EXTERNAL ANTI-INFLAMMATORY COUPLING COMPOUND DRUG, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

An external anti-inflammatory drug compound, and a preparation method therefor and the use thereof. The structural formula of the compound is A-YB, wherein A is a group after dehydrogenation of an amine compound having JAK inhibitory activity, Y is a direct connection or (CH.sub.2)O or, and B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B.sub.2. The compound has the special effects of having a strong transdermal property, controlled drug release, high efficacy, etc.

Claims

1. An anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide thereof, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, having a structure shown in general formula (I):
A-YB(I) wherein, A is a group after dehydrogenation of an amine compound having JAK inhibitory activity; Y is a direct connection; or (CH.sub.2)O or (CH.sub.2); B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B.sub.1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B.sub.2; and wherein, in the case where the carboxylic acid B.sub.1 is dehydroxylated to form a group, the Y group is a direct connection or (CH.sub.2)O; or in the case where the hydroxy-containing compound B.sub.2 is dehydrogenated to form a group, the Y group is (CH.sub.2).

2. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, having a structure shown in general formulas (II) or (IIa): ##STR00499## wherein R.sub.1 is selected from pyrazolyl or pyrrolyl unsubstituted or substituted with Ra; or N(CH.sub.3)C.sub.y; Ria represents a pyrrole ring substituted by a halogen-substituted C.sub.1-C.sub.6 alkylaminoacyl group and/or by a C.sub.1-C.sub.6 alkyl group; C.sub.y is a five- or six-membered carbocyclic ring or a five- or six-membered nitrogen-containing heterocyclic ring unsubstituted or substituted by R.sub.b; R.sub.a and R.sub.b are each independently groups containing at least one or two groups selected from a group consisting of an acyl group, a dithioyl group, a cyano group, an amino group or a C.sub.1-C.sub.6 alkyl-substituted amino group, and a four-, five-, or six-membered nitrogen-containing heterocyclic group, or the nitrogen-containing heterocyclic group substituted with C.sub.1-C.sub.6 alkyl; R.sub.2 in both general formulas (II) and (IIa) is B, i.e. is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B.sub.1 and is selected from R.sub.4ArR.sub.3CO, wherein, R.sub.3 is selected from C.sub.1-C.sub.6 alkylene; NH, R.sub.5NH, or C.sub.1-C.sub.6 alkylene substituted with a C.sub.1-C.sub.6 alkoxyamide group; or a direct connection, i.e. the Ar group is directly linked to CO; Ar is an aromatic ring group and R.sub.4 is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl containing C.sub.1-C.sub.6 cycloalkanoyl, C.sub.1-C.sub.6 alkylamido or aryl fused heterocyclic amido, C.sub.1-C.sub.6 carbonyloxy, halogen substituted benzoyl, C.sub.1-C.sub.6 alkyl or halogen substituted or unsubstituted phenoxy, C.sub.1-C.sub.6 alkyl or halogen substituted or unsubstituted phenyl or aryl fused heterocyclic ring, C.sub.1-C.sub.6 alkyl or halogen substituted or unsubstituted phenylamino, or R.sub.4 can also be absent; wherein the C.sub.1-C.sub.6 alkoxy can also form a bridged ring with Ar.

3. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein C.sub.y is substituted cyclohexyl or substituted piperidinyl.

4. The compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, wherein the compound is a coupling compound resulting from a condensation reaction of an amine compound A with a carboxylic acid compound B.sub.1.

5. The compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib: ##STR00500## ##STR00501##

6. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein B.sub.1 is a group after dehydroxylation of a carboxylic acid moiety selected from a 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: ##STR00502## ##STR00503##

7. The anti-inflammatory compound, or the stereoisomer, tautomer, N-oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the compound is a coupled compound obtained by condensation reaction of an amine compound A selected from the group consisting of tofacitinib, baricitinib, oclacitinib, upadacitinib, ruxolitinib and delgocitinib with a carboxylic acid compound B.sub.1 selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin.

8. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds: ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544##

9. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds: ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550##

10. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds: ##STR00551## ##STR00552## ##STR00553## ##STR00554## ##STR00555## ##STR00556## ##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561## ##STR00562##

11. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, having a structure shown in general formulas (III): ##STR00563## wherein R.sub.1 has the same meaning as R.sub.1 in general formula (II); Ria has the same meaning as R.sub.1a in formula (IIa); R.sub.2 in formula (III) and formula (IIIa) are both YB, B is B.sub.1 in formula (II) or (IIa), or B is B.sub.2; wherein the group B.sub.1 is a group formed by dehydroxylation of a carboxylic acid compound B.sub.1 and Y is (CH.sub.2)O; the group B.sub.2 is a group formed by dehydrogenation of a hydroxyl-containing compound B.sub.2 and Y is (CH.sub.2); the group B.sub.1 has the same meaning as the R.sub.2 group in formula (II) or in formula (IIa); the group B.sub.2 is R.sub.dCONHR.sub.d, wherein R.sub.c is a 4-hydroxy-benzothiazine dioxide-3-yl represented by the following structural formula (a), (wherein the phenyl ring may be substituted by halogen or C.sub.1-C.sub.6 alkyl), or a 4-hydroxy-Re substituted thienothiazine dioxide-3-yl represented by the following structural formula (b), wherein CONHR.sub.d is bonded at the 3-position of the thiazine ring, ##STR00564## wherein R.sub.d is thiazole, isothiazole, oxazole, isoxazole, or pyridine or the group thereof substituted with C.sub.1-C.sub.6 alkyl or halogen; R.sub.e is C.sub.1-C.sub.6 alkyl or halogen; a arrow next to R.sub.e in formula (b) indicates that its substitution position on the thiophene ring may be any carbon-linked hydrogen atom capable of undergoing substitution.

12. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11, wherein B.sub.1 is a group after dehydroxylation of any one of carboxylic acids selected from a 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: ##STR00565## ##STR00566## B.sub.2 is a group after dehydrogenation of a hydroxyl-containing compound of one of the following specific compounds: ##STR00567##

13. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11, obtained by a preparation method comprising the step of: 1) reacting A-CH.sub.2OH compound with an acyl chloride of B or directly with the B compound; wherein the A-CH.sub.2OH compound is prepared by the following step 1): reacting the amine compound A to form the A-CH.sub.2OH compound, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib: ##STR00568## ##STR00569##

14. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 13, wherein the compound is any one of the following specific compounds: ##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574## ##STR00575## ##STR00576## ##STR00577## ##STR00578## ##STR00579## ##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591## ##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598## ##STR00599## ##STR00600## ##STR00601## ##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614## ##STR00615## ##STR00616## ##STR00617## ##STR00618## ##STR00619## ##STR00620##

15. Use of the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, for anti-inflammatory symptom.

16. An anti-inflammatory drug preparation or drug composition including the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1.

17. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 3, wherein the substituted cyclohexyl group is 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.

18. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein Ra and Rb are each independently groups which consist of one group of acyl or dithioacyl and at least one group selected from a group consisting of cyano, amino or C.sub.1-C.sub.6 alkyl substituted amino and a four-, five-, or six-membered nitrogen-containing heterocyclyl, or the nitrogen-containing heterocyclyl substituted with C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is substitutable by halogen.

19. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11, R.sub.d is a thiazole or isoxazole substituted with methyl; or unsubstituted pyridyl.

20. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, Ar is an aromatic ring group 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 substituted with one or more groups selected from halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.1-C.sub.6 acyl group, or a C.sub.1-C.sub.6 alkoxy group.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0060] FIG. 1 is a graph of the PASI score of an ointment prepared from CPD-029 of the present invention through skin application to treat psoriasis in a mouse model test;

[0061] FIG. 2 is a graph of the PASI score of an ointment prepared from CPD-028 of the present invention through skin application to treat psoriasis in a mouse model test;

[0062] FIG. 3 is a graph of the PASI score of an ointment prepared from CPD-027 of the present invention through skin application to treat psoriasis in a mouse model test;

[0063] FIG. 4 is a graph of the PASI score of an ointment prepared from CPD-017 of the present invention through skin application to treat psoriasis in a mouse model test; and

[0064] FIG. 5 is a graph of the PASI score of an ointment prepared from CPD-002 of the present invention through skin application to treat psoriasis in a mouse model test.

DETAILED DESCRIPTION OF THE INVENTION

[0065] The present inventors have unexpectedly discovered through intensive studies that the coupling of an anti-inflammatory pharmaceutical compound containing a carboxylic acid or hydroxyl group with a JAK inhibitor compound to form a coupling compound having an acyloxy group and/or methoxy group has a high therapeutic effect and a particular effect of controlled-release pharmaceutical activity.

[0066] The anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof provided by the present invention, has a structure shown in general formula (I):

A-YB(1) [0067] wherein, A is a group after dehydrogenation of an amine compound having JAK inhibitory activity; [0068] Y is a direct connection or (CH.sub.2)O; [0069] B is a group formed by means of dehydroxylation of a carboxylic acid compound B.sub.1 with anti-inflammatory effect, or a group formed by means of dehydrogenation of a hydroxy-containing compound B.sub.2.

[0070] That is to say, the compounds of general formula (I) provided by the present invention actually include two main classes. The first main class refers to the case where A is a direct connection and the structural formula thereof is as shown in (II) or (IIa).

