Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine

QUIRAL SALT RESOLUTION

Field of the Invention

The present invention relates to methods for effecting the resolution of a chiral salt from racemic mixtures of enantiomers, and particularly precursor enantiomers used in the preparation of pyrrolo [2,3-d] pyrimidine compounds, which are protein inhibitors kinases The present invention also relates to pyrrolo [2,3-d] pyrimidine compounds and to methods for using such compounds as protein kinase inhibitors, such as the enzyme Janus kinase 3.

Background of the invention

Pyrrolo [2,3-d] pyrimidine compounds are protein kinase inhibitors such as the enzyme Janus kinase 3 (JAK3), and are therefore a useful therapy as immunosuppressive agents for organ transplantation, xenotransplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriaris, type I diabetes and diabetes complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications in which immunosuppression would be desirable. Compounds of pyrrolo [2,3-d] pyrimidine, pharmaceutical compositions thereof and methods of use are described in the pending patent application together with the present serial number 09/732669, filed on December 8, 2000, and assigned to the assignee of the present invention. The description of the aforementioned application is included in its entirety by reference. Initially racemic mixtures of the pyrrolo [2,3d] pyrimidine compounds are obtained, although the individual enantiomers isolated in substantially pure form are preferred, and are sometimes required, for use in drugs. It is possible to preorder the stereochemistry of the compounds through the use of stereospecific precursor compounds in their synthesis. The processes of the present invention accordingly, refer specifically to a process for the substantial resolution of a chiral salt of racemic mixtures of precursor compounds, used in the production of separate enantiomeric forms of the pyrrolo compounds [2,3- d] pyrimidine.

Summary of the invention

The present invention relates to methods for solving the enantiomers of the precursors used in the preparation of a compound of the following formula, and particularly of the group R¹ Of the same:

<img file="CU23337B7_D0001.tif" />

or the pharmaceutically acceptable salt thereof; being R¹ a group of formula

R⁵

R \ / (CHJ N ^and in which y is 0, 1 or 2;

R⁴ is selected from the group consisting of hydrogen, (C, -C6) alkyl, (Ci-C6) alkyl sulfonyl, (C2-C6) alkenyl, (C2-C6) alkynyl, the alkyl, alkenyl and alkynyl groups being optionally substituted with deuterium , hydroxyl, amino, trifluoromethio, alkoxy (Cj-Q), acyl (CjC6) oxy, alkyl (C ^ -Cé) amino, ((C ^ -CJ) alkyl 2amino, cyano, nitro, alkenyl (C2-C6), (C2-C6) alkynyl or acyl (C] -C6) amino; or R⁴ it is cycloalkyl (C3-C₁₀), the cycloalkyl group being optionally substituted with deuterium, hydroxyl, amino, trifluoromethio, acyl (Cj-Cjoxy, acyl (C ^ Cg) amino, alkyl (Cj-C₆) amino, (Cj-C alkyl₆) ) ₂amino, cyano, cyanoalkyl (C_tC₆), trifluoromethyl-alkyl (Cj-Q), nitro, nitroalkyl (CjC₆) or acyl (Cj-C₆) Not me;

R⁵ it is heterocycloalkyl (Cj-Cp), the heterocycloalkyl groups must be substituted with one to five carboxyl, cyano, amino, deuterium, hydroxyl, alkyl (Cj-C₆), alkoxy (Cj-C₆), halo-, acyl (C ^ -CJ, alkyl (Cj-C₆) amino, aminoalkyl (Cj-Cg), alkoxy (C, -C₆) -CO-NH, alkyl (Cj-C₆) aminoCO-, alkenyl (C₂-C₆), alkynyl (C₂-C₆), hydroxyalkyl (CjC₆), (Cj-Cg) alkoxy (C ^ Cg) alkyl, acyl (C, -C₆) oxyalkyl (CjC₆), nitro, cyanoalkyl (Cj-Cg), haloalkyl (Cj-Cg), nitroalkyl (C ^ Cg), trifluoromethyl, trifluoromethyl-alkyl (C, -Cg), acyl (C ^ Cg) amino, acyl (Cj-C₆) aminoalkyl (Cj-Cg), alkoxy (C ^ Cjacil (C ^ Cg) amino, aminoacyl (C [-C₆), aminoacyl (Cj-Cg) alkyl (Cj-Cg), alkyl (Cj-Cg) aminoacyl (C ^ Cg), (((Cj-Cg) alkyl)₂aminoacyl (Ο, -Ο₆), R¹⁵R¹⁶N-CO-O-, R¹⁵R¹⁶N-CO (C, -C6) alkyl, (C ^ Cg) -S (O) m, R alkyl¹⁵R¹⁶NS (O) m, R¹⁵R¹⁶NS (O) Malkyl (C ^ Cg), R¹⁵S (O) mR¹⁶N, R¹⁵S (O) mR¹⁶N-alkyl (CjC6), with m 0, 1 or 2, and each R being independently selected¹⁵ and R¹⁶ hydrogen or alkyl (CjC₆); or a group of formula II

<img file="CU23337B7_D0002.tif" />

II in which aesO, 1, 2, 3 or 4:

b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2 or 3;

X is S (O) _n, being η 0, 1 or 2; oxygen, carbonyl or

-C (= N-cyano) -;

Y is S (O)_n, being η 0, 1 or 2; or carbonyl; and

Z is carbonyl, C (0) 0-, C (O) NR- or S (O) „, being η 0, 1 or 2;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ each is independently selected from the group consisting of hydrogen or alkyl (Cj-C₆) optionally substituted with deuterium, hydroxyl, amino, trifluoromethyl, acyl (Cj-Cgioxi, acyl (CjC₆) amino, alkyl amino, ((C ^ -Cg) alkyl) ₂amino, cyano, cyanoalkyl (Cj-C₆), trifluoromethylalkyl (Cj-C₆), nitro, nitroalkyl (C, -C₆) or acyl (Cj-CJ amino;

R¹² it is carboxyl, cyano, amino, oxo, deuterium, hydroxyl, trifluoromethyl, alkyl (Cj-C6), trif luoromethylalkyl (C2C6), alkoxy (Cj-C6), halo, acyl (Cj-Cg), alkyl (Cj-C6) amino, ((C) -C6 alkyl) 2amino, (Cj-C6) aminoalkyl, (C [-C6) -CONH-, alkoxy (Ci-Cg) amino-CO-, (C2-C6) alkenyl, alkynyl (C2C6), alkyl (Cj-Cg) amino, hydroxyalkyl (Cj-Cg), alkoxy (^ C6) alkyl (C, -C6), acyl (Cj-Cg) oxyalkyl (C ^ Cg), nitro, cyanoalkyl (C ^ Cg), haloalkyl (Cj-Cg), nitroalkyl (C ^ Cg), trifluoromethyl, trif luoromethylalkyl (Cj-C6), acyl (CjC6) amino, acyl (Ct-C6) aminoalkyl (C ^ Cg), alkoxy (C, -C6) acyl (Cj-Cg) amino , aminoacyl (Cj-C6), aminoacyl (Cj-Cg) alkyl (^ C6), alkyl (Cj-Cg) aminoacyl (C ^ Cg), (alkyl (CjC6)) 2-aminoacyl (Cj-Cg), R¹⁵R¹⁶N-CO-O-, R¹⁵R¹⁶N-CO-alkyl (C ^ Cg), R¹⁵C (O) NH, R¹⁵OC (O) NH, R¹⁵NHC (O) NH, alkyl (C ^ Cg) -S (O) m, alkyl (Cj-Cg) -S (O)_m-alkyl (Cj-Cg), R¹⁵R¹⁶NS (O) m, R¹⁵R¹⁶NS (O) m-alkyl (Cj-CJ, R¹⁵S (O) mR¹⁶N, R¹⁵S (O) mR¹⁶N-alkyl (Cj-Cg), with m 0, 1 or 2, and R being selected¹⁵ and R¹⁶ each independently of hydrogen or alkyl (C_x-C₆) ;

