1.7 Hz, 1H), 7.40 - 7.20 (m, 3H), 6.95 (k, J=5.0 Hz, 1H), 6.84 - 6.73 (m, 3H), 6.47 (s, 2H), 4.74 (s, 1H), 3.24 (s, 3H), 3.01 (d, J=6.2 Hz, 2H), 2.65 (d, J=4.9 Hz, 3H), 2.29 (s, 3H), 2.11 (dd, J=10.1, 5.0 Hz, 2H), 2.00 - 1.86 (m, 1H), 1.74 (d, J=9.5 Hz, 4H), 1.36 (k, J=10.0, 7.2 Hz, 2H).

Example 121

4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyr Imidin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazin-3-carboxamide-1,1-dioxide

Synthesis 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyr Imidin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazin-3-carboxamide-1,1-dioxide

4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (piroxicam, 103 mg, 0.312 mmol) and triphenylphosphine (PPH-3, 164 mg, 0.624 mmol) were added to tetrahydrofuran (3 mL) under nitrogen atmosphere. After cooling to -10°C, diisopropyl azodicarboxylate (DIAD, 95 mg, 0.468 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature naturally, 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (150 mg, 0.374 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product.

The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a _yellow solid, _0.012 g, 5.3% yield. MS (m/z): [M+H] ⁺ calculated for _{C32H30N10O6S2} , _715.18 , found _, 715.2. ^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=8.3 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.24 (d, J=3.8 Hz, 1H), 6.92 - 6.86 (m, 1H), 6.60 (d, J=3.8 Hz, 1H), 6.05 (s, 2H), 4.56 (d, J=9.3 Hz, 2H), 4.18 (d, J=9.3 Hz, 2H), 3.35 (s, 2H), 3.08 - 2.96 (m, 5H), 1.36 (t, J=7.4 Hz, 3H).

Example 122

4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(5-methylthiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

Synthesis of 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(5-methylthiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

To tetrahydrofuran (2.8 ml) were added 4-hydroxy-2-methyl-N-(5-methylthiazol-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) under nitrogen atmosphere. Diisopropyl azodicarboxylate (DIAD, 92 mg, 0.45 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature naturally. 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (140 mg, 0.35 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.005 g, 1.9% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₀ N ₁₀ O ₆ S ₃ , 735.15, found, 735.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.61 (s, 1H), 8.94 (s, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.88 - 7.78 (m, 3H), 7.73 (d, J=3.7 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J=3.7 Hz, 1H), 5.62 (s, 2H), 4.60 (d, J=9.1 Hz, 2H), 4.24 (dd, J=9.1, 2.4 Hz, 2H), 3.69 (d, J=2.7 Hz, 2H), 3.27 - 3.20 (m, 2H), 2.85 (s, 3H), 2.32 (s, 3H), 1.27 - 1.20 (m, 3H). Example 123

(3S,4R)-3-ethyl-4-(3-((S)-2-(4-isobutylphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-((S)-2-(4-isobutylphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-H-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib, 338 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 122 mg, 1 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give _the title compound as _{a white} solid, 0.05 g, 17.6% yield. MS (m/z): [M+H] ⁺ calcd for _C30H35F3N6O2 , _569.28 ; found, 569.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 8.04 (d, J=4.2 Hz, 1H), 7.63 (s, 1H), 7.37 - 7.29 (m, 2H), 7.19 - 7.04 (m, 3H), 6.97 (t, J=6.3 Hz, 1H), 5.99 (k, J=6.9 Hz, 1H), 4.34 (k, J=6.5 Hz, 1H), 3.91 - 3.71 (m, 4H), 3.71 - 3.61 (m, 1H), 3.25 (dd, J=10.2, 5.7 Hz, 1H), 2.38 (dd, J=23.9, 7.1 Hz, 3H), 1.83 - 1.72 (m, 1H), 1.59 (d, J=6.9 Hz, 3H), 1.07 - 0.93 (m, 1H), 0.92 - 0.80 (m, 7H), 0.60 (t, J=7.3 Hz, 3H).

Example 124

(3S,4R)-3-ethyl-4-(3-(2-(4-isobutylphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(4-isobutylphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as _{a white} solid, 0.097 g, 34.1% yield. MS (m/z): _[ M+H] ⁺ calcd for _C30H35F3N6O2 , _569.28 ; found, 569.3. ^1H NMR (400 MHz, chloroform-d) δ 8.79 (s, 1H), 7.93 (t, J=3.7 Hz, 1H), 7.52 (d, J=4.3 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.06 - 6.94 (m, 3H), 6.78 (dd, J=4.2, 1.5 Hz, 1H), 5.98 (cd, J=6.9, 3.4 Hz, 1H), 4.70 (t, J=6.5 Hz, 1H), 4.08 (dt, J=12.2, 6.2 Hz, 1H), 3.98 - 3.61 (m, 4H), 3.29 (d, J=8.3 Hz, 1H), 2.62 - 2.46 (m, 1H), 2.31 (dd, J=9.0, 7.2 Hz, 2H), 1.82 -1.67 (m, 1H), 1.61 (dd, J=6.9, 1.2 Hz, 3H), 1.27 - 1.09 (m, 1H), 0.87 - 0.73 (m, 7H), 0.66 (dt, J=10.3, 7.3 Hz, 3H).

Example 125

(3S,4R)-3-ethyl-4-(3-(2-(2-fluoro-[1,1'-diphenyl]-4-yl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(2-fluoro-[1,1,-diphenyl]-4-yl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-H-(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-diphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol=50:1 to 25:1) to give the title compound as _{a white} solid, 0.03 g, 9.9% yield. MS (m/z): _[ M+H] ⁺ calcd for _C32H30F4N6O2 , _607.24 ; found, 607.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J=2.0 Hz, 1H), 8.10 (dd, J=4.2, 2.5 Hz, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.58 - 7.32 (m, 9H), 6.98 (t, J=5.8 Hz, 1H), 6.09 (p, J=6.9 Hz, 1H), 4.36 (s, 1H), 3.95 - 3.74 (m, 4H), 3.69 (dt, J=10.7, 6.1 Hz, 1H), 3.26 (dd, J=10.2, 5.3 Hz, 1H), 3.09 (td, J=7.3, 4.7 Hz, 1H), 1.66 (d, J=6.9 Hz, 3H), 1.12 - 0.96 (m, 1H), 0.93 - 0.75 (m, 1H), 0.63 (dt, J=10.2, 7.3 Hz, 3H).