##STR00123## [0071] wherein R.sub.1 is selected from pyrazolyl or N(CH.sub.3)C.sub.y unsubstituted or substituted with Ra; R.sub.1a represents a pyrrole ring substituted a halogen-substituted C.sub.1-C.sub.6 alkylaminoacyl group and/or a C.sub.1-C.sub.6 alkyl group; [0072] C.sub.y is a five- or six-membered carbocyclic ring or a five- or six-membered nitrogen-containing heterocyclic ring unsubstituted or substituted by R.sub.b; R.sub.a and R.sub.b are each independently at least one or two groups containing an acyl group, a dithioyl group, a cyano group, an amino group or a C.sub.1-C.sub.6 alkyl-substituted amino group; preferably R.sub.a and R.sub.b are each independently one of acyl or dithioacyl and at least one group selected from cyano, amino, or C.sub.1-C.sub.6 alkyl substituted amino, wherein the C.sub.1-C.sub.6 alkyl is substitutable by halogen; [0073] R.sub.2 in both general formulas (II) and (IIa) is B, i.e. is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B.sub.1 and is selected from R.sub.4ArR.sub.3CO, [0074] wherein R.sub.3 is selected from C.sub.1-C.sub.4 alkylene; NH, R.sub.5NH, or C.sub.1-C.sub.6 alkylene substituted with a C.sub.1-C.sub.6 alkoxyamide group; or a direct connection, i.e. the Ar group is directly linked to CO; R.sub.3 is preferably methyl substituted or unsubstituted methylene, C.sub.2H.sub.4, or a direct connection; R.sub.5 is C.sub.1-C.sub.6 alkylene; wherein the C.sub.1-C.sub.6 alkylene is substitutable by halogen (preferably halogen is selected from one or two or more of fluorine, chlorine or bromine); [0075] 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 (here, the aryl heterocyclic ring being preferably a benzo nitrogen- or oxygen-containing heterocyclic ring such as a benzopyrrole ring) substituted with a group selected from halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.1-C.sub.6 acyl group, or a C.sub.1-C.sub.6 alkoxy group; Ar is more preferably an aryl heterocyclic ring containing a nitrogen atom; and [0076] R.sub.6 is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6 cycloalkanoyl-containing C.sub.1-C.sub.6 alkyl; [0077] or R.sub.6 is C.sub.1-C.sub.6 alkyl or aromatic ring or aromatic condensed ring or aromatic condensed ring heterocyclic ring containing acyl and/or amino groups, such as C.sub.1-C.sub.6 alkylamido or aryl fused heterocyclic amido, C.sub.1-C.sub.6 carbonyloxy, halogen-substituted benzoyl, C.sub.1-C.sub.6 alkyl or halogen substituted or unsubstituted phenoxy, C.sub.1-C.sub.6 alkyl or halogen substituted or unsubstituted phenyl or aryl fused heterocyclic ring, C.sub.1-C.sub.6 alkyl or halogen substituted or unsubstituted phenylamino, or R.sub.6 can also be absent; wherein the C.sub.1-C.sub.6 alkoxy can also form a bridged ring with Ar.

[0078] The aforementioned terms in the present invention, as well as all C.sub.1-C.sub.6 appearing below, refer to a carbon atom number of 1-6. For example, C.sub.1-C.sub.6 alkyl refers to an alkyl group with a carbon atom number of 1-6. By analogy, the terms C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 acyl mentioned herein refer to alkoxy groups with a carbon atom number of 1-6 and groups with a carbon atom number of 1-6 containing C?O, respectively. C.sub.1-C.sub.6 alkylamide group refers to an alkyl group containing amide groups with a carbon atom number of 1-6. C.sub.1-C.sub.6 carboacyloxy group refers to an alkyl group or cycloalkyl group containing acyloxy COO with a carbon atom number of 1-6. C.sub.1-C.sub.6 cycloalkanoyl group refers to a cyclic alkyl group containing C?O group with a carbon atom number of 1-6. The term C.sub.1-C.sub.6 alkyl group containing C.sub.1-C.sub.6 cycloalkanoyl group refers to the situation where hydrogen on carbon atoms is substituted by C.sub.1-C.sub.6 cycloalkanoyl groups in an alkyl group with a carbon atom number of 1-6, i.e., C.sub.1-C.sub.6 alkyl group containing C.sub.1-C.sub.6 cycloalkanoyl group is equivalent to C.sub.1-C.sub.6 alkyl group substituted by C.sub.1-C.sub.6 cycloalkanoyl group. The C.sub.1-C.sub.6 in the present invention may be specifically C.sub.1-C.sub.6, C1-C5, C1-C4, C1-C3 or C1-C2, and may also be C1, i.e. only one carbon atom.

[0079] The first general compound described above is a compound A-B (specifically, A-B.sub.1) formed by means of dehydrogenation of an amine compound A having JAK inhibitory activity and dehydroxylation of a carboxylic acid compound B.sub.1.

[0080] The compound of general formula (I) provided by the present invention includes the second main class of compound having a structural formula and structure shown in general formula (III):

##STR00124## [0081] wherein R.sub.1 has the same meaning as R.sub.1 in general formula (II); R.sub.1a has the same meaning as R.sub.1a in formula (IIa); [0082] The R.sub.2 in general formula (III) and general formula (IIIa) are both YB, where Y is (CH.sub.2)O, and B is B.sub.1 in general formula (II) or (IIa), i.e. group B.sub.1 formed by the dehydroxylation of a carboxylic acid compound B.sub.1; or [0083] B is B.sub.2, the group B.sub.2 is R.sub.cCONHR.sub.d, wherein R.sub.c is a 4-hydroxy-benzothiazine dioxide-3-yl represented by the following structural formula (a), wherein the phenyl ring is substitutable by halogen or C.sub.1-C.sub.4 alkyl, or a 4-hydroxy-Re substituted thienothiazine dioxide-3-yl represented by the following structural formula (b), wherein CONHR.sub.d is attached at the 3-position of the thiazine ring,

##STR00125## [0084] wherein R.sub.d is thiazole, isothiazole, oxazole, isoxazole, or pyridine or a group thereof substituted with C.sub.1-C.sub.6 alkyl or halogen, preferably a thiazole or isoxazole substituted with methyl; and unsubstituted pyridyl; R.sub.e is C.sub.1-C.sub.6 alkyl or halogen (preferably halogen is selected from one or two or more of fluorine, chlorine, or bromine); the arrow next to R.sub.e in formula (b) indicates that its substitution position on the thiophene ring may be any carbon-linked hydrogen atom capable of undergoing substitution.

[0085] The second main compound of the present invention is obtained by using A-CH.sub.2OH to undergo a condensation reaction accompanied by loss of water with B.

[0086] In particular, the preparation of the second main class of compound comprises the following steps: [0087] 2) reacting A-CH.sub.2OH compound with an acyl chloride of B or directly with the B compound; Wherein the A-CH.sub.2OH compound is prepared by step 1): reacting A to generate an A-CH.sub.2OH compound.

[0088] The scope of the compound of general formula (I) of the present invention actually also includes the various stereoisomers, tautomers, N-oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates thereof, which can be obtained by those skilled in the art according to the common knowledge, that is to say, these compounds, and the various stereoisomers, tautomers, N-oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates thereof and the like, which can be modified by those skilled in the art according to common knowledge, can be used in the present invention to achieve the particular effects of the compounds of the present invention, such as strong transdermal performance, controllable drug release, and high efficacy, and therefore all fall within the scope of the present invention.

[0089] Examples The following is an example to illustrate how the compound of the present invention is prepared and its performance evaluation.

[0090] The NMR Instrument and Mass Spectrometer Instrument Models Used in Examples 1-149 Below are Described Below, Respectively:

[0091] Nuclear magnetic resonance spectrometer: Bruker 400M Nuclear Magnetic Resonance Instrument; Liquid Chromatography Mass Spectrometry Instrument: Agilent InfinityLab LC/MSD iQ

[0092] Table 1 below is a structural formula and a compound name of a target compound prepared in each example.