R² and R³ each is independently selected from the group consisting of hydrogen, deuterium, amino, halo-, hydroxyl, nitro, carboxyl, alkenyl (C2-C6), alkynyl (C2-C6), trifluoromethyl, trifluoromethoxy, (C] -C6) alkyl, (CtC5) alkoxy, (C3-C10) cycloalkyl, the alkyl, alkoxy or cycloalkyl groups being optionally substituted with one to three groups selected from halo-, hydroxyl, carboxyl, aminoalkyl (Cj-Cg) thio, alkyl (C ^ Cg) amino, ((CjC6) alkyl) 2amino, (C5-C9) heteroaryl, heterocycloalkyl (C2-C9), cycloalkyl (C3-C9) or aryl (C6-C10); or R² and R³ are each independently cycloalkyl (C3-C₁₀), cycloalkoxy (C₃-C₁₀), alkyl (Cj-C₆) amino, (C (alkyl)_t-C₆) ) ₂amino, ari i (C₆ C₁₀) amino, alkyl (Cj-Cgjtio, aryl (C₆-C₁₀) thio, alkyl (Cj-Cg) sulfyl, aryl (C₆-C₁₀) sulf inyl, alkyl (Cj-Cg) sulfonyl, aryl (C₆C₁₀) sulfonyl, acyl (Cj-C₆), alkoxy (C ^ Cg) -CO-NH-, alkyl (CjC₆) amino-CO-, heteroaryl (C₅-C₉), heterocycloalkyl (C₂-C₉) or aryl (c₆-c₁₀), the heteroaryl, heterocycloalkyl and aryl groups being optionally substituted with one to three halo-, (C) alkyl_rC₆), alkyl (C_rC₆) -CO-NH-, alkoxy (C_t-C₆) -CO-NH-, alkyl (Cj-Cg) -CO-NH-alkyl (Cj-Cg), alkoxy (C ^ Cg) -CO-NHalkyl (Cj-C₆), alkoxy (Cj-Cg) -CO-NH-alkoxy (Cj-Cg), carboxyl, carboxyalkyl (Cj-Cg), carboxyalkoxy (Cj-Cg), benzyloxycarbonylalkoxy (C_t-C₆), alkoxy (Q-Cg) carbonylalkoxy (Ci-C₆), aryl (C₆-C,₀), amino, aminoalkyl (C ^ Cg), alkoxy (C_rC₆) carbonylamino, aryl (C₆-C₁₀) alkoxy (Q-Cg) carbonylamino, alkyl (C, -C₆) amino, ((C ^ -Cg) alkyl)₂amino, alkyl (C, C₆) aminoalkyl (C_t-C₆), (alkyl (C ^ Cg))₂aminoalkyl (Cj-Cg), hydroxyl, alkoxy (Cj-C₆), carboxyl, carboxyalkyl (Cj-Cg), alkoxy (C, -C₆) carbonyl, (C ^ -Cg) alkoxycarbonylalkyl (Cj-Cg), (C ^ -Cg) alkoxy -CO-NH-, (C, -C alkyl)₆) -CO-NH-, cyano, heterocycloalkyl (C₅-C₉), amino-CO-NH-, alkyl (C ^ CJ aminoCO-NH-, (alkyl (Cj-C₆) ) ₂amino-CO-NH-, aryl (C₆-C₁₀) amino-CO-NH, heteroaryl (C₅-C₉) amino-CO-NH-, alkyl (Cj-Cj amino-CO-NHalkyl (Cj-C₆), (alkyl (C ^ Cg)) ₂amino-CO-NH-alkyl (C ^ Cg), aryl (C₆-C₁₀) amino-CO-NH-alkyl (C, -C₆), heteroaryl (C₅C₉) amino-CO-NH-alkyl (0, -0₆), alkyl (Q-Cg) sulfonyl, alkyl (Cj-Cg) sulfonylamino, alkyl (Cj-C₆) sulfonylaminoalkyl (C_tC₆), aril (C₆-C₁₀) sulfonyl, aryl (C₆-C₁₀) sulf onylamino, aryl (C₆-C₁₀) sulf onylaminoalkyl (C, -C₆), alkyl (Cj-Cg) sulfonylamino, alkyl (C ^ Cg) sulf onylaminoalkyl (Cj-C₆), heteroaryl (C₅-C₉) or heterocycloalkyl (C₂-C₉) .

The present invention also relates to the production of pharmaceutically acceptable acid-addition stereospecific salts of the compounds of formula I. The acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention are those that form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions, such as hydrochloride salts. , hydrobromide, iodhydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate).

The invention also relates to stereospecific salts of base addition formula I. The chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with said compounds. These non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (for example potassium and sodium) and alkaline earth metal cations (for example calcium and magnesium), ammonium or addition salts of water-soluble amine such as N-methylglucamine (meglumine), and lower alkanolammoniums and other pharmaceutically acceptable organic amine base salts.

The term "alkyl", as used herein, unless otherwise indicated, includes monovalent saturated hydrocarbon radicals with linear or branched moieties or combinations thereof.

The term "alkoxy", as used herein, includes 0-alkyl groups in which alkyl has been defined above.

The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. The compounds of this invention may contain double bonds. When said links are present, the compounds of the invention exist in cis and trans configurations, and as mixtures thereof. Unless otherwise indicated, the alkyl and alkenyl groups designated herein, as well as the alkyl moieties of other groups designated herein (for example alkoxy), may be linear or branched, and may also be cyclic ( for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine and iodine.

Heterocycloalkyl (C₂-C₉), when used herein, designates pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxyranyl, chromenyl, methylenedioxy, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidinyl, 1,3-thiazolidinyl, 1,3-thiazolidinyl -yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1, 2 - tetrahydrodiazin-2 - i lo, 1,3-tetrahydrodiazin-l-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. A person skilled in the art will understand that the connection of said heterocycloalkyl rings (C₂-C₉) is through a carbon or a nitrogen heteroatom hybridized in sp³.

Heteroaryl (C₂-C₉), when used herein, designates furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4oxadiazolyl, 1,2 , 3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl ,

1,3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [1] pyridinyl, benzo [b] thiophenyl, 5,6,7,8 -tetrahidroquinolin-3 -yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; A person skilled in the art will understand that the connection of said heterocycloalkyl rings (C₂-C₉) is through a carbon atom or a nitrogen heteroatom hybridized in sp³.

Arilo (C₆-C_the), when used herein, designates phenyl or naphthyl.