Example 126

(3R,4S)-3-(3-(2-(3-benzoylphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3R,4S)-3-(3-(2-(3-benzoylphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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]pyrazin-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)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give _the title compound as _{a white} solid, 0.13 g, 84.4% yield. MS (m/z): [M+H] ⁺ calcd for _C33H31F3N6O3 , _617.24 ; found, 617.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J=5.8 Hz, 1H), 8.07 (dd, J=4.3, 1.8 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.71 - 7.57 (m, 5H), 7.57 - 7.47 (m, 3H), 7.45 (d, J=4.3 Hz, 1H), 6.97 (t, J=6.3 Hz, 1H), 6.09 (p, J=7.0 Hz, 1H), 4.35 (k, J=6.5 Hz, 1H), 3.90 - 3.63 (m, 5H), 3.26 (dt, J=10.1, 5.1 Hz, 1H), 2.58 - 2.49 (m, 1H), 1.64 (dd, J=7.0, 2.1 Hz, 3H), 1.03 (dp, J=20.6, 7.0 Hz, 1H), 0.81 (s, 1H), 0.61 (dt, J=14.6, 7.3 Hz, 3H).

Example 127

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

Synthesis of (3R,4S)-3-(3-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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]pyrazin-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-dichloroanilino)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as _{a white} solid, _0.011 g, 6.6% yield. MS (m/z): _[ M+H] ⁺ calculated for _{C31H28Cl2F3N7O2} , _658.16 ; found, 658.1. ¹ H NMR (400 MHz, chloroform-d) δ 8.85 (s, 1H), 8.00 (d, J=4.1 Hz, 1H), 7.58 (s, 1H), 7.38 (dd, J=7.5, 1.5 Hz, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.08 (td, J=7.8, 1.6 Hz, 1H), 6.93 - 6.85 (m, 4H), 6.52 (d, J=8.0 Hz, 1H), 5.11 (s, 2H), 4.69 (t, J=6.3 Hz, 1H), 4.15 (q, J=6.1 Hz, 1H), 3.89 (tt, J=15.6, 8.6 Hz, 4H), 3.72 - 3.66 (m, 1H), 3.30 (t, J=8.2 Hz, 1H), 2.57 (dd, J=11.0, 6.3 Hz, 1H), 1.27 - 1.14 (m, 1H), 0.84-0.77 (m, 1H), 0.69 (t, J=7.3 Hz, 3H).

Example 128

(3S,4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (EDCI, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(3-phenoxyphenyl)propanoic acid (fenoprofen, 64 mg, 0.264 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (upadacitinib, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give _the title compound _{as a white} solid, 0.101 g, 66.8% yield. MS (m/z): [M+H] ⁺ calcd for _C32H31F3N6O3 , 605.24; found, 605.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=6.8 Hz, 1H), 8.04 (t, J=3.9 Hz, 1H), 7.65 (d, J=6.7 Hz, 1H), 7.49 - 7.26 (m, 4H), 7.23 - 6.80 (m, 7H), 5.97 (p, J=6.8 Hz, 1H), 4.38 - 4.30 (m, 1H), 3.92 - 3.75 (m, 3H), 3.69 (dd, J=8.4, 6.0 Hz, 2H), 3.26 (dt, J=10.3, 6.7 Hz, 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, 3.7 Hz, 3H).

Example 129

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

Synthesis of (3R,4S)-3-(3-(2-((2,3-dimethylphenyl)amino)benzoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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]pyrazin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give _the title compound _{as a} yellow solid, 0.012 g, 85.5% yield. MS (m/z): [M+H] ⁺ calcd for _C32H32F3N7O2 , _604.264 ; found, 604.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (s, 1H), 8.57 (s, 1H), 7.77 (d, J=3.9 Hz, 1H), 7.61 (s, 1H), 7.48 - 7.36 (m, 3H), 7.09 - 6.95 (m, 4H), 6.88 - 6.74 (m, 2H), 4.38 (t, J=6.5 Hz, 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=7.3 Hz, 3H).

Example 130

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

Synthesis of (3R,4S)-3-(3-(2-((3-chloro-2-methylphenyl)amino)benzoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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]pyrazin-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 h. After completion of the reaction, the reaction solution was diluted dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography ₍ dichloromethane/methanol = 50:1 to ₂₅ :1) to give the title compound as a _{yellow solid, 0.09 g, 29.7% yield. MS (m/z): [M+H]+ calculated for C31H29ClF3N7O2 ,} ^624.20 _; found, 624.2. ¹ H NMR (400 MHz, DMSO- _d6 ) δ 8.61 (s, 1H), 8.25 (s, 1H), 7.67 - 7.58 (m, Hz). 1H), 7.56 - 7.44 (m, 2H), 7.36 (d, J=4.2 Hz, 1H), 7.22 (d, J=4.9 Hz, 1H), 7.10-6.85 (m, 5H), 6.81-6.75 (m, 1H), 4.36 (d, J=6.6 Hz, 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).