TABLE-US-00001 TABLE 1 Structural formulas and compound names of target compounds prepared in examples Examples (Cmpd No.) Structure Chinese name 1 (CPD-001) [00126] 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 2 (CPD-002) [00127] 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 3 (CPD-003) [00128] (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 4 (CPD-004) [00129] 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 5 (CPD-005) [00130] 3-((3R, 4R)-3-((7-(2-((3-chloro-2-methylphenyl) amino)benzoyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)(methyl) amino)-4-methylpiperidin-1-yl)-3- oxopropanenitrile 6 (CPD-006) [00131] 3-((3R, 4R)-3-((7-((S)-2-(6-methoxynaphthalen-2-yl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) (methyl) amino)-4-methylpiperidin-1-yl)-3- oxopropanenitrile 7 (CPD-007) [00132] 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 8 (CPD-008) [00133] 3-((3R, 4R)-3-((7-(2-(2-fluoro-[1, 1-biphenyl]-4-yl)propanoyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)(methyl) amino)-4-methylpiperidin-1-yl)-3- oxopropanenitrile 9 (CPD-009) [00134] 3-((3R,4R)-3-((7-(2-(2-(2-(2-(2, 6-dichlorophenyl)amino)phenyl) acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) (methyl) amino)-4-methylpiperidin-1-yl)-3- oxopropanenitrile 10 (CPD-010) [00135] 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 11 (CPD-011) [00136] 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 12 (CPD-012) [00137] 3-((3R, 4R)-3-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy- 2-methyl-1H-indol-3-yl)acetyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)(methyl) amino)-4-methylpiperidin-1-yl)-3- oxopropanenitrile 13 (CPD-013) [00138] 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 14 (CPD-014) [00139] 3-((3R,4R)-3-((7-(2-(1,8-diethyl-1,3,4, 9-tetrahydropyrano[3,4-b]indol-1-yl) acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) (methyl) amino)-4-methylpiperidin-1-yl)-3- oxopropanenitrile 15 (CPD-015) [00140] 2-(4-((3R, 4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl) (methyl)amino)-7H-pyrrolo[2,3-d] pyrimidine-7-carbonyl)phenyl acetate 16 (CPD-016) [00141] 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 17 (CPD-017) [00142] (S)-2-(1-(ethylsulfonyl)- 3-(4-(7-(2-(4-isobutyl- phenyl)propanoyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin- 3-yl)acetonitrile 18 (CPD-018) [00143] (S)-2-(1-(ethylsulfonyl)- 3-(4-(7-(2-(6-methoxy naphthalen-2-yl)propanoyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) azetidin-3-yl)acetonitrile 19 (CPD-019) [00144] 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 20 (CPD-020) [00145] 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1, 1-biphenyl]-4-yl)propanoyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) azetidin-3-yl)acetonitrile 21 (CPD-021) [00146] 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(3-phenoxy- phenyl)propanoyl)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl)azetidin-3-yl) acetonitrile 22 (CPD-022) [00147] 2-(1-(ethylsulfonyl)-3- (4-(7-(2-(4-(2-oxocyclo- pentyl)methyl)phenyl)propanoyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) azetidin-3-yl)acetonitrile 23 (CPD-023) [00148] 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 24 (CPD-024) [00149] 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 25 (CPD-025) [00150] 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 26 (CPD-026) [00151] 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 27 (CPD-027) [00152] 1-((Trans-)-4-((7-((S)-2-(4-isobutylphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) (methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 28 (CPD-028) [00153] (R)-3-cyclopentyl-3-(4-(7- (S)-2-(4-isobutylphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl)propanenitrile 29 (CPD-029) [00154] 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 30 (CPD-030) [00155] 2-2-(1-(Ethylsulfonyl)- 3-(4-(7-(2-(4-(1-oxoiso- indolin-2-yl)phenyl)butanoyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl)azetidin- 3-yl)acetonitrile 31 (CPD-039) [00156] (R)-3-cyclopentyl-3-(4- (7-((S)-2-(6-methoxy- naphthalen-2-yl)propanoyl)- 7H-pyrrolo[2,3-d] pyrimidin-4-yl))-1H-pyrazol-1-yl) propanenitrile 32 (CPD-040) [00157] (3R)-3-(4-(7-(2-(3-benzoylphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile 33 (CPD-041) [00158] (3R)-3-cyclopentyl-3-(4-(7-(2-(2-fluoro-[1, 1-biphenyl]-4-yl)propanoyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) propanenitrile 34 (CPD-050) [00159] (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 35 (CPD-065) [00160] N-methyl-1-((trans)-4-(methyl (7-(2-(4-(1-oxoisoindolin-2-yl)phenyl) butanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) amino)cyclohexyl)methanesulfonamide 36 (CPD-056) [00161] 1-((Trans)-4-((7-(2-(2-fluoro-[1, 1-biphenyl]-4-yl)propanoyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)(methyl)amino) cyclohexyl)-N-methyl methanesulfonamide 37 (CPD-062) [00162] 1-((Trans)-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) (methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 38 (CPD-055) [00163] 1-((Trans)-4-((7-(2-(3-benzoylphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) (methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 39 (CPD-054) [00164] 1-((Trans)-4-((7-((S)- 2-(6-methoxynaphthalen- 2-yl)propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)(methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 40 (CPD-032) [00165] 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 41 (CPD-053) [00166] 1-((Trans)-4-((7-(2-((3- chloro-2-methylphenyl) amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)(methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 42 (CPD-060) [00167] 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 43 (CPD-052) [00168] 1-((Trans)-4-((7-(2-((2,3-dimethylphenyl) amino)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)(methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 44 (CPD-059) [00169] 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 45 (CPD-047) [00170] (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 46 (CPD-064) [00171] 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 47 (CPD-031) [00172] 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 48 (CPD-082) [00173] 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 49 (CPD-083) [00174] (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 50 (CPD-084) [00175] (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-biphenyl]-4-yl) propanoate 51 (CPD-085) [00176] (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 52 (CPD-086) [00177] (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 53 (CPD-087) [00178] (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 54 (CPD-043) [00179] (3R)-3-cyclopentyl-3-(4- (7-(2-(3-phenoxyphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl)propanenitrile 55 (CPD-088) [00180] (4-(((3R, 4R)-1-(2-cyanoacetyl)- 4-methylpiperidin-3-yl) (methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl- 1H-indol-3-yl)acetate 56 (CPD-089) [00181] (4-(((3R, 4R)-1-(2-cyanoacetyl)- 4-methylpiperidin-3-yl) (methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)methyl 2-acetoxybenzoate 57 (CPD-038) [00182] (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 58 (CPD-061) [00183] N-(4-(2-(4-(methyl ((trans)-4-((N-methylsulfamoyl)methyl) cyclohexyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2-oxoethyl)phenyl)acetamide 59 (CPD-140) [00184] (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 60 (CPD-092) [00185] 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 61 (CPD-093) [00186] 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 62 (CPD-094) [00187] 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 63 (CPD-139) [00188] (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 64 (CPD-141) [00189] (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 65 (CPD-136) [00190] (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 66 (CPD-138) [00191] (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 67 (CPD-137) [00192] (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 68 (CPD-058) [00193] N-methyl-1-((trans)-4-(methyl (7-(2-(3-phenoxyphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) amino)cyclohexyl)methanesulfonamide 69 (CPD-095) [00194] 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-biphenyl]-4-yl)propanoate 70 (CPD-096) [00195] 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 71 (CPD-097) [00196] 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 72 (CPD-098) [00197] 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 73 (CPD-099) [00198] 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 74 (CPD-150) [00199] 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 75 (CPD-042) [00200] (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 76 (CPD-145) [00201] 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 77 (CPD-044) [00202] (3R)-3-cyclopentyl-3- (4-(7-(2-(4-((2-oxocyclo- pentyl)methyl)phenyl)propanoyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) propanenitrile 78 (CPD-046) [00203] (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 79 (CPD-045) [00204] (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 80 (CPD-049) [00205] 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 81 (CPD-147) [00206] 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 82 (CPD-037) [00207] (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 83 (CPD-146) [00208] 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 84 (CPD-149) [00209] 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 85 (CPD-148) [00210] 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 86 (CPD-114) [00211] (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 87 (CPD-115) [00212] (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 88 (CPD-103) [00213] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl (S)-2-(4-isobutylphenyl)propanoate 89 (CPD-104) [00214] (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 90 (CPD-105) [00215] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl 2-(3-benzoylphenyl)propanoate 91 (CPD-162) [00216] (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 92 (CPD-107) [00217] (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 93 (CPD-158) [00218] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl 2-(4-acetamidophenyl)acetate 94 (CPD-157) [00219] (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 95 (CPD-033) [00220] 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 96 (CPD-051) [00221] 1-((Trans)-4-((7-(2-(4-isobutylphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) (methyl)amino)cyclohexyl)-N-methyl methanesulfonamide 97 (CPD-142) [00222] 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-benzo [e][1,2]thiazine-3-carboxamide 1,1-dioxide 98 (CPD-036) [00223] (R)-3-cyclopentyl-3-(4- (7-2-(4-isobutylphenyl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl)propanenitrile 99 (CPD-116) [00224] (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H- pyrazol-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl) methyl 2-(3-benzoylphenyl)propanoate 100 (CPD-117) [00225] (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-biphenyl]-4-yl) propanoate 101 (CPD-118) [00226] (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 102 (CPD-119) [00227] (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H- pyrazol-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl) methyl 2-(3-phenoxyphenyl)propanoate 103 (CPD-120) [00228] (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 104 (CPD-121) [00229] (R)(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 105 (CPD-163) [00230] (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 106 (CPD-164) [00231] (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 107 (CPD-165) [00232] (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 108 (CPD-184) [00233] (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H- pyrazol-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl) methyl 2-(4-isobutylphenyl)propanoate 109 (CPD-166) [00234] (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 110 (CPD-167) [00235] (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H- pyrazol-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl) methyl 2-(4-acetamidophenyl)acetate 111 (CPD-168) [00236] (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 112 (CPD-182) [00237] 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 113 (CPD-106) [00238] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl 2-(2-fluoro-[1, 1-biphenyl]-4-yl) propanoate 114 (CPD-108) [00239] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl 2-(3-phenoxyphenyl)propanoate 115 (CPD-109) [00240] (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 116 (CPD-110) [00241] (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 117 (CPD-154) [00242] (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 118 (CPD-155) [00243] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl 2-((2, 3-dimethylphenyl)amino)benzoate 119 (CPD-183) [00244] (4-(Methyl((trans)-4-((N-methylsulfamoyl) methyl)cyclohexyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl 2-(4-isobutylphenyl)propanoate 120 (CPD-156) [00245] (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 121 (CPD-151) [00246] 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-benzo [e][1,2]thiazine-3-carboxamide 1,1-dioxide 122 (CPD-101) [00247] 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 123 (CPD-066) [00248] (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 124 (CPD-067) [00249] (3S,4R)-3-ethyl-4-(3- ((R)-2-(4-isobutylphenyl) propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide 125 (CPD-072) [00250] (3S,4R)-3-ethyl-4-(3-(2-(2-fluoro-[1, 1-biphenyl]-4-yl)propanoyl)-3H-imidazo[1, 2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2, 2-trifluoroethyl)pyrrolidine-1-carboxamide 126 (CPD-071) [00251] (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 127 (CPD-073) [00252] (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 128 (CPD-074) [00253] (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 129 (CPD-068) [00254] (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 130 (CPD-069) [00255] (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 131 (CPD-070) [00256] (3S,4R)-3-ethyl-4-(3-((S)-2-(6-) methoxynaphthalen-2-yl) propanoyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide 132 (CPD-075) [00257] (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 133 (CPD-076) [00258] (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 134 (CPD-077) [00259] (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 135 (CPD-078) [00260] (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) pyrrolidine-1-carboxamide 136 (CPD-079) [00261] 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 137 (CPD-080) [00262] 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 138 (CPD-081) [00263] (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 139 (CPD-186) [00264] 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 140 (CPD-187) [00265] 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 141 (CPD-190) [00266] 3-((3S,4R)- 6-(7-((S)-2-(6-methoxynaphthalen-2-yl) propanoyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methyl-1,6-diazaspiro[3.4]octan- 1-yl)-3-oxopropanenitrile 142 (CPD-090) [00267] 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 143 (CPD-201) [00268] 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 144 (CPD-202) [00269] (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 145 (CPD-191) [00270] 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 146 (CPD-143) [00271] 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 147 (CPD-159) [00272] 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 148 (CPD-152) [00273] 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-carboxamide 1,1-dioxide 149 (CPD-160) [00274] 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

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

[0093] ##STR00275##

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

[0094] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 dicyclohexyl carbodiimide (DCC, 412 mg, 2 mmol) were added in an ice waterbath, followedby stirring atreflux for 16 hours. After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.36N.sub.6O.sub.2, 501.65; found, 501.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0095] ##STR00276##

Synthesis of 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

[0096] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 dicyclohexyl carbodiimide (DCC, 412 mg, 2 mmol) were added in an ice water bath, followed by stirring at reflux for 16 hours. After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.36N.sub.6O.sub.2, 501.65; found, 501.2. .sup.1H NMR (400 MHz, DMSO-d6) ? 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

[0097] ##STR00277##

First Step: Synthesis 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

[0098] ##STR00278##

[0099] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 the 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, 9 g, 71% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.22H.sub.34N.sub.6O.sub.2Si, 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

[0100] ##STR00279##

[0101] 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 and the temperature was raised to room temperature and stirring was continued for 24 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0? C. to adjust the pH to 8. Then, the mixture was poured into a separation funnel and separated. The organic layer was washed with a saturated salt water solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title product 3.5 g, 90% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.17H.sub.22N.sub.6O.sub.2, 343.18; found, 343.1.