The compounds used in this invention include all conformational isomers (for example cis and back isomers). The compounds used in the present invention have asymmetric centers and are therefore chiral and exist in different enantiomeric and diastereoisomeric forms. This invention relates to the resolution of optical isomers and stereoisomers of the constituent precursors, and therefore of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and treatment methods that may employ or contain them. . In this regard, the invention includes both configurations E and Z. The compounds of formula I may also exist as tautomers. This invention relates to said tautomers and mixtures thereof. In particular, the resolution of racemic mixtures of enantiomers of compounds, used to provide the R substituent¹ of formula I, is effected by treating the racemic mixture with a specific optical isomer of a tartaric acid or tartrate disubstituted in an appropriate solvent such as ethanol with or without water as an additional solvent. The resolution in obtaining the desired enantiomer in excess of 90% is possible according to the process of the present invention using resolution agents such as optical isomers of tartaric acid and derivatives of tartaric acid such as di-ptoluoyl-L-tartaric acid and the salt of (S) - (+) -andene (phenyl, 2-oxide of (S) - (+) -2-hydroxy-5,5-dimethyl-4-phenyl 1,3,3-dioxyphosforinanne ).

The interaction between the opposites of the resolution material and the specific enantiomer provides a resolution of the racemic mixture in which a precipitate of the resolution material and an enantiomer provides one of the desired stereospecific materials, and in which the enantiomer can thus be isolated separately. remaining in solution. Thus, depending on the specific enantiomer desired and the separation process to be used (i.e., the precipitate or the solution), the specific stereo nature of the resolving agent can be selected concomitantly, for example an L form of the resolving agent such as a tartrate derivative provides a precipitate of a form R of the substituent R¹ and A solution containing the form L, and vice versa.

The above-mentioned resolution agents are effective in providing a 3R, 4R enantiomer of formula

III (in precipitate or in solution, as described):

<img file="CU23337B7_D0003.tif" />

According to the present invention, the resolution process of the compound of formula III is carried out by the steps of:

a) mixing a racemic mixture of the compound of formula III in an appropriate solution with a resolution compound with a defined stereospecificity, for a time sufficient to allow substantial precipitation of a stereospecific isomer of the racemic mixture of the solution;

b) depending on the stereospecific form of the desired compound, collect the precipitate and purify it or collect the mother liquors and recrystallize the enantiomer contained therein.

With some materials a suspension is formed instead of a solution, the resolution of the present invention involving a conversion from suspension to suspension. The term "solution" comprises both a solution and a suspension.

The temperature at which the resolution and precipitation is effected is preferably room temperature, and although the precipitation time is not limited, the efficiency is preferably not more than about four hours. To facilitate resolution it is desirable to use enantiomers in the racemic mixture that are in a stable form, and the compound of formula II is more stable in the form of acid addition salt such as hydrochloride salt, rather than the free base form, and it is preferred that the racemic compound mixture be converted accordingly before resolution. Thus, for example, the formation of the hydrochloride salt of the compound of formula II is preferably carried out in ethanol with a small amount of toluene as an additional solvent. Alternatively, methanol, isopropanol, acetonitrile or tetrahydrofuran (or mixtures thereof with or without water as an additional solvent) with the additional solvents toluene, ethyl acetate, dichloromethane, dichloroethane or tetrahydrofuran can be used in salt formation. The HCl salt is particularly preferred, since this form provides superior and enriched purification of other stereoisomers of the previous step.

A preferred displacement solvent to be used in the resolution is ethyl acetate. Also useful as solvents are toluene, acetonitrile or heptanes.

A preferred insulating solvent is acetone. Other solvents useful in this regard include isopropanol, ethanol, methyl ethyl ketone, methylisopropyl ketone, acetonitrile and tetrahydrofuran. The solvents can also be used as additional solvents with each other or with water.

Preferred resolution compounds include tartaric acid and its derivatives, such as toluoyltartaric and benzoyltartaric acids in a stereospecific conformation, as described. Other resolution compounds include stereospecific andene acid and derivatives thereof.

To facilitate precipitation and recrystallization, the addition of seeds is optional but preferred to obtain a material with greater ee with less recrystallizations.

The following examples are presented to illustrate the procedure and efficacy of the present invention. It is understood that the aforementioned examples and the details contained therein are not considered as limitations of the present invention.

The present invention also relates to a process for preparing the compound of formula

<img file="CU23337B7_D0004.tif" />

or the pharmaceutically acceptable salt thereof; being R¹ a group of formula

R⁵

Rk_N/ (CH₂), in which y is 0, 1 or 2;

R⁴ is selected from the group consisting of hydrogen, (C] -Cfi) alkyl, (C, -C6) alkyl sulfonyl, (C2-C6) alkenyl, (C2-C6) alkynyl, the alkyl, alkenyl and alkynyl groups being optionally substituted with deuterium, hydroxyl, amino, trifluoromethyl, alkoxy (Cj-CJ, acyl &lt;C2C6) oxy, alkyl (C ^ -Cg) amino, (alkyl (Cj-Cg)) 2amino, cyano, nitro, alkenyl (C2-C6), (C2-C6) alkynyl or acyl (C, -C6) amino; or R⁴ it is cycloalkyl (C3-C₁₀), the cycloalkyl group being optionally substituted with deuterium, hydroxyl, amino, trifluoromethyl, acyl (Cj-Cg) oxy, acyl (Cj-C₆) amino, (Cj-Cg) alkyl, ((C¡-Cg) alkyl) ₂amino, cyano, cyanoalkyl (CjC₆), trlfluoromethylalkyl (Cj-Cg), nitro, nitroalkyl (0, -Cg) or acyl (Cj-Cg) amino;

R⁵ it is heterocycloalkyl (Cj-C ,,), the heterocycloalkyl groups must be substituted with one to five carboxyl, cyano, amino, deuterium, hydroxyl, alkyl (Cj-Cg), alkoxy (Ci-Cg), halo-, acyl (Cj -Cg), alkyl (C¡-C6) amino, aminoalkyl (Cj-Cg), alkoxy (Cj-Cg) -CO-NH, alkyl (Cj-C6) aminoCO-, alkenyl (C2-C6), alkynyl (C2 -C6), hydroxyalkyl (CjC6), alkoxy (Cj-Cg) alkyl (G-Cg), acyl (G-Cg) oxyalkyl (CxC6), nitro, cyanoalkyl (G-C6), haloalkyl (Cj-Cg), nitroalkyl (C] -C6), trifluoromethyl, trifluoromethylalkyl (Cj-Cg), acyl (Ci-Cg) amino, acyl (Cj-Cg) aminoalkyl (Cj-Cg), alkoxy (C, -C6) acyl (Cj-Cg ) amino, aminoacyl (C ^ Cg), aminoacyl (C ^ Cg) alkyl (Cj-Cg), alkyl (Cj-Cg) aminoacyl (Cj-Cg), ((alkyl (Cj-Cg)) 2-aminoacyl (Cj-Cg ), R¹⁵R¹⁶N-CO-O-, R¹⁵R¹⁶N-COalkyl (Cj-Cg), alkyl (C ^ Cg) -S (O) m, R¹⁵R¹⁶NS (O) m, R¹⁵R¹⁶NS (0) Malkyl (Cj-Cg), R¹⁵S (O) mR¹⁶N, R¹⁵S (O) mR¹⁶N-alkyl (G ~ C₆), being m 0, 1 or 2, and each R being independently selected¹⁵ and R¹⁶ of hydrogen or alkyl (C_tC₆); or a group of formula II