Example 131

(3S,4R)-3-ethyl-4-(3-((S)-2-(6-)methoxynaphthalin-2-yl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-((S)-2-(6-)methoxynaphthalin-2-yl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give _the title compound as _{a white} solid, 0.028 g, 18.9% yield. MS (m/z): [M+H] ⁺ calcd for _C31H31F3N6O3 , _593.24 ; found, 593.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.08 (d, J=4.2 Hz, 1H), 7.91 - 7.68 (m, 3H), 7.63 (s, 1H), 7.57 (dd, J=8.5, 1.8 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.25 (d, J=2.6 Hz, 1H), 7.12 (dd, J=9.0, 2.6 Hz, 1H), 6.96 (t, J=6.2 Hz, 1H), 6.13 (k, J=6.9 Hz, 1H), 4.33 (d, J=6.7 Hz, 1H), 3.97 - 3.72 (m, 7H), 3.65 (dd, J=10.3, 6.7 Hz, 1H), 3.24 (dd, J=10.3, 5.7 Hz, 1H), 2.53 - 2.42 (m, 1H), 1.68 (d, J=6.9 Hz, 3H), 1.03 - 0.92 (m, 1H), 0.89 - 0.71 (m, 1H), 0.57 (t, J=7.3 Hz, 3H).

Example 132

(3S,4R)-3-ethyl-4-(3-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoyl)-3H-i]imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(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]propanoic 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 h. After completion of the reaction, the reaction solution was diluted dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as a white solid, 0.066 g, 43.4% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₂ H ₃₅ F ₃ N ₆ O ₃ , 609.27, found, 609.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J = 0.9 Hz, 1H), 8.04 (t, J = 3.9 Hz, 1H), 7.63 (d, J=7.0 Hz, 1H), 7.44 - 7.30 (m, 3H), 7.22 - 7.07 (m, 2H), 6.97 (t, J=6.3 Hz, 1H), 6.00 (p, J=7.0 Hz, 1H), 4.34 (d, J=6.2 Hz, 1H), 3.96 - 3.72 (m, 4H), 3.67 (ddd, J=10.9, 6.7, 4.6 Hz, 1H), 3.25 (dt, J=10.3, 5.1 Hz, 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, 8.4 Hz, 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 (ddk, J=19.7, 12.8, 7.1, 6.6 Hz, 1H), 0.80 (ddt, J=16.9, 13.8, 6.5 Hz, 1H), 0.62 (dt, J=10.3, 7.3 Hz, 3H).

Example 133

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

Synthesis of (3R,4S)-3-(3-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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]pyrazin-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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as _{a light} yellow solid, 0.139 g, 77.3% yield. MS (m/z): _[ M+H] ⁺ calculated for _{C36H33ClF3N7O4} , _720.22 , found, 720.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.10 (d, J=4.1 Hz, 1H), 7.75 - 7.63 (m, 5H), 7.50 (d, J=4.2 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.00 (dd, J=7.7, 5.0 Hz, 2H), 6.73 (dd, J=9.0, 2.5 Hz, 1H), 5.06 (d, J=4.3 Hz, 2H), 4.41 (q, J=6.4 Hz, 1H), 3.93 - 3.83 (m, 3H), 3.83 - 3.67 (m, 5H), 3.27 (dd, J=10.2, 5.9 Hz, 1H), 2.58 (s, 1H), 2.27 (s, 3H), 1.07 (ddd, J=12.8, 7.4, 4.9 Hz, 1H), 0.82 (ddd, J=13.3, 10.0, 7.0 Hz, 1H), 0.65 (t, J=7.3 Hz, 3H).

Example 134

(3R,4S)-3-(3-(2-(4-acetamidophenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3R,4S)-3-(3-(2-(4-acetamidophenyl)acetyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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]pyrazin-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-acetamidophenyl)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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as a white solid, 0.082 g, 59% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₇ H ₂₈ F ₃ N ₇ O ₃ , 556.22, found, 556.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 8.89 (s, 1H), 8.06 (d, J=4.2 Hz, 1H), 7.65 (s, 1H), 7.57 - 7.48 (m, 2H), 7.46 (d, J=4.1 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.99 (t, J=6.4 Hz, 1H), 4.88 (d, J=3.6 Hz, 2H), 4.39 (k, J=6.7 Hz, 1H), 3.92 - 3.74 (m, 4H), 3.70 (dd, J=10.2, 6.7 Hz, 1H), 3.26 (dd, J=10.2, 5.9 Hz, 1H), 2.56 (s, 1H), 2.03 (s, 3H), 1.06 (ddd, J=12.9, 7.7, 5.2 Hz, 1H), 0.89 - 0.73 (m, 1H), 0.64 (t, J=7.3 Hz, 3H).

Example 135

(3R,4S)-3-(3-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl)-3H-imidase o[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide

Synthesis (3R,4S)-3-(3-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl)-3H-imidazo [1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide

(3S,4R-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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-tetrahydropyran[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 completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as a white solid, 0.108 g, 66.5% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₄ H ₃₈ F ₃ N ₇ O ₃ , 650.30, found, 650.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (d, J=10.5 Hz, 1H), 8.79 (s, Hz) 1H), 8.01 (t, J=4.1 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.40 (d, J=4.2 Hz, 1H), 7.22 (td, J=7.5, 1.6 Hz, 1H), 6.99 (t, J=6.3 Hz, 1H), 6.89 (td, J=7.4, 5.1 Hz, 2H), 4.61 (dd, J=47.7, 14.4 Hz, 1H), 4.36 (d, J=6.7 Hz, 1H), 4.13 (dd, J=41.9, 14.4 Hz, 1H), 3.95 - 3.74 (m, 6H), 3.69 (dd, J=10.3, 6.9 Hz, 1H), 3.26 (dd, J=10.3, 5.8 Hz, 1H), 2.90 -2.81 (m, 2H), 2.60 (k, J=4.7 Hz, 2H), 2.24 - 2.14 (m, 2H), 1.25 (td, J=7.4, 2.7 Hz, 4H), 1.10 - 1.00 (m, 1H), 0.82 (dtd, J=13.7, 7.0, 3.4 Hz, 1H), 0.71 (k, J=7.1 Hz, 3H), 0.64 (dtd, J=7.3, 2.8 Hz, 3H).