[0102] 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

##STR00280##

[0103] 3-((3R, 4R)-3-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] 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 hours, the reaction mixture was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 4.05 g, 39.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.38N.sub.6O.sub.3, 531.67; found, 531.2. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 (q, 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

[0104] ##STR00281##

[0105] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 314 mg, 1.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.1 g, yield 18.6%. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.33N.sub.7O.sub.2, 536.65; found, 536.2. .sup.1H NMR (400 MHz, DMSO) ? 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-1-yl)-3-oxopropanenitrile

[0106] ##STR00282##

[0107] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 187 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.6 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tofenamic acid, 204 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) was dissolved in dichloromethane (10 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.12 g, 35.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.30C.sub.1N.sub.7O.sub.2, 557.07; found, 557.2. .sup.1H NMR (400 MHz, DMSO-d6) ? 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 (tq, 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-1-yl)-3-oxopropanenitrile

[0108] ##STR00283##

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-1-yl)-3-oxopropanenitrile

[0109] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.32N.sub.6O.sub.3, 525.63; found, 525.3. .sup.1H NMR (400 MHz, DMSO) ? 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

[0110] ##STR00284##

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

[0111] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.32N.sub.6O.sub.3, 549.65; found, 549.3. .sup.1H NMR (400 MHz, DMSO) ? 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=7.7 Hz, 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-biphenyl]-4-yl) propanoyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

[0112] ##STR00285##

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

[0113] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2-fluoro-4-biphenyl) 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 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.73 g, 67.8% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.31FN.sub.6O.sub.2, 539.63; found, 539.2. .sup.1H NMR (400 MHz, DMSO) ? 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 (q, 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-(2, 6-dichlorophenyl) amino) phenyl) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

[0114] ##STR00286##

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

[0115] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2, 6-dichlorophenylamino) phenylacetic acid (diclofenac, 651 mg, 2.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.29Cl.sub.2N.sub.7O.sub.2, 590.51; found, 590.2. .sup.1H NMR (400 MHz, DMSO) ? 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

[0116] ##STR00287##

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

[0117] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.32N.sub.6O.sub.3 537.64; found, 537.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (qd, J=7.0, 4.5 Hz, 1H), 5.09 (ddq, J=14.2, 9.9, 4.8 Hz, 1H), 4.12-3.67 (m, 2H), 3.63-3.41 (m, 4H), 3.33 (d, J=15.6 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-1-yl)-3-oxopropanenitrile

[0118] ##STR00288##

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

[0119] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.36N.sub.6O.sub.3, 541.67; found, 541.3. .sup.1H NMR (400 MHz, DMSO) ? 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-1-yl)-3-oxopropanenitrile

[0120] ##STR00289##

[0121] Synthesis of 3-((3R, 4R)-3-((7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 233 mg, 0.65 mmol) 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 saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.35H.sub.34C.sub.1N.sub.7O.sub.4, 653.15; found, 653.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0122] ##STR00290##

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

[0123] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.26H.sub.29N.sub.7O.sub.3, 488.56; found, 488.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-methylpiperidin-1-yl)-3-oxopropanenitrile

[0124] ##STR00291##

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

[0125] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 1, 8-diethyl-1, 3, 4, 9-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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.33H.sub.39N.sub.7O.sub.3, 582.72; found, 582.3.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.5 Hz, 2H), 2.60 (dt, J=9.4, 4.7 Hz, 2H), 2.45-2.30 (m, 1H), 2.16 (qq, 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] pyrimidine-7-carbonyl) phenyl acetate

[0126] ##STR00292##

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

[0127] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 2-acetoxybenzoic acid (aspirin, 216 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.06 g, 12.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.25H.sub.26N.sub.6O.sub.4, 475.52; found, 475.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (dq, 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

[0128] ##STR00293##

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

[0129] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, yield 55%. MS (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.35N.sub.7O.sub.4, 546.64; found, 546.3.1H NMR (400 MHz, DMSO-d6) ? 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

[0130] ##STR00294##

Synthesis of (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

[0131] 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-dimethylamino pyridine (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) was dissolved in dichloromethane (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.5 g, 44.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.33N.sub.7O.sub.3S, 560.69; found, 560.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0132] ##STR00295##

Synthesis of (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

[0133] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.25 g, 42.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.29N.sub.7O.sub.4S, 584.67; found, 584.2. .sup.1H NMR (400 MHz, DMSO) ? 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, 211), 3.83 (s, 3H), 3.68 (s, 2H), 3.23 (q, 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

[0134] ##STR00296##

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

[0135] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.129N.sub.7O.sub.4S, 608.69; found, 608.3. .sup.1H NMR (400 MHz, DMSO) ? 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 (q, 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 (q, 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-biphenyl]-4-yl) propanoyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl) azetidin-3-yl) acetonitrile

[0136] ##STR00297##

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

[0137] 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-dimethylamino pyridine (DMAP, 610 mg, 5 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.28FN.sub.7O.sub.3S, 598.67; found, 598.2. .sup.1H NMR (400 MHz, DMSO) ? 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 (q, 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 (q, 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

[0138] ##STR00298##

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

[0139] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.29N.sub.7O.sub.4S, 596.68; found, 596.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.3 Hz, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.24 (t, J=7.4 Hz, 311).

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

[0140] ##STR00299##

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

[0141] 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-dimethylamino pyridine (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) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 17 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.31H.sub.33N.sub.7O.sub.4S, 600.71; found, 600.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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=7.9 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

[0142] ##STR00300##

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

[0143] 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-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 197 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.35H.sub.31C.sub.1N.sub.8O.sub.5S, 712.19; found, 711.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0144] ##STR00301## ##STR00302##

Synthesis of 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

[0145] 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-dimethylamino pyridine (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) was 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.26H.sub.26N.sub.8O.sub.4S, 547.61; found, 547.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0146] ##STR00303##

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

[0147] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.33H.sub.36N.sub.8O.sub.4S, 641.76; found, 641.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.3 Hz, 2H), 2.89 (q, J=7.5 Hz, 2H), 2.64 (dt, J=6.8, 4.2 Hz, 2H), 2.21 (q, 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

[0148] ##STR00304##

Synthesis of 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

[0149] 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), N-Boc-L-phenylglycine (301.5 mg, 1.2 mmol), 4-dimethylamino pyridine (DMAP, 183 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.32N.sub.8O.sub.5S, 605.69; found, 605.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.3 Hz, 2H), 1.40 (s, 9H), 1.24 (t, J=7.4 Hz, 3H).

Example 27

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

[0150] ##STR00305##

[0151] N-methyl-1-((1R, 4R)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 338 mg, 1 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.28H.sub.39N.sub.5O.sub.3S, 526.71; found, 526.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0152] ##STR00306##

[0153] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 306 mg, 1 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.34N.sub.6O.sub.4, 495.64; found, 495.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (qd, 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=27.2, 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

[0154] ##STR00307##

[0155] 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylamino pyridine (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) was dissolved in dichloromethane (10 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.34H.sub.35N.sub.7O.sub.3, 590.70; found, 590.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0156] ##STR00308##

[0157] 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-dimethylamino pyridine (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) was dissolved in dichloromethane (15 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.46 g, 70.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.32N.sub.8O.sub.4S, 649.74; found, 649.3. .sup.1H NMR (400 MHz, DMSO) ? 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

[0158] ##STR00309##

[0159] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.16 g, 61.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.30N.sub.6O.sub.2, 519.62; found, 519.3. .sup.1H NMR (400 MHz, DMSO) ? 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

[0160] ##STR00310##

[0161] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.33H.sub.30N.sub.6O.sub.2, 543.64; found, 543.2. .sup.1H NMR (400 MHz, DMSO) ? 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 (q, 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-biphenyl]-4-yl) propanoyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl) propanenitrile

[0162] ##STR00311##

[0163] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 6 mg, 0.05 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.29FN.sub.6O, 533.62; found, 533.2. .sup.1H NMR (400 MHz, DMSO) ? 9.00 (s, 111), 8.88 (s, 111), 8.41 (s, 111), 8.15 (d, J=4.1 Hz, 111), 7.52-7.29 (m, 9H), 6.08 (q, J=6.7 Hz, 111), 4.54 (td, J=9.4, 4.0 Hz, 111), 3.28-3.15 (m, 2H), 2.43 (dd, J=16.9, 8.4 Hz, 111), 1.87-1.76 (m, 1H), 1.70-1.38 (m, 711), 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

[0164] ##STR00312##

[0165] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.17 g, 58.3% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.35H.sub.33N.sub.7O.sub.2, 584.70; found, 584.3. .sup.1H NMR (400 MHz, DMSO) ? 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-(1-oxoisoindolin-2-yl) phenyl) butanoyl)-7H-pyrrolo [2, 3-d]pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide

[0166] ##STR00313##

[0167] (N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.22 g, 59.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.38N.sub.6O.sub.4S, 615.77; found, 615.3. .sup.1H NMR (400 MHz, DMSO) ? 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-biphenyl]-4-yl) propanoyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide

[0168] ##STR00314##

[0169] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.34FN.sub.5O.sub.3S, 564.69; found, 564.3. .sup.1H NMR (400 MHz, DMSO) ? 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 (q, 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-(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-methyl methanesulfonamide

[0170] ##STR00315##

[0171] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (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) was dissolved in dichloromethane (15 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.32H.sub.42N.sub.6O.sub.4S, 607.79; found, 607.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide

[0172] ##STR00316##

[0173] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.35N.sub.5O.sub.4S, 574.71; found, 574.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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 (dq, 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-methyl methanesulfonamide

[0174] ##STR00317##

[0175] N-Methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.35N.sub.5O.sub.4S, 550.69; found, 550.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=4.5 Hz, 1H), 6.79 (d, J=3.0 Hz, 1H), 6.21 (q, 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

[0176] ##STR00318##

[0177] 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-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 313 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.22 g, 35.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.27ClN.sub.8O.sub.3S, 616.11; found, 616.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-methyl methanesulfonamide

[0178] ##STR00319##

[0179] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 204 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.33ClN.sub.6O.sub.3S, 581.20; found, 581.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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) acetyl)-7H-pyrrolo [2, 3-d]pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methylmethanesulfonamide

[0180] ##STR00320##

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-methyl methanesulfonamide

[0181] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (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) was dissolved in dichloromethane (15 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.14 g, 41.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.37C.sub.1N.sub.6O.sub.5S, 677.22; found, 677.3 0.1H NMR (400 MHz, DMSO-d.sub.6) ? 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-methyl methanesulfonamide

[0182] ##STR00321##

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

[0183] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 157 mg, 0.65 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 7 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.36N.sub.6O.sub.3S, 561.26; found, 561.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (h, J=3.3 Hz, 4H), 1.37-1.26 (m, 211).