<img file="CU23337B7_D0005.tif" />

in which aesO, 1, 2, 3 or 4:

II

<td>b, c, e, f</td><td>and g are</td><td>every</td><td>one</td><td>independently 0 or 1;</td>

<td>d is 0, 1,</td><td>2 or 3;</td><td></td><td></td><td></td>

<td>X is S (O)_n,</td><td>being</td><td>n 0,</td><td>1 or</td><td>two; oxygen, carbonyl or</td>

<td>C (= N-cyano) -;</td><td></td><td></td><td></td><td></td>

<td>Y is S (O)_n,</td><td>being</td><td>n 0,</td><td>1 or</td><td>two; or carbonyl; and</td>

Z is carbonyl, C (O) O-, C (O) NR- or S (O)_n, being η 0, 1

OR 2;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ each is independently selected from the group consisting of hydrogen or alkyl (Cj-C₆) optionally substituted with deuterium, hydroxyl, amino, trifluoromethyl, acyl (Cj-C₆) oxy, acyl (C_xC₆) amino, (C ^ Cg) alkyl amino, ((C, -C alkyl)₆) )₂amino, cyano, cyanoalkyl (Cj-C₆), trifluoromethylalkyl (Cj-C₆), nitro, nitroalkyl (Cj-Cg) or acyl (Cj-Cg) amino;

R¹² it is carboxyl, cyano, amino, oxo, deuterium, hydroxyl, trifluoromethyl, alkyl (Cj-Cg), trifluoromethylalkyl (C₂C₆), alkoxy (Cj-Cg), halo, acyl (C, -C₆), alkyl (C_t-C₆) amino, (alkyl (Cj-Cg)) ₂amino, aminoalkyl (Cj-C₆), alkoxy (Cj-Cg) -CONH-, alkyl (C, -Cg) amino-CO-, alkenyl (C₂-C₆), alkynyl (C₂C₆), alkyl (C, -C₆) amino, hydroxyalkyl (Cj-C₆), alkoxy (CjC₆) alkyl (Cj-C₆), acyl (C ^ Cg) oxyalkyl (Cj-C₆), nitro, cyanoalkyl (Cj-Cg), haloaiquyl (Cj-Cg), nitroalkyl (Cj-C₆), trifluoromethyl, trifluoromethylalkyl (C_t-Cg), acyl (CjC₆) amino, acyl (C ^ Cg) aminoalkyl (Cj-Cg), alkoxy (Cj-CgJacil (C] -Cg) amino, aminoacyl (Cj-Cg), aminoacyl (Cj-Cg) alkyl (C ^

C₆), alkyl (Cj-CJ aminoacyl (Cj-Cg), (alkyl (C_tC₆) haminoacyl (C ^ Cg), R¹⁵R¹⁶N-CO-O-, R¹⁵R¹⁶N-CO-alkyl (CrC6), R¹⁵C (O) NH, R¹⁵OC (O) NH, R¹⁵NHC (O) NH, alkyl (C, -C6) -S (O) _m, alkyl (C! -C₆) -S (O) Η, -alkyl (C ^ Cg), R¹⁵R^,6NS (O) ra, R¹⁵R¹⁶NS (O) m-alkyl (C_rC₆), R¹⁵S (O) mR¹⁶N, R¹⁵S (O) mR¹⁶N-alkyl (Cj-C₆), being mO, 1 or 2, and R being selected¹⁵ and R¹⁶ each independently of hydrogen or alkyl (Q-Cg);

R² and R³ each is independently selected from the group consisting of hydrogen, deuterium, amino, halo-, hydroxyl, nitro, carboxyl, alkenyl (C2-C6), alkynyl (C2C6), trifluoromethio, trif luorome toxi, alkyl (Cj-C6), alkoxy (Cj-C6), cycloalkyl (C3-C10), the alkyl, alkoxy or cycloalkyl groups being optionally substituted with one to three groups selected from halo-, hydroxyl, carboxyl, aminoalkyl (Cj-Cgjtio, alkyl (Cj-Cg) amino , (alkyl (CjC6)) 2amino, heteroaryl (C5-C9), heterocycloalkyl (C2-C9), cycloalkyl (C3-C9) or aryl (C6C10), · or R² and R³ are each independently cycloalkyl (C3-C₁₀), cycloalkoxy (C₃-C₁₀), alkyl (Q-Cj amino, (alkyl (Cj-C₆) ) ₂amino, ari 1 (Cg C₁₀) amino, alkyl (Cj-C₆) uncle, ari 1 (C₆-C₁₀) uncle, alkyl (C, -C₆) sulfinyl, aryl (C₆-C₁₀) sulfinyl, alkyl (Cj-Cg) sulfonyl, aryl (C₆C₁₀) sulfonyl, acyl (C₁-C₆), alkoxy (C ^ Cg) -CO-NH-, alkyl (C₃C₆) amino-CO-, heteroaryl (C₅-C₉), heterocycloalkyl (C₂-C₉) or aryl (C₆-C₁₀), the heteroaryl, heterocycloalkyl and aryl groups being optionally substituted with one to three halo-, (Cj-Cg) alkyl, (C ^ Cg) -CO-NH-, alkoxy (C_rC₆) -CO-NH-, alkyl (Cj-Cg) -CO-NH-alkyl (C ^ Cg), alkoxy (Cj-C₆) -CO-NHalkyl (Cj-Cg), alkoxy (Cj-Cg) -CO-NH-alkoxy (C ^ Cg), carboxyl, carboxyalkyl (C ^ Cg), carboxyalkoxy (Cj-Cg), benzyloxycarbonylalkoxy (Cj-Cg) ), alkoxy (Cj-Cg) carbonylalkoxy (Ci-C₆), aryl (C₆-C₁₀), amino, aminoalkyl (Cj-Cg), alkoxy (CjC₆) carbonylamino, ari 1 (Cg-C₁₀) alkoxy (Cj-Cg) carbonylamino, alkyl (Cj-Cg) amino, (alkyl (Cj-C)₆) ) ₂amino, alkyl (CjC₆) aminoalkyl (Cj-Cg), ((C ^ Cg) alkyl) ₂aminoalkyl (Cj-Cg), hydroxyl, alkoxy (C, -C₆), carboxyl, carboxyalkyl (Cj-C₆), alkoxy (Cj-Cg) carbonyl, alkoxy (C ^ Cg) carbonylalkyl (Cj-Cg), alkoxy (Οχ-Cg) -CO-NH-, alkyl (C¡-C₅) -CO-NH-, cyano, heterocycloalkyl (C₅-C₉), amino-CO-NH-, (Cj-Cg) alkyl aminoCO-NH-, ((C ^ Cg) alkyl)₂amino-CO-NH-, aryl (C₆-C_l0) amino-CO-NH, heteroaryl (C₅-C₉) amino-CO-NH-, (C ^ Cg) alkyl amino-CO-NHalkyl (C, -C₆), (alkyl (Cj-Cg)) ₂amino-CO-NH-alkyl (Cx-Cg), aryl (C₆-C₁₀) amino-CO-NH-alkyl (Cj-C₆), heteroaryl (C₅C₉) amino-CO-NH-alkyl (Cj-Cg), alkyl (Cj-Cg) sulfonyl, alkyl (Cj-Cg) sulf onylamino, alkyl (C [-C₆) sulfonylaminoalkyl (ΟχC₆), aril (C₆-C₁₀) sulfonyl, aryl (C₆-C₁₀) sulf onylamino, aryl (C₆-C₁₀) sulfonylaminoalkyl (Οχ-Cg), alkyl (Οχ-Cg) sulfonylamino, alkyl (Οχ-Cg) sulfonylaminoalkyl (Οχ-Cg), heteroaryl (C₅-C₉) or heterocycloalkyl (C₂-C₉), said process comprising the steps of: a) mixing a racemic mixture of enantiomeric compounds of formula /^r5