Example 136

2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carbonyl)phenylacetate

Synthesis of 2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carbonyl)phenylacetate

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (EDCI, 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 (upadacitinib, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as a white solid, 0.025 g, 18.4% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₆ H ₂₅ F ₃ N ₆ O ₄ , 543.19, found, 543.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 7.85 (d, J=4.2 Hz, 1H), 7.78-7.71 (m, 2H), 7.60 (s, 1H), 7.51 - 7.44 (m, 2H), 7.34 (dd, J=8.1, 1.0 Hz, 1H), 6.99 (t, J=6.3 Hz, 1H), 4.43 - 4.35 (m, 1H), 3.92 - 3.75 (m, 4H), 3.70 (dd, J=10.2, 6.9 Hz, 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, 4.9 Hz, 1H), 0.83 - 0.75 (m, 1H), 0.64 (t, J=7.3 Hz, 3H).

Example 137

Tert-butyl-((S)-2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-3-yl)-2-oxo-1-phenethyl)carbamate

Synthesis of tert-butyl-((S)-2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-3-yl)-2-oxo-1-phenethyl)carbamate

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) _{to give the} title compound as a white solid, 0.088 g, 57.4% yield. MS (m/z): [M+H] ⁺ calculated for _C30H34F3N7O4 , _614.26 , found, 614.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (s, 1H), 8.07 (t, J=4.2 Hz, 1H), 7.99 (dd, J=7.5, 4.5 Hz, 1H), 7.67 - 7.24 (m, 8H), 6.97 (td, J=6.3, 2.3 Hz, 1H), 4.37 - 4.29 (m, 1H), 3.91 - 3.72 (m, 4H), 3.67 (dt, J=10.3, 6.4 Hz, 1H), 3.28 - 3.18 (m, 1H), 2.52 - 2.43 (m, 1H), 1.40 (d, J=2.5 Hz, 9H), 1.05 - 0.92 (m, 1H), 0.88 - 0.68 (m, 1H), 0.62 (dt, J=14.5, 7.3 Hz, 3H).

Example 138

(3S,4R)-3-ethyl-4-(3-(2-(4-(1-)oxoisoindolin-2-yl)phenyl)butanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Synthesis of (3S,4R)-3-ethyl-4-(3-(2-(4-(1-)oxoisoindolin-2-yl)phenyl)butanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-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)butanoic acid (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1) to give the title compound as a white solid, 0.145 g, 88.2% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₅ H ₃₄ F ₃ N ₇ O ₃ , 658.27, found, 658.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J=1.8 Hz, 1H), 8.07 (dd, J=7.3, 4.1 Hz, 1H), 7.91 - 7.80 (m, 2H), 7.75 (dd, J=7.6, 3.0 Hz, 1H), 7.71 - 7.59 (m, 3H), 7.58 - 7.46 (m, 3H), 7.41 (t, J=4.7 Hz, 1H), 6.96 (td, J=6.3, 2.1 Hz, 1H), 5.86 (t, J=7.4 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 4.37 - 4.29 (m, 1H), 3.91 - 3.73 (m, 4H), 3.67 (dt, J=10.2, 6.4 Hz, 1H), 3.25 (dd, J=10.3, 5.8 Hz, 1H), 2.56 - 2.49 (m, 1H), 2.34 -2.19 (m, 1H), 1.94 (dtd, J=12.8, 7.5, 4.7 Hz, 1H), 1.12-0.99 (m, 1H), 0.95 (td, J=7.3, 5.7 Hz, 3H), 0.80 (ddd, J=16.9, 14.2, 7.4 Hz, 1H), 0.62 (dt, J=17.9, 7.3 Hz, 3H).

Example 139

3-((3S,4R)-6-(7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3S,4R)-6-(7-(2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile

3-((3S,4R-3-methyl-6-(7H-pyrrolo[2,3-(1]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), 2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:1 to 10:1) to give the title compound as a white solid, 0.081 g, 67.7% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₉ H ₃₄ N ₆ O ₂ , 499.27, found, 499.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.67 (d, J = 4.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.90 (d, J=4.1 Hz, 1H), 6.10 (k, J=6.8 Hz, 1H), 4.20 - 4.06 (m, 2H), 4.04 - 3.24 (m, 3H), 3.68 (d, J=3.3 Hz, 2H), 3.65 -3.53 (m, 1H), 2.72 - 2.55 (m, 2H), 2.36 (d, J=7.1 Hz, 2H), 2.20 (s, 1H), 1.82 - 1.75 (m, 1H), 1.54 (d, J=6.9 Hz, 3H), 1.13 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 6H).

Example 140

3-((3S,4R)-6-(7-((S)-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3S,4R)-6-(7-((S)-2-(4-isobutylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile

3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:1 to 10:1) to give the title compound as a white solid, 0.071 g, 59.4% yield. MS (m/z): [M+H] ⁺ calcd for C ₂₉ H ₃₄ N ₆ O ₂ , 499.27, found, 499.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.67 (d, J=4.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.90 (d, J=4.1 Hz, 1H), 6.10 (q, J=6.8 Hz, 1H), 4.20 - 4.05 (m, 2H), 4.04 - 3.24 (m, 3H), 3.68 (d, J=3.3 Hz, 2H), 3.65 -3.53 (m, 1H), 2.73 - 2.55 (m, 2H), 2.36 (d, J=7.1 Hz, 2H), 2.20 (s, 1H), 1.77 (hept, J=6.8 Hz, 1H), 1.54 (d, J=6.9 Hz, 3H), 1.13 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 6H).

Example 141

3-((3S,4R)-6-(7-((S)-2-(6-methoxynaphthalin-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3S,4R)-6-(7-((S)-2-(6-methoxynaphthalin-2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile

3-((3S,4R-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:1 to 10:1) to give the title compound as a _white solid, _0.013 g, 10.3% yield. MS (m/z): [M+H] ⁺ calculated for _C30H30N6O3 , _523.24 , found, 523.2. ¹ H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 7.76 (d, J=1.7 Hz, 1H), 7.67 - 7.56 (m, Hz). 2H), 7.51 (dd, J=8.6, 1.8 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.08 - 6.98 (m, 2H), 6.53 (d, J=4.2 Hz, 1H), 6.19 (k, J=6.9 Hz, 1H), 4.30 - 3.91 (m, 2H), 3.82 (d, J=13.5 Hz, 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, 7.2 Hz, 1H), 2.10 - 1.99 (m, 1H), 1.21 - 1.08 (m, 3H), 0.85-0.75 (m, 3H).