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

[0184] ##STR00322##

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

[0185] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.39N.sub.5O.sub.4S, 566.27; found, 566.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0186] ##STR00323##

Synthesis of (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

[0187] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.28 g, 81.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.37N.sub.7O.sub.2, 576.30; found, 576.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.5 Hz, 2H), 2.64-2.56 (m, 2H), 2.44 (q, J=8.4 Hz, 1H), 2.18 (q, 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

[0188] ##STR00324##

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

[0189] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (163 mg, 0.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.28H.sub.38N.sub.6O.sub.5S, 571.26; found, 571.3. .sup.1H NMR (400 MHz, DMSO-d6) ? 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

[0190] ##STR00325## ##STR00326##

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

[0191] 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-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 289 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 289 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.30N.sub.8O.sub.3S, 595.22; found, 595.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-cyanoacetyl)-4-methylpiperidin-3-yl) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin-7-yl) methyl (S)-2-(6-methoxynaphthalen-2-yl) propanoate

[0192] ##STR00327## ##STR00328##

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

[0193] 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-dimethylamino pyridine (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 for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.107 g, 38.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.34N.sub.6O.sub.4, 555.26; found, 555.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0194] ##STR00329## ##STR00330##

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

[0195] 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-dimethylamino pyridine (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) was 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.153 g, 52.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.34N.sub.6O.sub.4, 579.26; found, 579.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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-biphenyl]-4-yl) propanoate

[0196] ##STR00331## ##STR00332##

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-biphenyl]-4-yl) propanoate

[0197] 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-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 183 mg, 0.75 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was 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 was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.083 g, 29.2% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.33FN.sub.6O.sub.3, 569.26; found, 569.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (q, 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

[0198] ##STR00333## ##STR00334##

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-((2, 6-dichlorophenyl) amino) phenyl) acetate

[0199] 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-dimethylamino pyridine (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) was 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 was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.31Cl.sub.2N.sub.7O.sub.3, 620.19; found, 620.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (dq, 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 (dq, 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

[0200] ##STR00335## ##STR00336##

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

[0201] 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-dimethylamino pyridine (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) was 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 was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.13 g, 45.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.34N.sub.6O.sub.4, 567.26; found, 567.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (d, 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=7.2 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

[0202] ##STR00337## ##STR00338##

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

[0203] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.08 g, 28% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.38N.sub.6O.sub.4, 571.30; found, 571.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (ddd, 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

[0204] ##STR00339## ##STR00340##

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

[0205] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (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 saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.30N.sub.6O.sub.2, 531.24; found, 531.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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) amino)-7H-pyrrolo [2, 3-d] pyrimidin-7-yl) methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl) acetate

[0206] ##STR00341## ##STR00342##

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-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl) acetate

[0207] 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-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.036 g, 10.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.36H.sub.36C.sub.1N.sub.7O.sub.5, 682.25; found, 682.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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, J=11.4, 7.1 Hz, 3H).

Example 56

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

[0208] ##STR00343## ##STR00344##

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

[0209] 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-dimethylamino pyridine (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) was 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 was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.178 g, 70.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.26H.sub.28N.sub.6O.sub.5, 505.21; found, 505.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (d, 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 [2, 3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

[0210] ##STR00345## ##STR00346##

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

[0211] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 306 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 261 mg, 1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 289 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.28C.sub.1N.sub.7O, 550.20; found, 550.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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=7.7 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

[0212] ##STR00347## ##STR00348##

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

[0213] N-Methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.25H.sub.32N.sub.6O.sub.4S, 513.22; found, 513.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0214] ##STR00349## ##STR00350##

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

[0215] 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-dimethylamino pyridine (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) was 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.154 g, yield 59.5%. MS (m/z): [M+H].sup.+ calcd for C.sub.27H.sub.31N.sub.7O.sub.4, 518.24; found, 518.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (ft, 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

[0216] ##STR00351## ##STR00352##

First step: synthesis 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

[0217] 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile (baricitinib, 7420 mg, 20 mmol) and N, N-diisopropylethyl amine (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, 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].sup.+ calcd for C.sub.22H.sub.31N.sub.7O.sub.3SSi, 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

[0218] 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 in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 24 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0? C. to adjust the pH to 8. Then, the mixture was poured into a separation funnel and separated. The organic layer was washed with a saturated salt water solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title product 3.5 g, 90% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.17H.sub.19N.sub.7O.sub.3S, 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

[0219] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.025 g, 8.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.35N.sub.7O.sub.4S, 590.25, found 590.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0220] ##STR00353## ##STR00354##

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-(6-methoxynaphthalen-2-yl) propanoate

[0221] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.31 g, 50.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.31N.sub.7O.sub.5S, 614.21; found, 614.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.0 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.24 (q, J=7.3 Hz, 2H), 1.44 (d, J=7.1 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

[0222] ##STR00355## ##STR00356##

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

[0223] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.33H.sub.31N.sub.7O.sub.5S, 638.21; found, 638.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.1 Hz, 1H), 3.71 (s, 2H), 3.25 (q, J=7.3 Hz, 2H), 1.41 (d, J=7.1 Hz, 3H), 1.26 (t, J=7.3 Hz, 3H).

Example 63

[0224] (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

##STR00357##

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

[0225] 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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.18 g, 58.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.41N.sub.7O.sub.4, 612.32; found, 612.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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, 311).

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

[0226] ##STR00358##

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

[0227] 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) was 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.148 g, 51.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.37N.sub.7O.sub.5, 576.29; found, 576.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0228] ##STR00359## ##STR00360##

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

[0229] 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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.012 g, 33.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.35H.sub.37N.sub.7O.sub.4, 620.29; found, 620.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (q, J=6.6, 5.1 Hz, 3H), 3.37-3.27 (m, 3H), 2.54-2.40 (m, 1H), 2.07 (dq, J=14.1, 7.3 Hz, 2H), 1.93 (s, 1H), 1.76 (tt, 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

[0230] ##STR00361##

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-methylphenyl) amino) benzoate

[0231] 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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.145 g, 42.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.32ClN.sub.7O.sub.3, 586.23; found, 586.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (q, 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, 311).

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

[0232] ##STR00362##

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, 3-dimethylphenyl) amino) benzoate

[0233] 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.012 g, 45.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.35N.sub.7O.sub.3, 566.28; found, 566.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (ddd, 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

[0234] ##STR00363##

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

[0235] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.35N.sub.5O.sub.4S, 562.24; found, 562.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-biphenyl]-4-yl) propanoate

[0236] ##STR00364## ##STR00365##

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-biphenyl]-4-yl) propanoate

[0237] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.27 g, 86.1% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.30FN.sub.7O.sub.4S, 628.21; found, 628.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.0 Hz, 1H), 3.69 (s, 2H), 3.23 (q, J=7.3 Hz, 2H), 1.40 (d, J=7.1 Hz, 3H), 1.25 (t, J=7.2 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

[0238] ##STR00366##

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

[0239] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.31H.sub.28C.sub.2N.sub.8O.sub.4S, 679.13; found, 679.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0240] ##STR00367## ##STR00368##

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

[0241] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 1345 mg, 0.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimiide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.22 g, 70.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.31N.sub.7O.sub.5S, 626.21; found, 626.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) S 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.SUB.1.-pyrrolo [2, 3-d]pyrimidin-7-yl) 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate

[0242] ##STR00369## ##STR00370##

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

[0243] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 148 mg, 06 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.26 g, 82.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.35N.sub.7O.sub.5S, 630.24; found, 630.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0244] ##STR00371## ##STR00372##

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-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl) acetate

[0245] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 214 mg, 0.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.26 g, 75.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.36H.sub.33C.sub.1N.sub.8O.sub.6S, 741.19; found, 741.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0246] ##STR00373## ##STR00374##

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

[0247] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), N-Boc-L-phenylglycine (151 mg, 0.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.34N.sub.8O.sub.6S, 635.23; found, 635.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0248] ##STR00375##

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

[0249] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.27Cl.sub.2N.sub.7O, 584.17; found, 584.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0250] ##STR00376## ##STR00377##

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

[0251] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water 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].sup.+ calcd for C.sub.35H.sub.34N.sub.8O.sub.5S, 679.24; found, 679.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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 (q, 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

[0252] ##STR00378##

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

[0253] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.26 g, 81.1% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.34N.sub.6O.sub.2, 535.27; found, 535.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.97 (s, 1H), 8.87 (d, J=1.6 Hz, 111), 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, 111), 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, 711), 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

[0254] ##STR00379##

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

[0255] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.27H.sub.27N.sub.7O.sub.2, 482.22; found, 482.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0256] ##STR00380## ##STR00381##

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

[0257] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (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) was dissolved in dichloromethane (10 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.3 g, 77.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.36H.sub.32C.sub.1N.sub.7O.sub.3, 646.23; found, 646.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=8.2 Hz, 1H), 2.28 (s, 3H), 1.90-1.80 (m, 1H), 1.68-1.31 (m, 711).