Rk_Nx (CH₂)_and

H in which y, R⁴ and R⁵ they are as defined above, in a solvent, with a resolution compound having a defined stereospecificity, to form a solution, said resolution agent being able to bind at least one but not all said enantiomers to form a precipitate containing this at least one of said enantiomers;

b) leave the mixture at rest for a sufficient period of time to allow substantial precipitation of a stereospecific enantiomer of the racemic mixture of the solution, the other of said enantiomers remaining in said solution;

c) depending on the stereospecific enantiomer of the desired compound, collect the precipitate and purify it or collect the solution containing another of said enantiomers and recrystallize the enantiomer contained in said solution; and

d) reacting the desired stereospecific enantiomer thus formed with a compound of formula

<img file="CU23337B7_D0006.tif" />

XVI in which R is hydrogen or a protecting group and R² and R³ They are as defined above.

The present invention also relates to a compound of the formula in which

<img file="CU23337B7_D0007.tif" />

each one is independently selected from the group consisting of hydrogen, deuterium, amino, halo-, hydroxyl, nitro, carboxyl, alkenyl (C₂-C₆), alkynyl (C₂-C₆), trifluoromethyl, trif luorome toxi, alkyl (Cj-Cg), alkoxy (C ^ -Cg), cycloalkyl (C₃-C₁₀), the alkyl, alkoxy or cycloalkyl groups being optionally substituted with one to three groups selected from halo-, hydroxyl, carboxyl, aminoalkyl (Ci-Cg / thio, alkyl (Cj-Cg) amino, (alkyl (Cj-Cg)) ₂amino, heteroaryl (C₅-C₉), heterocycloalkyl (C₂-C₉), cycloalkyl (C₃-C₉) or aryl (C₆-C₁₀); or R² and R³ are each independently cycloalkyl (C₃-C₁₀), cycloalkoxy (C₃-C₁₀), alkyl (C ^ Cg) amino, (alkyl (Cj-Cg)) ₂amino, aryl (C₆-C₁₀) amino, alkyl (Cj-Cg) thio, aryl (C₆-C₁₀) thio, alkyl (Cj-Cg) sulfyl, aryl (C₆-C₁₀) sulf inyl, alkyl (Cj-Cg) sulf onyl, aryl (C₆C_1Q) sulf onyl, acyl (Cj-Cg), alkoxy (Cj-C₆) -CO-NH-, alkyl (CjCg) amino-CO-, heteroaryl (C₅-C₉), heterocycloalkyl (C₂-C₉) or aryl (C₆-C₁₀), the heteroaryl, heterocycloalkyl and aryl groups being optionally substituted with one to three halo-, (C ^ Cg) alkyl, (Cj-Cg) -CO-NH-, alkoxy (Cj-Cg) -CO-NH-, alkyl (Ci-Cg) -CO-NH-alkyl (Cj-Cg), alkoxy (C ^ Cg) -CO-NHalkyl (Cj-Cg), alkoxy (Cj-Cg) -CO-NH-alkoxy (C_t-C₆), carboxyl, carboxyalkyl (Cj-Cg), carboxyalkoxy (Cj-Cg), benzyloxycarbonylalkoxy (Cj-Cg), alkoxy (C, -Cg) carbonylalkoxy (Cj-Cg), aryl (C₆-C₁₀), amino, aminoalkyl (Cj-Cg), alkoxy (C₂C₆) carbonylamino, aryl (^ 6 ^_ C_J0) alkoxy (Cj-Cg) carbonylamino, alkyl (Cj-Cg) amino, ((C ^ Cg) alkyl) ₂amino, alkyl (C_tCg) aminoalkyl (Cj-C₆), (alkyl (C, -C₆) ) ₂aminoalkyl (Cj-Cg), hydroxyl, alkoxy (Cj-Cg), carboxyl, carboxyalkyl (C ^ Cg), alkoxy (Cj-Cg) carbonyl, alkoxy (Cj-C₆) carbonyl alkyl (Ci-C₆), alkoxy (Cj-Cg) -CO-NH-, alkyl (C, -C₆) -CO-NH-, cyano, heterocycloalkyl (C₅-C₉), amino-CO-NH-, (C ^ Cg) alkyl aminoCO-NH-, ((C ^ Cg) alkyl) ₂amino-C0-NH-, aryl (C₆-C₁₀) amino-CO-NH, heteroaryl (C₅-C₉) amino-CO-NH-, alkyl (Cj-Cg) amino-CO-NH25 alkyl (Cj-Cg), (alkyl (Cj-Cg)) ₂amino-CO-NH-alkyl (Cj-Cg), aryl (C₆-C₁₀) amino-CO-NH-alkyl (Cj-C₆), heteroaryl (C₅C₉) amino-CO-NH-alkyl (C ^ Cg), alkyl (C, -C₆) sulf onyl, alkyl (Cj-Cg) sulf onylamino, alkyl (Cj-Cg) sulf onylaminoalkyl (CjC₆), aril (C₆-C₁₀) sulf onyl, aryl (C₆-C₁₀) sulfonylamino, aryl (Cg-C₁₀) sulfonylaminoalkyl (Cj-Cg), alkyl (cq-Cg) sulfonylamino, alkyl (C ^ -Cg) sulf onylaminoalkyl (Q-Cg), heteroaryl (C₅-C₉) or heterocycloalkyl (C₂-C₉) .

The present invention also relates to specifically preferred compounds selected from the group consisting of:

Methyl - [(3R, 4R) -4-methyl-l- (propane-1-sulfonyl) -piperidin3-yl] - (7 H -pyrrolo [2,3-d] pyrimidin-4-yl) -amine;

(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methyl ester;

3,3,3-Trifluoro-l - {(3R, 4R) -4-methyl-3- [methyl- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-l-yl } -propan1-one;

(3R, 4R) -4-methyl-3- [methyl- (7H-pyrro lo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-l-carboxylic acid dimethylamide;

{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-l-carbonyl) amino) acetic acid ethyl ester;

3 - {(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin25

4-yl) -amino] -piperidin-l-yl} -3-oxo-propionitrile;

3,3,3-Trifluoro-1 - {(3R, 4R) -4-methyl-3- [methyl- (5-methyl-7Hpyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin -l-il} -propan1-one;

l- {(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -amino] -piperidin-l-yl} -but-3-in- canvas;

1- {(3R, 4R) -3 - [(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) methylamino] -4-methylpiperidin-1-yl} -propan-1-one ;

1- {(3R, 4R) - 3- [(5-Fluoro-7H-pyrro lo [2,3-d] pyrimidin-4-yl) -methylamino] -4-methyl-piperidin-l-yl} -propan - canvas;

(3R, 4R) -N-cyano-4-methyl-3 - [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] -N'-propylpiperidine-l-carboxamidine;

and (3R, 4R) -N-cyano-4, N ', N' -Trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxamidine.