Example 142

4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimide in-7-yl)methoxy)-2-methyl-N(5-methylthiazol-2-yl)-2H-benzo[e][1,2]thiazin-3-carboxamide-1,1-dioxide

Synthesis of 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(5-methylthiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

To tetrahydrofuran (3.4 ml) were added 4-hydroxy-2-methyl-N-(5-methylthiazol-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) under nitrogen atmosphere. After cooling to -10°C, diisopropyl azodicarboxylate (DIAD, 148 mg, 0.73 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature. 3-((3R,4R-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (170 mg, 0.5 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.009 g, 2.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₃ N ₉ O ₅ S ₂ , 676.20, detected, 676.2. ¹ H NMR (400 MHz, chloroform-d ) δ 14.01 (s, 1H), 8.28 (s, 1H), 8.03 (dd, J = 7.6, 1.4 Hz, 1H), 7.84 (dd, J = 7.4, 1.5 Hz, 1H), 7.73 - 7.52 (m, 3H), 7.30 (d, J = 4.5 Hz, 1H), 6.51 (dd, J = 11.0, 3.8 Hz, 1H), 6.42 (s, 2H), 5.01 (d, J = 26.1 Hz, 1H), 4.04 (dd, J = 13.2, 4.2 Hz, 1H), 3.86 - 3.68 (m, 1H), 3.64 (dd, J=13.2, 8.7 Hz, 1H), 3.56 - 3.39 (m, 3H), 3.29 (d, J=18.7 Hz, 3H), 3.09 (s, 3H), 2.53 - 2.39 (m, 1H), 2.21 (d, J=1.4 Hz, 3H), 2.00 - 1.80 (m, 1H), 1.73 - 1.63 (m, 1H), 1.02 (dd, J=9.5, 7.1 Hz, 3H).

Example 143

3-((3S,4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3S,4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile

3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic acid (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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:1 to 10:1) to give the title compound as _{a white} solid, 0.018 g, 12.7% yield. MS (m/z): [M+H]+ calcd for _C34H33N7O3 , _588.26 , found, 588.0. ^1H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 7.86 - 7.79 (m, 1H), 7.70 (dd, J=8.7, 1.1 Hz, 2H), 7.60 (dd, J=4.2, 1.5 Hz, 1H), 7.56 - 7.46 (m, 3H), 7.46 - 7.39 (m, 2H), 6.55 (t, J=4.1 Hz, 1H), 5.93 (t, J=7.5 Hz, 1H), 4.74 (s, 2H), 4.26 (t, J=8.4 Hz, 1H), 4.16 (dd, J=12.0, 8.2 Hz, 1H), 4.12 3.94 (m, 2H), 3.73 (s, 1H), 3.62 (ddd, J=8.4, 6.0, 2.4 Hz, 1H), 3.14 (d, J=3.0 Hz, 2H), 2.81 (tt, J=13.0, 5.9 Hz, 1H), 2.67 (s, 1H), 2.22 (dt, J=14.2, 7.3 Hz, 1H), 2.09 (s, 1H), 1.96 - 1.86 (m, 1H), 1.16 (dd, J=7.1, 4.4 Hz, 3H), 0.92 (td, J=7.3, 1.2 Hz, 3H).

Example 144

(4-((3S,4R)-1-(2-cyanoacetyl)-3-methyl-1,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl-(S)-2-(4-isobutylphenyl)propanoate

First step: synthesis of 3-((3S,4R)-3-methyl-6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]-oct-1-yl)-3-oxopropanenitrile

Under nitrogen protection, 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (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 half an hour, (2-(chloromethoxy)ethyl)trimethylsilane (140 mg, 0.838 mmol) was added to ice-water and stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. _The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 200:1 to 20:1) to give the title compound, 0.234 g, 82.5% yield. MS (m/z): [M+H] ⁺ calculated for _C22H32N6O2Si , _441.24 ; found, 441.2. Step 2: Synthesis of 3-((3S,4R)-6-(7-(hydroxymethyl ₎ -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile

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]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (0.234 g, 0.53 mmol) in dichloromethane (15 ml) under nitrogen atmosphere in an ice-water bath. After half an hour, the ice-water bath was removed, the temperature was raised to room temperature and stirring was continued for 2 hours. To the above reaction solution, saturated sodium bicarbonate solution was added at 0 °C to adjust the pH to 8. Then, the mixture was poured into a separatory funnel for separation. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to ₉ :1) to give the title compound, _0.055 g, 30.4% yield. MS (m/z): [M+H] ⁺ calcd for _C17H20N6O2 , _341.16 ; found, 341.1.

Step 3: Synthesis of (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl(S)-2-(4-isobutylphenyl)propanoate

3-((3S,4R-6-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile (55 mg, 0.16 mmol), 4-dimethylaminopyridine (DMAP, 19 mg, 0.16 mmol), (S)-(+)-2-(4-isobutylphenyl)propanoic 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 The stirring was continued for 16 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:1 to 10:1) to give the title compound as a white solid, 0.02 g, 23.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₀ H ₃₆ N ₆ O ₃ , 529.28, found, 529.2. ¹ H NMR (400 MHz, chloroform-d) δ 8.28 (s, 1H), 7.09 - 6.92 (m, 5H), 6.45 (d, J=3.7 Hz, 1H), 6.10 (d, J=10.6 Hz, 1H), 6.01 (d, J=10.6 Hz, 1H), 4.31-4.14 (m, 2H), 4.03 (d, J=11.9 Hz, 2H), 3.77 (s, 1H), 3.67-3.59 (m, 2H), 3.16 (s, 2H), 2.83 (dt, J=13.0, 7.5 Hz, 1H), 2.67 (g, J=7.0 Hz, 1H), 2.35 (d, J=7.2 Hz, 2H), 2.10 (s, 1H), 1.75 (dt, J=13.5, 6.7 Hz, 1H), 1.38 (d, J=7.2 Hz, 3H), 1.18 (d, J=2.8 Hz, 3H), 0.81 (d, J=6.7 Hz, 6H).