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

[0258] ##STR00382##

Synthesis of 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

[0259] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), N-Boc-L-phenylglycine (196 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 55.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.33N.sub.7O.sub.3, 540.26; found, 540.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (h, 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

[0260] ##STR00383## ##STR00384##

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

[0261] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 137 mg, 0.53 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.26 g, 80.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.29C.sub.1N.sub.8O.sub.4S, 645.17; found, 645.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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, 111), 7.37 (td, J=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 (q, J=7.3 Hz, 2H), 2.24 (s, 3H), 1.26 (t, J=7.3 Hz, 3H).

Example 82

(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

[0262] ##STR00385##

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

[0263] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 188 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.31N.sub.7O, 530.26; found, 530.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0264] ##STR00386## ##STR00387##

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

[0265] 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-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 22-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 127 mg, 0.53 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.27 g, 86.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.32N.sub.8O.sub.4S, 625.23; found, 625.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0266] ##STR00388## ##STR00389##

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-acetamidophenyl) acetate

[0267] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water 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].sup.+ calcd for C.sub.27H.sub.28N.sub.8O.sub.5S, 577.19; found, 577.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0268] ##STR00390## ##STR00391##

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-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indol-1-yl) acetate

[0269] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.17 g, 50.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.38N.sub.8O.sub.5S, 671.27; found, 671.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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, 311).

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

[0270] ##STR00392## ##STR00393##

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

[0271] (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-diisopropylethyl amine (0.7 mL, 4.9 mmoL) were added in dichloromethane (8 mL) under nitrogen. 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.23H.sub.32N.sub.6OSi, 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

[0272] 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 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 an additional 2 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0? C. to adjust the pH to 8. Then the mixture was poured into a separating funnel for separation. The organic layer was washed with a saturated salt water solution and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.18H.sub.20N.sub.6, 337.17; found, 337.3. .sup.1H NMR (400 MHz, DMSO-d6) ? 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 (td, J=9.6, 4.2 Hz, 1H), 3.42-3.26 (m, 2H), 2.53 (q, J=8.5 Hz, 1H), 1.92 (dtd, J=11.8, 7.5, 4.2 Hz, 1H), 1.76-1.50 (m, 4H), 1.50-1.23 (m, 3H).

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

[0273] (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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.106 g, 56.1% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.36N.sub.6O.sub.2, 525.29; found, 525.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0274] ##STR00394## ##STR00395##

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-methoxynaphthalen-2-yl) propanoate

[0275] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.146 g, 63.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.32N.sub.6O.sub.3, 549.25; found, 549.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0276] ##STR00396## ##STR00397##

First step: synthesis of N-methyl-1-((trans)-4-(methyl (7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide

[0277] 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-diisopropylethyl amine (780 mg, 6 mmol) were added in dichloromethane (50 mL) under nitrogen. 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 salt water 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].sup.+ calcd for C.sub.21H.sub.37N.sub.5O.sub.3SSi, 468.24; found, 468.2.

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

[0278] 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 in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 24 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0? C. to adjust the pH to 8. Then the mixture was poured into a separating funnel for separation. The organic layer was washed with a saturated salt water solution and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.16H.sub.25N.sub.5O.sub.3S, 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

[0279] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.29H.sub.41N.sub.5O.sub.4S, 556.29; found, 556.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (dd, 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

[0280] ##STR00398##

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

[0281] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (150 mg, 0.41 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the 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].sup.+ calcd for C.sub.30H.sub.37N.sub.5O.sub.5S, 580.25; found, 580.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (q, J=10.6 Hz, 2H), 4.72 (s, 1H), 4.24 (q, 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

[0282] ##STR00399##

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

[0283] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.37N.sub.5O.sub.5S, 604.25; found, 604.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=4.9 Hz, 1H), 6.60 (d, J=3.7 Hz, 1H), 6.14 (s, 2H), 4.63 (s, 1H), 3.95 (q, 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) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin-7-yl) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate

[0284] ##STR00400##

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

[0285] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), N-Boc-L-phenylglycine (196 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.40N.sub.6O.sub.6S, 601.27; found, 601.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.21 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39-7.25 (m, 6H), 6.94 (q, 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

[0286] ##STR00401##

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

[0287] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.34Cl.sub.2N.sub.6O.sub.4S, 645.17; found, 645.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.9, 7.2 Hz, 211).

Example 93

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

[0288] ##STR00402##

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

[0289] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.26H.sub.34N.sub.6O.sub.5S, 543.23; found, 543.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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 (q, 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

[0290] ##STR00403##

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

[0291] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.14 g, 36.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.44N.sub.6O.sub.5S, 637.31; found, 637.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0292] ##STR00404## ##STR00405##

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

[0293] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.33N.sub.7O.sub.3S, 560.69; found, 560.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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, 611).

Example 96

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

[0294] ##STR00406##

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

[0295] N-methyl-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonamide (oclacitinib, 150 mg, 0.44 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.28H.sub.39N.sub.5O.sub.3S, 526.28; found, 526.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-methylpiperidin-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

[0296] ##STR00407## ##STR00408##

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-benzo [e] [1, 2] thiazine-3-carboxamide 1, 1-dioxide

[0297] 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.sub.3, 79 mg, 0.3 mmol) were added to tetrahydrofuran (0.4 mL) and stirred under nitrogen. 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 minutes, 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 was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.32H.sub.33N.sub.9O.sub.5S, 656.23, found 656.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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=7.7 Hz, 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

[0298] ##STR00409## ##STR00410##

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

[0299] (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropane (Ruxolitinib, 50 mg, 0.163 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.34N.sub.6O.sub.4, 495.64; found, 495.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0300] ##STR00411## ##STR00412##

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

[0301] (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-dimethylamino pyridine (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) was 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.143 g, 50% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.32N.sub.6O.sub.3, 573.25; found, 573.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-biphenyl]-4-yl) propanoate

[0302] ##STR00413## ##STR00414##

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-biphenyl]-4-yl) propanoate

[0303] (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-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.15 g, 53.3% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.31FN.sub.6O.sub.2, 563.25; found, 563.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.1 Hz, 1H), 3.33-3.14 (m, 2H), 2.42 (h, 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

[0304] ##STR00415## ##STR00416##

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

[0305] (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-dimethylamino pyridine (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) was 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 was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.29Cl.sub.2N.sub.7O.sub.2, 614.18; found, 614.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (qd, J=17.2, 6.9 Hz, 2H), 2.43 (h, J=8.3 Hz, 1H), 1.82 (qt, 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

[0306] ##STR00417## ##STR00418##

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

[0307] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.133 g, 457.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.32N.sub.6O.sub.3, 561.25; found, 561.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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 (h, 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

[0308] ##STR00419## ##STR00420##

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

[0309] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.125 g, 44.3% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.36N.sub.6O.sub.3, 565.28; found, 565.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=7.0 Hz, 1H), 3.23 (qd, 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

[0310] ##STR00421## ##STR00422##

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

[0311] (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-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.176 g, 52.1% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.37H.sub.34C.sub.1N.sub.7O.sub.4, 676.24; found, 676.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0312] ##STR00423## ##STR00424##

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

[0313] (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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.152 g, 49.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.36H.sub.35N.sub.7O.sub.3, 614.28; found, 614.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (qd, J=17.2, 6.9 Hz, 2H), 2.42 (h, 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

[0314] ##STR00425## ##STR00426##

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

[0315] (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.147 g, 52.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.33N.sub.7O.sub.2, 560.27; found, 560.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (qd, J=17.2, 6.9 Hz, 2H), 2.43 (q, 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

[0316] ##STR00427## ##STR00428##

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

[0317] (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-dimethylamino pyridine (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 salt water solution.

[0318] The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.161 g, 55.6% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.30ClN.sub.7O.sub.2, 580.21; found, 580.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=8.4 Hz, 1H), 2.24 (s, 3H), 1.82 (dtd, J=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

[0319] ##STR00429## ##STR00430##

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

[0320] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.36N.sub.6O.sub.2, 525.29, found 525.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=10.7 Hz, 2H), 4.55 (td, J=9.7, 4.2 Hz, 1H), 3.76 (q, J=7.0 Hz, 1H), 3.30-3.15 (m, 2H), 2.43 (q, 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

[0321] ##STR00431## ##STR00432##

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

[0322] (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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 50.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.35H.sub.39N.sub.7O.sub.3, 606.31; found, 606.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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 (t, 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

[0323] ##STR00433## ##STR00434##

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

[0324] (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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.133 g, 52% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.29N.sub.7O.sub.3, 512.23; found, 512.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0325] ##STR00435## ##STR00436##

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

[0326] (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 saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.35N.sub.7O.sub.4, 570.28; found, 570.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0327] ##STR00437## ##STR00438##

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

[0328] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.191 g, 91% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.35N.sub.7O.sub.4S, 590.25, found 590.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (dh, J=13.5, 6.7 Hz, 1H), 1.48-1.38 (m, 6H), 0.85 (d, J=6.6 Hz, 611).