The present invention also relates to a pharmaceutical composition for (a) the treatment or prevention of a disorder or condition selected from rejection of organ transplants, xenotransplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibition of protein kinases or Janus kinase 3 (JAK3) in a mammal, including a human being, comprising an amount of a preferred compound specifically described above or a pharmaceutically acceptable salt thereof. , effective in such disorders or conditions and a pharmaceutically acceptable vehicle.

The present invention also relates to a method for the inhibition of tyrosine kinase or Janus kinase 3 (JAK3) proteins in a mammal, including a human being, comprising administering to said mammal an effective amount of a preferred compound specifically described above or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating or preventing a disorder or condition selected from rejection of organ transplants, xenotransplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications of diabetes, cancer, asthma , atopic dermatitis, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being, comprising administering to the said mammal an amount of a preferred compound specifically described above, or a pharmaceutically acceptable salt thereof,

I effective in treating such a condition.

<td>The present invention</td><td colspan="2">also refers to a compound</td>

<td colspan="3">formula</td>

<td></td><td>j</td><td></td>

<td></td><td></td><td>Μ)., »</td>

The present invention also relates to a compound of formula

<img file="CU23337B7_D0008.tif" />

The present invention also relates to a compound of formula. . .

<img file="CU23337B7_D0009.tif" />

Detailed Description of the Invention The following reaction Schemes illustrate the preparation of the compounds of the present invention. A 2 5 unless otherwise indicated, R², R³, R⁴ and R⁵ in the Reaction Schemes and in the discussion that follow they are as defined above.

PREPARATION A

Cl

<img file="CU23337B7_D0010.tif" />

PREPARATION Β

<img file="CU23337B7_D0011.tif" />

SCHEME 1

<img file="CU23337B7_D0012.tif" />

SCHEME 2

<img file="CU23337B7_D0013.tif" />

<img file="CU23337B7_D0014.tif" />

XV

<img file="CU23337B7_D0015.tif" />

In reaction 1 of Preparation A, the compound of

4-chloropyrrolo [2,3-d] pyrimidine of formula XXI, wherein R is hydrogen or a protecting group such as benzenesulfonyl or benzyl, is converted to the 4-chloro-5halopyrrolo [2,3-d] pyrimidine compound of formula XX, in which Y is chlorine, bromine or iodine, by reaction of XXI with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated at reflux, in chloroform, for a period of time between about 1 hour and about 3 hours, preferably for about 1 hour. Alternatively, in reaction 1 of Preparation A, the 4-chloropyrrolo [2,3-d] pyrimidine of formula XXI, wherein R is hydrogen, becomes the corresponding 4-chloro-5-nitropyrrolo [2,3-d] pyrimidine of formula XX, in which Y is nitro, by reaction of XXI with nitric acid in sulfuric acid at a temperature between about -10 ° C and about 10 ° C, preferably at about 0 ° C, for a period of time between about 5 minutes and about 15 minutes, preferably for about 10 minutes. The compound of formula XXI, in which Y is nitro, is converted into the corresponding 4-chloro-5-aminopyrrolo [2,3-d] pyrimidine of formula XX, in which Y is amino, by reaction of XXI, in a variety of conditions known to a person skilled in the art such as hydrogenolysis with palladium or tin (IV) chloride and hydrochloric acid.

In reaction 2 of Preparation A, the 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of formula XX, in which R is hydrogen, becomes the corresponding compound of formula XIX, in which that R² is alkyl (Cj-C₆) or benzyl, by treatment of XX with N-butyllithium, at a temperature of about -78 ° C, and reaction of the dianion intermediate formed in this way with an alkyl halide or benzyl halide at a temperature between about -78 ° C and room temperature, preferably at room temperature. Alternatively, the dianion thus formed is reacted with molecular oxygen to form the corresponding 4-chloro-5-hydroxypyrrolo [2,3-d] pyrimidine of formula XIX, in which R² It is hydroxyl. The compound of formula XX, in which Y is bromine or iodine and R is benzenesulfonate, becomes the compound of formula XIX, in which R² it is aryl (Qr Cu) or vinyl, by treatment of XX with N-butyllithium, at a temperature of about -78 ° C, followed by the addition of zinc chloride, at a temperature of about -78 ° C. The corresponding organo zinc intermediate formed in this way is then reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The reaction mixture is stirred at a temperature between about 50 ° C and about 80 ° C, preferably at about 70 ° C for a period of time between about one hour and about 3 hours, preferably for about 1 hour.

In reaction 3 of Preparation A, the compound of formula XIX is converted into the corresponding compound of formula XVI by treatment of XIX with N-butyllithium, lithium diisopropylamine or sodium hydride, at a temperature of approximately -78 ° C, in presence of a solvent

<td>10 aprotico</td><td>polar,</td><td>such</td><td>as tetrahydrofuran</td><td>. The intermediate</td>

<td>anionic</td><td>formed</td><td>from</td><td>this way after</td><td>makes react</td>

<td>with (a)</td><td>halide</td><td>from</td><td>alkyl or halide of</td><td>benzyl</td>

temperature between about -78 ° C and room temperature, preferably at -78 ° C, when R³ it is benzyl alkyl; (b) an aldehyde or ketone, at a temperature between about -78 ° C and room temperature, preferably at -78 ° C, when R³ it is alkoxy; and (c) zinc chloride at a temperature between about -78 ° C and room temperature, preferably at -78 ° C, and the corresponding organo zinc intermediate thus formed is then reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The resulting reaction mixture is stirred at a temperature between about 50 ° C and about 80 ° C, preferably at about 70 ° C, for a period of time between about 1 hour and about 3 hours, preferably, for about 1 hour . Alternatively, the anion thus formed is reacted with molecular oxygen to form the corresponding 4-chloro-6-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XVI, in R³ It is hydroxy.

In reaction 1 of Preparation B, the compound of

4-Chloropyrrolo [2,3-d] pyrimidine of formula XXI, becomes the corresponding compound of formula XXII, according to the procedure described above in reaction 3 of Preparation A.

In reaction 2 of Preparation B, the compound of formula XXII is converted into the corresponding compound of formula XVI, according to the procedures described above in reactions 1 and 2 of Preparation A.

In reaction 1 of Scheme 1, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVII is converted into the corresponding compound of formula XVI, wherein R is benzenesulfonyl or benzyl, by treatment of XVII with benzenesulfonyl chloride , benzyl chloride or benzyl bromide in the presence of a base, such as sodium hydride or potassium carbonate, and a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran. The reaction mixture is stirred at a temperature between approximately

0 ° C and about 70 ° C, preferably about 30 ° C for a period of time between about 1 hour and about 3 hours, preferably for about 2 hours.