Example 145

3-((3S,4R)-6-(7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile

Synthesis of 3-((3S,4R)-6-(7-(2-(3-benzoylphenyl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile

3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl)-3-oxopropanenitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), 2-(3-benzoylphenyl)propanoic 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 h. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give a crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol=30:1 to 10:1) to give the title compound as _{a white} solid, 0.038 g, 29% yield. MS (m/z): [M+H] ⁺ calcd for _C32H30N6O3 , _547.24 , found, 547.1. ^1H NMR (400 MHz, 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=7.7 Hz, 1H), 6.65 (dd, J=4.3, 1.5 Hz, 1H), 6.19 (k, J=7.0 Hz, 1H), 4.32 (t, J=8.4 Hz, 1H), 4.24 (dd, J=12.1, 7.2 Hz, 1H), 4.14 (s, 1H), 4.04 (dd, J=12.1, 8.4 Hz, 1H), 3.85 - 3.77 (m, 1H), 3.69 (dd, J=8.3, 5.9 Hz, 1H), 3.21 (d, J=2.7 Hz, 2H), 2.93 - 2.80 (m, 1H), 2.78-2.68 (m, 1H), 2.17 (dk, J=13.2, 7.3 Hz, 1H), 1.65 (d, J=7.0 Hz, 3H), 1.26 - 1.19 (m, 3H).

Example 146

4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimide in-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide

Synthesis of 4-((4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide

To tetrahydrofuran (2 ml) were added 4-hydroxy-2-methyl-T-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide (tenoxicam, 98 mg, 0.292 mmol) and triphenylphosphine (PPh3, 230 mg, 0.876 mmol) under nitrogen atmosphere. Diisopropyl azodicarboxylate (DIAD, 88 mg, 0.438 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature. 3-((3R,4R)-3-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (100 mg, 0.292 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.011 g, 5.6% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₀ H ₃₁ N ₉ O ₅ S ₂ , 662.19, found, 662.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 16.02 (s, 1H), 8.63 (t, J=10.2 Hz, 1H), 8.38 - 8.23 (m, 2H), 8.19 - 8.10 (m, 1H), 8.06 (dd, J=5.2, 2.2 Hz, 1H), 7.75 (dd, J=6.7, 3.8 Hz, 1H), 7.49 (dd, J=5.2, 1.8 Hz, 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=3.8 Hz, 3H), 2.99 (d, J=2.0 Hz, 3H), 2.41 - 2.33 (m, 1H), 1.90 - 1.69 (m, 1H), 1.63 - 1.56 (m, 1H), 1.00 (d, J=7.1 Hz, 3H).

Example 147

2-methyl-4-((4-(methyl-((trans)-4-(((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

Synthesis of 2-methyl-4-((4-(methyl-((trans)-4-(((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide

4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-benzo[e][1,2]thiazine-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) under nitrogen atmosphere. After cooling to -10 °C, diisopropyl azodicarboxylate (DIAD, 124 mg, 0.613 mmol) was added dropwise to the mixture with stirring. After stirring at -10 °C for 20 min, the mixture was allowed to warm to room temperature. 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (150 mg, 0.409 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.012 g, 4.8% yield. MS (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₆ N ₈ O ₆ S ₂ , 681.22, found, 681.2. ^1H NMR (400 MHz, chloroform-d) δ 15.31 (s, 1H), 8.59 (d, J=6.6 Hz, 1H), 8.39 (d, J=9.1 Hz, 1H), 8.32 (s, 1H), 8.10 (dd, J=7.7, 1.4 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=7.6, 1.4 Hz, 1H), 7.77 - 7.61 (m, 3H), 6.85-6.65 (m, 2H), 6.55 (d, J=3.8 Hz, 1H), 5.40-5.31 (m, 2H), 4.69 (s, 1H), 3.19 (s, 3H), 3.10 (s, 3H), 2.95 (d, J=6.2 Hz, 2H), 2.82 (d, J=5.3 Hz, 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).

Example 148

4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrim idin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide

Synthesis of 4-((4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-2-methyl-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-car boxamide 1,1-dioxide

To tetrahydrofuran (2 ml) were added 4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide (tenoxicam, 75 mg, 0.224 mmol) and triphenylphosphine (PPH3, 196 mg, 0.748 mmol) under nitrogen atmosphere. After cooling to -10°C, diisopropyl azodicarboxylate (DIAD, 75 mg, 0.374 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature naturally. 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-))pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (100 mg, 0.249 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After completely removing the starting material, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.008 g, 4.9% yield. MS (m/z): _[ M ₊ H] ⁺ calculated for _{C30H28N10O6S3} , _721.14 , found, _721.2 . ¹ H NMR (400 MHz, 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, 1.0 Hz, 1H), 6.60 (d, J=3.7 Hz, 1H), 6.17 (s, 2H), 4.56 (d, J=9.2 Hz, 2H), 4.18 (d, J=9.2 Hz, 2H), 3.35 (s, 2H), 3.12 - 2.99 (m, 5H), 1.35 (td, J=7.5, 3.8 Hz, 3H).