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-biphenyl]-4-yl) propanoate

[0329] ##STR00439## ##STR00440##

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-biphenyl]-4-yl) propanoate

[0330] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.072 g, 24.2% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.36FN.sub.5O.sub.4S, 594.25; found, 594.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0331] ##STR00441## ##STR00442##

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

[0332] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.118 g, 39.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.37N.sub.5O.sub.5S, 592.25; found, 592.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0333] ##STR00443## ##STR00444##

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

[0334] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.41N.sub.5O.sub.5S, 596.28; found, 596.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.15 (d, J=1.9 Hz, 1H), 7.25 (d, J=3.7 Hz, 1H), 7.07 (qd, J=8.3, 2.9 Hz, 4H), 6.89 (q, 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 (q, 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

[0335] ##STR00445## ##STR00446##

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

[0336] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.136 g, 38.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.35H.sub.39C.sub.1N.sub.6O.sub.6S, 707.23; found, 707.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0337] ##STR00447## ##STR00448##

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

[0338] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (20 mg, 0.058 mmol), 4-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.156 g, 48.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.40N.sub.6O.sub.5S, 645.28; found, 645.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.17 (s, 1H), 7.86-7.75 (m, 3H), 7.68 (dd, J=6.3, 1.2 Hz, 2H), 7.55 (ddd, J=8.1, 6.3, 2.0 Hz, 1H), 7.34-7.24 (m, 3H), 6.88 (q, 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

[0339] ##STR00449## ##STR00450##

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

[0340] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.096 g, 32.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.38N.sub.6O.sub.4S, 591.27; found, 591.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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, 3H), 2.06 (d, J=14.3 Hz, 5H), 1.92-1.79 (m, 1H), 1.70 (h, 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

[0341] ##STR00451## ##STR00452##

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

[0342] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (201 mg, 0.5 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.41N.sub.5O.sub.4S, 556.29, found 556.2.sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0343] ##STR00453## ##STR00454##

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

[0344] 1-((Trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (200 mg, 0.58 mmol), 4-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 yellow solid, 0.137 g, 44.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.35ClN.sub.6O.sub.4S, 611.21; found, 611.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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 (q, 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] pyrimidin-7-yl) methoxy)-2-methyl-N-(pyridin-2-yl)-2H-benzo [e] [1, 2] thiazine-3-carboxamide 1, 1-dioxide

[0345] ##STR00455## ##STR00456##

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-benzo [e] [1, 2] thiazine-3-carboxamide 1, 1-dioxide

[0346] 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.sub.3, 164 mg, 0.624 mmol) were added to tetrahydrofuran (3 mL) under nitrogen. 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 minutes, 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 the stirring was continued. The reaction was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.32H.sub.30N.sub.10O.sub.6S.sub.2, 715.18, found 715.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0347] ##STR00457## ##STR00458##

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

[0348] 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 (PPh.sub.3, 137 mg, 0.52 mmol) were added to tetrahydrofuran (2.8 mL) under nitrogen. Diisopropyl azodicarboxylate (DIAD, 92 mg, 0.45 mmol) was added dropwise to the mixture with stirring. After stirring at ?10? C. for 20 minutes, 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 the stirring was continued. The reaction was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.31H.sub.30N.sub.10O.sub.6S.sub.3, 735.15, found 735.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0349] ##STR00459## ##STR00460##

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

[0350] (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, 338 mg, 1 mmol), 4-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.35F.sub.3N.sub.6O.sub.2, 569.28; found, 569.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, J=6.9 Hz, 1H), 4.34 (q, 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

[0351] ##STR00461## ##STR00462##

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

[0352] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.097 g, 34.1% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.35F.sub.3N.sub.6O.sub.2, 569.28; found, 569.3. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (qd, 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-biphenyl]-4-yl) propanoyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]pyrazin-8-yl)-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

[0353] ##STR00463## ##STR00464##

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

[0354] (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-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(2-fluoro-4-biphenyl) 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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.03 g, 9.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.30F.sub.4N.sub.6O.sub.2, 607.24; found, 607.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0355] ##STR00465## ##STR00466##

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

[0356] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.13 g, 84.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.31F.sub.3N.sub.6O.sub.3, 617.24; found, 617.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0357] ##STR00467## ##STR00468##

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

[0358] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.28Cl.sub.2F.sub.3N.sub.7O.sub.2, 658.16; found, 658.1. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0359] ##STR00469##

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

[0360] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.31F.sub.3N.sub.6O.sub.3, 605.24; found, 605.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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, 311).

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

[0361] ##STR00470##

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

[0362] (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-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 64 mg, 0.264 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.012 g, 85.5% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.32F.sub.3N.sub.7O.sub.2, 604.264; found, 604.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0363] ##STR00471##

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

[0364] (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-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 68 mg, 0.264 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.31H.sub.29CF.sub.3N.sub.7O.sub.2, 624.20; found, 624.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.61 (s, 1H), 8.25 (s, 1H), 7.67-7.58 (m, 1H), 7.56-7.44 (m, 2H), 7.36 (d, J=4.2 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-) methoxynaphthalen-2-yl) propanoyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]pyrazin-8-yl)-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

[0365] ##STR00472##

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

[0366] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.028 g, 18.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.31H.sub.31F.sub.3N.sub.6O.sub.3, 593.24; found, 593.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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

[0367] ##STR00473##

Synthesis of (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

[0368] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.32H.sub.35F.sub.3N.sub.6O.sub.3, 609.27, found 609.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (ddq, 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

[0369] ##STR00474##

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

[0370] (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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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 light yellow solid, 0.139 g, 77.3% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.36H.sub.33C.sub.1F.sub.3N.sub.7O.sub.4, 720.22, found 720.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0371] ##STR00475##

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

[0372] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.27H.sub.28F.sub.3N.sub.7O.sub.3, 556.22, found 556.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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 (q, 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-imidazo [1, 2-a]pyrrolo [2, 3-e] pyrazin-8-yl)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

[0373] ##STR00476## ##STR00477##

Synthesis of (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) pyrrolidine-1-carboxamide

[0374] (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-dimethylamino pyridine (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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.34H.sub.38F.sub.3N.sub.7O.sub.3, 650.30, found 650.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.55 (d, J=10.5 Hz, 1H), 8.79 (s, 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 (q, 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 (q, J=7.1 Hz, 3H), 0.64 (td, 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

[0375] ##STR00478## ##STR00479##

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

[0376] (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-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-acetoxy benzoic acid (aspirin, 47.5 mg, 0.264 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Upadacitinib, 73 mg, 0.377 mmol) was 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.025 g, 18.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.26H.sub.25F.sub.3N.sub.6O.sub.4, 543.19, found 543.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0377] ##STR00480##

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

[0378] (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-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), N-Boc-L-phenylglycine (66 mg, 0.264 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.34F.sub.3N.sub.7O.sub.4, 614.26, found 614.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0379] ##STR00481##

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

[0380] (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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.145 g, 88.2% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.35H.sub.34F.sub.3N.sub.7O.sub.3, 658.27, found 658.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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

[0381] ##STR00482##

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

[0382] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.29H.sub.34N.sub.6O.sub.2, 499.27, found 499.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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), 4.20-4.06 (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

[0383] ##STR00483##

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

[0384] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.071 g, 59.4% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.34N.sub.6O.sub.2, 499.27, found 499.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 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-methoxynaphthalen-2-yl) propanoyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-3-methyl-1, 6-diazaspiro [3.4] octan-1-yl)-3-oxopropanenitrile

[0385] ##STR00484##

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

[0386] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.30N.sub.6O.sub.3, 523.24, found 523.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.38 (s, 1H), 7.76 (d, J=1.7 Hz, 1H), 7.67-7.56 (m, 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 (q, 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] pyrimidin-7-yl) methoxy)-2-methyl-N-(5-methylthiazol-2-yl)-2H-benzo [e] [1, 2] thiazine-3-carboxamide 1, 1-dioxide

[0387] ##STR00485##

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

[0388] 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 (PPh.sub.3, 190 mg, 0.73 mmol) were added to tetrahydrofuran (3.4 mL) under nitrogen. 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 the stirring continued. The reaction was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.31H.sub.33N.sub.9O.sub.5S.sub.2, 676.20, found 676.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0389] ##STR00486##

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

[0390] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.018 g, 12.7% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.34H.sub.33N.sub.7O.sub.3, 588.26, found 588.0. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (t, 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, 311).

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

[0391] ##STR00487## ##STR00488##

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

[0392] 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-diisopropylethyl amine (0.17 mL, 0.966 mmoL) were added in dichloromethane (2 mL). After stirring at room temperature for half an hour, (2-(chloromethoxy) ethyl) trimethylsilane (140 mg, 0.838 mmol) was added in an 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 salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.22H.sub.32N.sub.6O.sub.2Si, 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

[0393] 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 in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 2 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0? C. to adjust the pH to 8. Then the mixture was poured into a separating funnel for separation. The organic layer was washed with a saturated salt water solution and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.17H.sub.20N.sub.6O.sub.2, 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

[0394] 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-dimethylamino pyridine (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 stirring was continued for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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].sup.+ calcd for C.sub.30H.sub.36N.sub.6O.sub.3, 529.28, found 529.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (h, 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

[0395] ##STR00489## ##STR00490##

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

[0396] 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-dimethylamino pyridine (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 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain 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, 0.038 g, 29% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.30N.sub.6O.sub.3, 547.24, found 547.1. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (q, 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 (dq, 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] pyrimidin-7-yl) methoxy)-2-methyl-N-(pyridin-2-yl)-2H-thieno [3, 2-e] [1, 2] thiazine-3-carboxamide 1, 1-dioxide

[0397] ##STR00491## ##STR00492##

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

[0398] 4-Hydroxy-2-methyl-N-(pyridin-2-yl)-2H-thieno [3, 2-e] [1, 2] thiazine-3-carboxamide 1, 1-dioxide (tenoxicam, 98 mg, 0.292 mmol) and triphenylphosphine (PPh.sub.3, 230 mg, 0.876 mmol) were added to tetrahydrofuran (2 mL) under nitrogen. Diisopropyl azodicarboxylate (DIAD, 88 mg, 0.438 mmol) was added dropwise to the mixture with stirring. After stirring at ?10? C. for 20 minutes, 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 was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.30H.sub.31N.sub.9O.sub.5S.sub.2, 662.19, found 662.2. .sup.1H NMR (400 MHz, DMSO-d6) ? 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

[0399] ##STR00493## ##STR00494##

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

[0400] 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 (PPh.sub.3, 214 mg, 0.817 mmol) were added to tetrahydrofuran (3 mL) under nitrogen. 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 minutes, 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-methylmethane sulfonamide (150 mg, 0.409 mmol) was added and the stirring was continued. The reaction was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.31H.sub.36N.sub.8O.sub.6S.sub.2, 681.22, found 681.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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, 211).

Example 148

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-carboxamide 1, 1-dioxide

[0401] ##STR00495## ##STR00496##

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-carboxamide 1, 1-dioxide

[0402] 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 (PPh.sub.3, 196 mg, 0.748 mmol) were added to tetrahydrofuran (2 mL) under nitrogen. 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 minutes, 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 the stirring was continued. The reaction was monitored by TLC. After complete exhaust 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, 0.008 g, 4.9% yield. MS (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.28N.sub.10O.sub.6S.sub.3, 721.14, found 721.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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

[0403] ##STR00497## ##STR00498##

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

[0404] 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 (PPh.sub.3, 196 mg, 0.748 mmol) were added to tetrahydrofuran (2 mL) under nitrogen. 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 minutes, 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-methylmethane sulfonamide (100 mg, 0.272 mmol) was added and the stirring was continued. The reaction was monitored by TLC. After complete exhaust 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].sup.+ calcd for C.sub.29H.sub.34N.sub.8O.sub.6S.sub.3, 687.18, found 687.2. .sup.1H NMR (400 MHz, Chloroform-d) ? 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 (q, J=6.2 Hz, 1H), 1.92-1.59 (m, 4H), 1.43-1.33 (m, 2H).