In reaction 2 of Scheme 1, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVI is converted into the corresponding 4-aminopyrrolo [2,3 d] pyrimidine compound of formula XV by coupling XVI with an amine of formula HNR⁴R⁵. The reaction is carried out in water or in an alcoholic solvent, such as tert-butanol, methanol or ethanol, or other high-boiling organic solvents, such as dimethylformamide, triethylamine, 1,4-dioxane or 1,2-dichloroethane, at temperature between about 60 ° C and about 12 0 ° C, preferably at about 80 ° C. Typical reaction times are between about 2 hours and about 100 hours, preferably about 48 hours. When R⁵ It is a nitrogen-containing heterocycloalkyl group, each nitrogen has to be protected with a protective group, such as benzyl. The removal of the protective group R⁵ it is carried out under appropriate conditions for that particular protecting group in use that does not affect the protective group R of the pyrrolo [2,3-d] pyrimidine ring. The elimination of the protective group of R⁵ when it is benzyl, it is carried out in an alcoholic solvent, such as ethanol, in the presence of hydrogen and a catalyst, such as palladium hydroxide on carbon, at temperatures that vary from room temperature to about 70 ° C. The nitrogen-containing heterocycloalkyl group in R⁵ thus formed, it can be further reacted with a variety of different electrophiles of formula II. For urea formation, electrophiles of formula II such as isocyanates, carbamates and carbamoyl chlorides are reacted with the nitrogen of R⁵ of the heteroalkyl group in a solvent, such as acetonitrile or dimethylformamide, in the presence of a base, such as sodium or potassium carbonate, at a temperature between about 20 ° C and about 100 ° C, for a period of time between about 24 hours and approximately 72 hours. For the formation of amide and sulfonamide, electrophiles of formula II, such as acyl chlorides and sulfonyl chlorides, are reacted with the nitrogen of R⁵ of the heteroalkyl group in a solvent such as methylene chloride, in the presence of a base such as pyridine at room temperature for a period of time between about 12 hours and about 24 hours. The amide formation can also be performed by reacting a carboxylic acid with the heteroalkyl group in the presence of a carbodiimide such as 1- (3dimethylaminopropyl) -3-ethylcarbodiimide in a solvent such as methyl chloride at room temperature, for a period of approximately 12 to about 24 hours, or with an activated ester, such as Nhydroxysuccinimide ester, or 4-nitrophenyl ester or in a solvent such as methylene chloride, tetrahydrofuran or ethanol. For the formation of alkyl, electrophiles of formula II such as amides, α-β unsaturated, acids, nitriles, esters and α-halo amides are reacted with the nitrogen of R⁵ of the heteroalkyl group in a solvent such as methanol at room temperature for a period of time between about 12 hours and about 18 hours. The formation of alkyl can also be carried out by reacting aldehydes with the heteroalkyl group in the presence of a reducing agent, such as sodium cyanoborohydride, in a solvent, such as methanol, at room temperature for a period of time between about 12 hours and about hours.

In reaction 3 of Scheme 1, the removal of the protective group of the compound of formula XV, wherein R is benzene sulfonyl, to give the corresponding compound of formula I is performed by treatment of XV with an alkaline base, such as sodium hydroxide or potassium hydroxide, in an alcoholic solvent, such as methanol or ethanol, or mixed solvents such as alcohol / tetrahydrofuran or alcohol / water. The reaction is carried out at room temperature for a period of time between about 15 minutes and about 1 hour, preferably for 30 minutes. The removal of the protective group of the compound of formula XV in which R is benzyl is carried out by treatment of XV with sodium in ammonia at a temperature of about 78 ° C, for a period of time between about 15 minutes and about 1 hour .

In reaction 1 of Scheme 2, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XX is converted into the corresponding 4-aminopyrrolo [2,3-d] pyrimidine compound of formula XXIV according to the procedure described above in reaction 2 of Scheme 1.

In reaction 2 of Scheme 2, the 4-amino5-halopyrrolo [2,3-d] pyrimidine compound of formula XXIV, wherein R is benzene sulfonate and Z is bromine or iodine, becomes the corresponding compound of formula XXIII by reaction of XXIV with (a) arylboronic acid, when R² it is an aryl, in an aprotic solvent such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium (0) at a temperature between about 50 ° C and about 100 ° C, preferably at about 70 ° C, over a period of time between about 2 hours and about 48 hours, preferably for about 12 hours; (b) alkynes, when R² it is alkynyl, in the presence of a catalytic amount of copper (I) and palladium (0) iodide, and a polar solvent, such as dimethylformamide, at room temperature, for a period of time between about 1 hour and about 5 hours, preferably for about 3 hours; and (c) alkenes or stretch us, when R² it is vinyl or styrene, in the presence of a catalytic amount of palladium in dimethylformamide, dioxane or tetrahydrofuran, at a temperature between about 80 ° C and about 100 ° C, preferably at about 100 ° C, for a period of time between about 2 hours and about 48 hours, preferably about 48 hours.

In reaction 3 of Scheme 2, the compound of formula XVIII is converted into the corresponding compound of formula XV, according to the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Scheme 3., the compound of formula XVII is converted into the corresponding compound of formula I, according to the procedure described above in reaction 2 of Scheme 1.

The compounds of the present invention that are of basic character, are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts have to be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt, then simply convert the latter back into the free base compound by treatment with an alkaline reagent and subsequently convert the last free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as acetone, methanol or ethanol After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

The compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts and, particularly, calcium, sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of reagents are preferably used to ensure that the reaction is completed and that maximum yields of the desired final product are obtained.

The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention can be formulated for oral, buccal, intranasal, parenteral administration (eg, intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention can also be formulated for sustained release.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); vehicles (eg lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or humectants (for example sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented in the form of a dry product for reconstitution with water or other suitable vehicle before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (for example sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifiers (for example lecithin or acacia gum); non-aqueous vehicles (for example almond oil, oily esters or ethyl alcohol) and preservatives (for example methyl or propyl p-hydroxybenzoates, or sorbic acid).

For oral administration, the composition may take the form of tablets or tablets formulated in a conventional manner.

The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion.

Formulations for injection may be presented in unit dosage form, for example in ampoules or multi-dose containers, with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, for example sterile pyrogen-free water, before use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, which contain for example conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently supplied in the form of a solution or suspension of a pump spray container that the patient presses or pumps, or in the form of an aerosol spray presentation from a Pressurized container or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressure spray, the unit dose can be determined by providing a valve to deliver a measured amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made for example of gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the active compounds of the invention for oral, parenteral or oral administration to an average adult human for the treatment of the conditions designated above (eg rheumatoid arthritis) is 0.1 to 1,000 mg of active ingredient per unit dose. , which could be administered for example 1 to 4 times a day.

Aerosol formulations for the treatment of the conditions designated above (for example asthma) in the average adult human are preferably arranged so that each measured dose or burst of aerosol contains from 20 / xg to 1,000 / xg of the compound of the invention. The total daily dose with an aerosol will be in the range of 0.1 mg to 1,000 mg. Administration may be several times a day, for example 2, 3, 4 or 8 times, providing for example 1, 2 or 3 doses each time.