Example 149

2-methyl-4-((4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide

Synthesis of 2-methyl-4-((4-(methyl-((trans)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy)-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide

To tetrahydrofuran (2 ml) were added 4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-thieno[3,2-e][1,2]thiazine-3-carboxamide-1,1-dioxide (tenoxicam, 75 mg, 0.224 mmol) and triphenylphosphine (PPh3, 196 mg, 0.748 mmol) under nitrogen atmosphere. After cooling to -10°C, diisopropyl azodicarboxylate (DIAD, 75 mg, 0.374 mmol) was added dropwise to the mixture with stirring. After stirring at -10°C for 20 min, the mixture was allowed to warm to room temperature naturally. 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclohexyl)-N-methylmethanesulfonamide (100 mg, 0.272 mmol) was added and stirring was continued. The reaction mixture was monitored by TLC. After complete removal of the starting material, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20:1 to 9:1) to give the title compound as a yellow solid, 0.006 g, 3.9% yield. MS (m/z): [M+H] ⁺ calculated for C ₂₉ H ₃₄ N ₈ O ₆ S ₃ , 687.18, found, 687.2. ¹ H NMR (400 MHz, chloroform-d) δ 8.89 (s, 1H), 8.29 - 8.16 (m, 1H), 8.03 (s, 1H), 7.82 (dt, J=8.4, 1.0 Hz, 1H), 7.54 (ddd, J=8.5, 7.4, 1.9 Hz, 1H), 7.00 (ddd, J=7.3, 4.9, 1.0 Hz, 1H), 6.90 (d, J=3.8 Hz, 1H), 6.42 (d, J=3.8 Hz, 1H), 6.16 (s, 2H), 4.59 - 4.39 (m, 1H), 3.24 (d, J=5.0 Hz, 1H), 3.16 (s, 3H), 3.04 (d, J=14.0 Hz, 3H), 2.98 (d, J=6.3 Hz, 2H), 2.85 (dd, J=5.3, 3.6 Hz, 3H), 2.19 (d, J=12.8 Hz, 3H), 2.03 (k, J=6.2 Hz, 1H), 1.92 - 1.59 (m, 4H), 1.43 - 1.33 (m, 2H).

Method for analyzing the hydrolysis rate of compounds according to the present invention

1. Preparation of solution for preparation of standard working curve Approximately 10 mg of JAK inhibitor reference substances (tofacitinib and baricitinib) were weighed into a 25 mL volumetric flask, added with acetonitrile/water=7/3 (v/v) for dissolution, and diluted to the mark; the resulting solution was used as a stock solution. The stock solution was diluted with an appropriate dilution factor to obtain linear solutions of each concentration: 0.0002 mg/mL, 0.0004 mg/mL, 0.004 mg/mL, 0.04 mg/mL, and 0.08 mg/mL.

Approximately 10 mg of JAK inhibitor reference substances (oclacitinib, ruxolitinib, delgocitinib, and upadacitinib) were weighed into a 25 mL volumetric flask, added with acetonitrile/water = 7/3 (v/v) for dissolution, and diluted to the mark; the resulting solution was used as a stock solution. The stock solution was diluted with an appropriate dilution factor to obtain linear solutions of each concentration: 0.0002 mg/mL, 0.0004 mg/mL, 0.004 mg/mL, 0.04 mg/mL, and 0.08 mg/mL.

2. Preparation of sample solution

Approximately 5 mg of a sample (the compound obtained in the present invention) was weighed in a 20 ml volumetric flask, acetonitrile/water=7/3 (v/v) was added to dissolve, and diluted to the mark; the resulting solution was used as a stock solution.

An appropriate amount for HPLC was loaded as the sample obtained on day 0. The test solution was sealed with a sealing film and placed in a shaker with a constant temperature of 37°C. The test samples were collected at the same time on days 1, 2, 3, and 4, respectively. The amount of JAK inhibitor released in the sample was calculated from the mass of the sample and the standard curve of JAK inhibitor.

3. Formula for calculation

where A of _{the JAK inhibitor} is the peak area,

a - slope of the standard curve of the JAK inhibitor on the chromatogram of the sample,

b - the segment cut off by the standard curve on the axis,

W - sample mass (mg),

M1 - molecular weight of the sample,

M2 is the molecular weight of the JAK inhibitor.

4. Chromatography conditions

The chromatography conditions during the test are given in Table 2.

Table 3 shows the results of the analysis of the drug release rate of the drugs obtained as a result of the coupling reactions in the above-described examples of the present invention.

As can be seen from the results shown in Table 3 above, the combination of an anti-inflammatory drug compound containing a carboxylic acid group or a hydroxyl group with a JAK inhibitor compound to form a compound obtained through the coupling reaction and containing an acyloxy group and/or a methoxy group according to the present invention has a significant therapeutic effect and a special effect in the form of a controlled release drug activity.

Pharmacodynamic evaluation studies of the compounds of the present invention

A study to evaluate the efficacy of a transdermal ointment patch formulated from the compounds using an IMQ-induced psoriasis model in mice

Experimental design

BALB/c mice (male) aged 6-8 weeks were selected for depilation of a 2 x 3 cm area of the back skin. 62.5 mg of 5% IMQ cream was applied once daily for 9 consecutive days to induce the model. Mice were housed in an SPF animal facility in IVC cages at 20-26°C and 40-70% humidity with a 12-hour light-dark cycle. Food was provided ad libitum except when fasting was required.

The mice were randomly divided into groups of 8 mice, the administration concentration was 20 mg/g, the administration amount was 50 mg, the route of administration and frequency were skin swab, 2 times/day. The positive control was dexamethasone acetate (DEX) cream, which is a commercially available product containing DEX 0.75 mg/g (999 Piyanping, Sanjiu PHarmaceutical). The administration was started from day 1 (the first day) (the day of model induction) to day 9.

2. Preparation of the ointment under study

The topical preparations are mainly semi-liquid dosage forms. The base and solvent of the semi-liquid dosage form are generally widely used in medicine and household chemicals. The excipients that can be added to the preparation are also common excipients listed in the excipient guide. Therefore, the compounds of the present invention were prepared into the corresponding test ointments. The compound for the preparation of the ointment was dissolved with diisopropyl adipate to obtain a petrolatum-based ointment. In order to improve the stability of the ointment, microcrystalline cellulose was added to the composition as an excipient. The melting point of white petrolatum is 45-60°C. The solution, white petrolatum and microcrystalline cellulose were thoroughly mixed while the petrolatum was in a molten state. After cooling to solidification, the resulting composition was divided into aluminum ointment containers; The specific mass ratios of the base, solvent and auxiliary substances are presented in Table 4.