[0405] Analysis Method for Hydrolysis Rate of Compounds of the Present Invention

[0406] 1. Preparation of Standard Working Curve Solution

[0407] About 10 mg of JAK inhibitors (tofacitinib and baricitinib) reference substances were weighed into a 25 mL volumetric flask, acetonitrile/water=7/3 (v/v) was added to dissolve and dilute to the marked volume, serving as a stock solution. The stock solution was diluted with a suitable 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.

[0408] About 10 mg of JAK inhibitors (Oclacitinib, Ruxolitinib, Delgocitinib, and Upadacitinib) reference substances were weighed into a 25 mL volumetric flask, acetonitrile/water=7/3 (v/v) was added to dissolve and dilute to the marked volume, serving as a stock solution. The stock solution was diluted with a suitable 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.

[0409] 2. Preparation of Sample Solution

[0410] About 5 mg of the sample (the compound prepared in the present invention) was weighed into a 20 mL volumetric flask, acetonitrile/water=7/3 (v/v) was added to dissolve and dilute to the marked volume, serving as a stock solution. An appropriate amount of HPLC was loaded as the 0-day sample. The test solution was sealed with a sealing film and placed in a 37? C. constant temperature shaker. The test samples were taken at the same time on days 1, 2, 3, and 4 respectively. the release amount of JAK inhibitor in the sample was calculated according to the sample weight and JAK inhibitor standard curve.

[0411] 3. Calculation Formula [0412] % Release of JAK Inhibitor [0413] wherein

TABLE-US-00002 A.sub.JAK inhibitor is the peak area of JAK a is the slope of the standard inhibitor in the sample chromatogram curve b is the intercept of the standard curve W is the sample weight (mg) M1 is the molecular weight of the M2 is the molecular weight of sample the JAK inhibitor

[0414] 4. Chromatographic Conditions

[0415] The chromatographic conditions of the test are shown in Table 2.

TABLE-US-00003 TABLE 2 Chromatographic conditions Chromatographic WatersXbridge Shield RP18, 150 ? 4.6 mm, 3.5 ?m column Flow rate (LPM) 0.8 mL/min Column temperature 30? C. Detection 220 nm Loading volume 5 ?L wavelength Mobile phase 10 mM KH.sub.2PO.sub.4(Adjust pH6.5 with KOH)/ACN = 9/1(v/v); B: ACN Time 0 10 16 17 22 Elution gradient A % 85 20 20 85 85 B % 15 80 80 15 15

[0416] Table 3 Shows the Drug Release Rate Results of the Compound Drugs Prepared in the Above Examples of the Present Disclosure.

TABLE-US-00004 TABLE 3 Drug Release Rate Table Ex. No. Release Rate (%/day) Ex. 1 8.26 Ex. 2 8.5 Ex. 3 0.05 Ex. 4 3.32 Ex. 5 4.7 Ex. 6 9.82 Ex. 7 15.65 Ex. 8 14.77 Ex. 9 13.49 Ex. 10 11.25 Ex. 11 9.17 Ex. 12 18.94 Ex. 13 12.18 Ex. 14 0.98 Ex. 15 1.86 Ex. 16 39.31 Ex. 17 2.44 Ex. 18 2.97 Ex. 19 6.25 Ex. 20 5.06 Ex. 21 4.6 Ex. 22 2.75 Ex. 23 7.63 Ex. 24 5.96 Ex. 25 0.68 Ex. 26 36.19 Ex. 27 7.48 Ex. 28 2.98 Ex. 29 7.08 Ex. 30 1.63 Ex. 31 3.08 Ex. 32 7.12 Ex. 33 5.01 Ex. 34 1.57 Ex. 35 4.57 Ex. 36 14.98 Ex. 37 1.05 Ex. 38 18.42 Ex. 39 10.11 Ex. 40 0.62 Ex. 41 4.27 Ex. 42 22.18 Ex. 43 2.99 Ex. 44 10.18 Ex. 45 1.93 Ex. 46 25.52 Ex. 47 0.36 Ex. 48 0.03 Ex. 49 0.11 Ex. 50 0.05 Ex. 51 0.35 Ex. 52 0.1 Ex. 53 0.06 Ex. 54 4.93 Ex. 55 0.16 Ex. 56 0.07 Ex. 57 0.57 Ex. 58 12.46 Ex. 59 0.15 Ex. 60 <0.01 Ex. 61 <0.01 Ex. 62 0.01 Ex. 63 0.02 Ex. 64 0.88 Ex. 65 0.01 Ex. 66 0.06 Ex. 67 0.02 Ex. 68 10.6 Ex. 69 0.03 Ex. 70 0.42 Ex. 71 0.01 Ex. 72 <0.01 Ex. 73 0.2 Ex. 74 0.44 Ex. 75 10.38 Ex. 76 0.05 Ex. 77 3.69 Ex. 78 6.27 Ex. 79 7.38 Ex. 80 27.29 Ex. 81 0.013 Ex. 82 0.43 Ex. 83 0.003 Ex. 84 0.06 Ex. 85 0.61 Ex. 86 <0.01 Ex. 87 0.01 Ex. 88 0.17 Ex. 89 0.16 Ex. 90 0.35 Ex. 91 1.65 Ex. 92 0.82 Ex. 93 0.83 Ex. 94 0.72 Ex. 99 0.21 Ex. 100 0.24 Ex. 104 0.45 Ex. 105 0.17 Ex. 107 0.22 Ex. 110 0.08 Ex. 113 0.42 Ex. 116 0.42 Ex. 117 0.08 Ex. 120 0.42 Ex. 122 15.32 Ex. 123 3.02 Ex. 124 2.75 Ex. 125 6.17 Ex. 126 7.80 Ex. 130 11.67 Ex. 131 3.56 Ex. 133 10.13 Ex. 138 2.15 Ex. 140 8.10 Ex. 142 0.05 Ex. 143 4.29 Ex. 144 0.05

[0417] As can be seen from the results in Table 3 above, the coupling of an anti-inflammatory drug compound containing a carboxylic acid or hydroxyl group with a JAK inhibitor compound to form a coupling compound having an acyloxy group and or methoxy group according to the present invention has a high therapeutic effect and a special effect of controlled-release drug activity.

[0418] Pharmacodynamic Evaluation Studies of Compounds of the Invention

[0419] Efficacy Evaluation Study of Ointment Transdermal Patch Formulated by Compounds Using IMQ-Induced Psoriasis Mouse Model

[0420] Experimental Design

[0421] BALB/c mice (male) aged 6-8 weeks were selected to have depilated back skin with an area of 2?3 cm. 5% IMQ cream 62.5 mg was applied once a day for 9 consecutive days for model induction. Mice were housed in an SPF-grade animal room in IVC cages at a temperature of 20-26? C. and a humidity of 40-70% under a 12-hour light-dark cycle. Diet ad libitum, except where fasting is required.

[0422] Mice were randomly divided into groups, a number of 8 mice, administration concentration 20 mg/g, administration amount 50 mg, administration route, and frequency: skin smear, BID. The positive control was compound dexamethasone acetate (Dex) cream which is a commercially available product with a Dex content of 0.75 mg/g (999 Piyanping, Sanjiu Pharmaceutical). Dosing started from day 1 (the first day) (the day of model induction) to day 9.

[0423] 2. Preparation of Test Ointment

[0424] Topical preparations are mostly semi-solid dosage forms. The base and solvent of a semi-solid dosage form are generally widely used in medicine and daily chemical products. The excipients which can be added are also the common excipients in the manual of excipients. Therefore, the patent compounds are prepared into corresponding test ointments. The ointment compound was dissolved with diisopropyl adipate to prepare a vaseline-based ointment. In order to improve the stability of the ointment, microcrystalline cellulose was added as an excipient in the formulation. The white vaseline has a melting point of 45-60? C. The solution, white vaseline, and microcrystalline cellulose are thoroughly mixed while the vaseline is in a molten state. After cooling to solidification, it was divided into an aluminum ointment, and the specific weight ratios of base, solvent, and excipients are shown in Table 4.

TABLE-US-00005 TABLE 4 Composition of ointment formulations for efficacy experiments Cmpd No. CPD-002 CPD-017 CPD-027 CPD-028 CPD-029 Compound 2 2 2 2 2 percentage Solvent 15 15 15 15 15 percentage Matrix 80 80 80 80 80 percentage Excipient 3 3 3 3 3 Percentage Total (w/w) 100 100 100 100 100

[0425] 3. Model Evaluation

[0426] Dorsal modeling site skin PASI was performed on the experimental animals. The scoring criteria are shown in Table 5 below:

TABLE-US-00006 TABLE 5 Scoring criteria Score Erythema Dandruff Skin thickening 0 Normal Normal Normal 1 Mild Mild: small amount of shavings Mild 2 Moderate Moderate: a large amount of Moderate scurf 3 Severe Severe: skin scab Severe 4 Extremely Extremely severe: heavy scab Extremely severe severe

[0427] Statistical analysis of PASI scores was performed using Two-way ANOVA. All data were analyzed using GraphPad Prism 8.0 software with a p<0.05 significant difference (*, p<0.05; **, p<0.01).

[0428] 4. Efficacy

[0429] PASI Score Curve

[0430] 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 daily to induce psoriasis, and the excipient group was treated with 15% (w/w) diisopropyl adipate, 80% vaseline, and 3% microcrystalline cellulose.

[0431] As can be seen from FIGS. 1-5, the Dex cream group (0.75 mg/g) had a significant therapeutic effect on day 4-day 10 (days 4-10) compared with the excipient group; CPD-017, CPD-027, CPD-028, and CPD-029 had a significant therapeutic effect in day 5-day 10 (days 5-10); CPD-002 had a significant therapeutic effect in day 4 day 8 (days 4-8).