3. Model evaluation

PASI was performed on the dorsal skin area used for modeling in experimental animals. The evaluation criteria are given below in Table 5:

Statistical analysis of PASI scores was performed using two-way analysis of variance. All data were analyzed using GraphPad Prism 8.0 software, significant differences were defined as p<0.05 (*, p<0.05; **, p<0.01).

4. Efficiency

PASI Score Curve

The PASI score curves of CPD-029, CPD-028, CPD-027, CPD-017, and CPD-002 compared with the model group, excipient group, and Dex cream group are shown in Figs. 1, 2, 3, 4, and 5, respectively. Among them, the model group was treated with 62.5 mg of 5% IMQ cream applied to the back skin of mice once a day to induce psoriasis, and the excipient group was treated with 15% (w/w) diisopropyl adipate, 80% petrolatum, and 3% microcrystalline cellulose.

As shown in Fig. 1-5, the Dex cream (0.75 mg/g) group showed significant therapeutic effect on day 4-day 10 (day 4-10) compared with the excipient group; CPD-017, CPD-027, CPD-028, and CPD-029 showed significant therapeutic effect on day 5-day 10 (day 5-10); CPD-002 showed significant therapeutic effect on day 4-day 8 (day 4-8).

Claims (89)

1. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof having a structure represented by the general formula (I) A-Y-B (I), where A is a group after dehydrogenation of an amino compound selected from the group consisting of any of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib: B is a group formed by dehydroxylation of a carboxylic acid compound B ₁ , or a group formed by dehydrogenation of a hydroxy-containing compound B ₂ ; and wherein when the carboxylic acid B ₁ is dehydroxylated to form a group, the Y group is a direct bond or -(CH ₂ )-O-; when the hydroxy-containing compound B ₂ is dehydrogenated to form a group, the Y group is -(CH ₂ )-, wherein the group formed by dehydroxylation of the carboxylic acid compound B ₁ is a group after dehydroxylation of any of the carboxylic acid groups selected from the group consisting of the following groups: ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid: wherein the group formed by dehydrogenation of the hydroxy-containing compound B ₂ is a group obtained after dehydrogenation of the hydroxy-containing compound of one of the following specific compounds: 2. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a group formed after dehydrogenation of tofacitinib, ruxolitinib and baricitinib. 3. The anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is a composite compound obtained by a condensation reaction of an amino compound A selected from the group consisting of tofacitinib, baricitinib, oclacitinib, upadacitinib, ruxolitinib and delgocitinib with a carboxylic acid compound B ₁ selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin; preferably, said amino compound is tofacitinib, ruxolitinib and baricitinib. 4. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is any of the following specific compounds: 5. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is any of the following specific compounds: 6. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is any of the following specific compounds: 7. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 1, obtained by a method comprising the steps of: 2) the reaction of compound A- _CH2 -OH with acyl chloride B or directly with compound B; where the compound A-CH ₂ -OH is preferably obtained in the following step: 1) the reaction of amino compound A to form compound A- _CH2 -OH. 8. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein A is a group obtained after dehydrogenation of an amino compound selected from the group consisting of any of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib: preferably A is a group formed after dehydrogenation of tofacitinib, ruxolitinib and baricitinib. 9. An anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein said compound is any of the following specific compounds: 10. A method for producing an anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, comprising the steps of: subjecting A and B to a condensation reaction with loss of water in the presence of a catalyst and an organic solvent, wherein the catalyst is one or two or more of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N-carbonyldiimidazole), DMTMM (4-(4,6-dimethoxytriazine)-4-methylmorpholine hydrochloride), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HCTU (6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) and NPC; the organic solvent is preferably one or two or more solvents selected from the group consisting of DCM (dichloromethane), DMF (dimethylformamide), petroleum ether, acetone, chloroform, ethyl acetate, acetonitrile and THF (tetrahydrofuran), preferably dichloromethane and/or dimethylformamide; furthermore, the reaction is preferably carried out in the presence of a basic substance, said basic substance being preferably one or two or more substances selected from the group consisting of DMAP (dimethylaminopyridine), triethylamine, DIPEA (N,N-diisopropylethylamine) and hydroxides or salts of sodium, potassium, lithium and ammonium, wherein B is a group formed by dehydroxylation of a carboxylic acid compound _B1 , where the Y group is a direct bond. 11. A method for producing an anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to any one of claims 7-9, comprising the steps of: 2) the reaction of compound A-CH ₂ -OH with acyl chloride B or directly with compound B, where the compound A-CH ₂ -OH is preferably obtained in the following step: 1) the reaction of amino compound A to obtain compound A-CH ₂ -OH, where stage 1) includes: a) adding (2-(chloromethoxy)ethyl)trimethylsilane to A in the presence of _a catalyst and a solvent to obtain A- _CH2OC2H4 - _Si ( _CH3 ) ₃ ; and b) obtaining A- _CH2OH from A- _{CH2OC2H4 - Si} ( _CH3 ) ₃ in the presence of a catalyst and a solvent; step 2) comprises: reacting A- _CH2OH with the acid chloride obtained from compound _B1 or directly with compound _B2 to obtain A- _CH2OB ; wherein in step b) the reaction is carried out in the presence of TFA (trifluoroacetic acid) as a catalyst and DCM (dichloromethane) as a solvent; in step 2) A- _CH2OH is reacted with the acid chloride obtained from compound _B1 in the presence of _Et3N (triethylamine) as a catalyst and DCM (dichloromethane) as a solvent or is reacted with compound _B2 in the presence of _PPh3 (triphenylphosphine) and DIAD (diisopropyl azodicarboxylate) as a catalyst and THF (tetrahydrofuran) as a solvent. 12. Use of an anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 for the production of external anti-inflammatory drugs or external medicinal compositions. 13. An external anti-inflammatory medicinal product containing an anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9. 14. An external medicinal composition containing an anti-inflammatory compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9.