A compound of formula (I) administered in a pharmaceutically acceptable form alone or in combination with one or more additional agents that modulate the mammalian immune system, or with anti-inflammatory agents, agents that may include, but are not limited to, cyclosporin A (by example, Sandimmune^(R) o Neoral^(R)), rapamycin, FK-506 (tacrolimus), leflunomide, desoxispergualine, mycophenolate (eg, Cellcept^(R)), azathioprine (for example, Imuran®), daclizumab (for example Zenapax^(R)), OKT3 (for example Orthocolone^(R)), AtGam, aspirin, paracetamol, ibuprofen, naproxen, piroxicam and anti-inflammatory spheroids (for example prednisolone or dexamethasone), and the said agents can be administered as part of the same dosage form or a separate one, by the same route of administration, or a different one, and in the same administration program, or a different one, according to standard pharmaceutical practice.

FK506 (Tacrolimus) is administered orally at 0.100.15 mg / kg body weight, every 12 hours within 48 hours of the postoperative period. Doses are controlled according to serum Tacrolimus levels.

Cyclosporine A (oral or intravenous formulation of Sandimmune, or oral solution or Neoral capsules^(R)) is administered orally at 5 mg / kg body weight, every 12 hours, within 48 hours of the postoperative period. The dose is controlled by serum cyclosporin A levels.

The active agents can be formulated for sustained release according to methods well known to those skilled in the art. Examples of the aforementioned formulations can be found in United States patents 3,538,214, 4,060,598, 4,173,626, 3,119,742 and 3,492,397.

The ability of the compounds of formula I or their pharmaceutically acceptable salts to inhibit Janus kinase 3 and, consequently, to demonstrate their effectiveness in treating disorders or conditions characterized by Janus kinase 3, is shown by the following in vitro tests.

Biological Assay

JAK3 Enzyme Assay (JH1: GST)

The JAK3 kinase assay utilizes a protein expressed in SF9 cells infected with baculovirus (a

<td colspan="6">GST fusion protein and the catalytic domain of JAK3</td>

<td>human) purified</td><td>by</td><td>chromatography</td><td>from</td><td>affinity</td><td>in</td>

<td>glutathione-sepharose.</td><td>He</td><td>substrate for</td><td>the</td><td>reaction</td><td>is</td>

Poly (glutamic acid) -Tyrosine (PTG (4: 1), Sigma, Catalog No. P0275), applied on Nunc Maxi Sorp plates at 100 pg / ml overnight at 37 ° C. The morning after coating, the plates are washed three times and JAK3 is added to the wells containing 100 pl of kinase buffer (5 mM HEPES, pH 7.3, 5 mM NaCl 12, MgCl₂ 24 mM) + 0.2 pM ATP + 1 mM Na orthovanadate). The reaction proceeds for 3.0 minutes at room temperature and the plates are washed three more times. The level of phosphorylated tyrosine in a given well is quantified by a conventional ELISA using an anti-phosphotyrosine antibody (ICN PY20, cat. No. 69-1511).

Inhibition of Proliferation of Immature T Cells

Dependent on Human IL-2

This test measures the inhibitory effect of compounds on the proliferation of immature IL-2-dependent T cells in vivo. Since signaling through the IL-2 receptor requires JAK-3, active JAK-3 inhibitors should inhibit the proliferation of immature IL-2-dependent T cells.

The cells of this assay are isolated from recent human blood. After separation of the mononuclear cells using Accuspin System-Histopaque-1077 (Sigma No. A7054), primary human T cells are isolated by negative selection using Lympho-Kwik T (One Lambda, Inc., cat. No. LK- 50T). T cells are grown at 1-2x10⁶/ ml in Medium (RPMI + 10% thermally inactivated fetal calf serum (Hyclone cat. No. A-llll-L) + 1% Penicillin / Streptomycin (Gibco)) and proliferation is induced by the addition of 10 gg / ml PHA (Murex Diagnostics, Cat. No. HA 16). After 3 days at 37 ° C in 5% CO₂, the cells are washed 3 times in Medium, resuspended at a density of 1-2 χ 10⁶ cells / ml in Medium plus 100 Units / ml of human recombinant IL-2 (R&amp;D Systems, Cat. No. 202-IL). After 1 week, the cells are IL-2 dependent and can be maintained for up to 3 weeks by feeding twice a week with equal volumes of Medium + 100 Units / ml of IL-2.

To test the ability of an assay compound to inhibit the proliferation of IL-2-dependent T-cells, IL-2-dependent cells are washed 3 times, resuspended in medium and then cultured (50,000 cells / well / 0, 1 ml) in a 96-well flat-bottom microtiter plate (Falcon, No. 353075). From a 10 mM stock solution of test compound in DMSO, serial dilutions are added to half of the compound in triplicate wells starting at 10 μΜ. After one hour, 10 Units / ml of IL-2 are added to each test well. The plates are then incubated at 37 ° C, with 5% CO₂ for 72 hours The plates are then subjected to pulses of³H-Thymidine (0.5 μύί / ροοίΐΐο) (NEN Cat. No. NET-027A) and incubate for an additional 18 hours. The culture plates are then collected with a 96-well plate collector and the amount of³H-thymidine incorporated into proliferative cells is determined by counting in a Packard Top Count scintillation counter. Data are analyzed representing% inhibition of proliferation versus concentration of test compound. From this graph a CI value is determined₃₀ (μΜ).

The following Examples illustrate the preparation of the compounds of the present invention, but this is not limited to the details thereof. Melting points are uncorrected. NMR data are presented in parts per million (δ) and use the deuterium closure signal of the sample solvent (deuteriochloroform as reference unless otherwise specified). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N, N-dimethylformamide. Low Resolution Mass Spectra (LRMS) were recorded on a Hewlett Packard 5989®, using chemical ionization (ammonium), or a Chemical Ionization Platform at Atmospheric Pressure (APCI) Fisons (or Micro Mass) using a mixture

50/50 acetonitrile / water with 0.1% formic acid as an ionizing agent. Ambient temperature refers to a temperature of 20-25 ° C.

EXAMPLE 1 (stable salt formation) (l-benzyl-4-methylpiperidin-3-yl) methylamine bishydrochloride

25 1 of 32% HCl in water was added to a solution of 23.4 kg of (l-benzyl-4-methylpiperidin-3-yl) methylamine in 10 1 of toluene and 120 1 of ethanol at 3 ° C, keeping the reaction temperature below 10 ° C. 100 1 of solvent was distilled off under partial vacuum, and 215 1 of ethyl acetate was added at 30 ° C. 210 1 of solvent was distilled off under partial vacuum and 215 1 seconds of ethyl acetate were added, and another 210 1 of solvent was distilled off under partial vacuum. 111 1 of acetone was added at 35 ° C, the suspension was cooled to 0 ° C, and then the product, (l-benzyl-4-methylpiperidin-3-yl) methylamine bishydrochloride was filtered, and washed with 55 1 of acetone. The wet cake was resuspended 3 times in ethanol (10 volume equivalents at reflux) to improve the cis: trans diastereoisomeric ratio of 91: 9 to&gt; 97: 3. The total recovery was 19.4 kg (62% yield). NMR-'H (CD₃OD, 400 MHz): 7.55 (m,

<td colspan="2">5H), 4.88 (S,</td><td colspan="3">3H), 4.52 (d, J = 12.8 Hz, IH), 4.45 (d, J = 12.8</td>

<td>Hz, IH)</td><td> , 3,76</td><td>(m, IH), 3.67 (m, IH)</td><td> , 3,40-3,00</td><td>(m, 3H), 2.78</td>

<td>(3, 3H)</td><td> , 2,55</td><td>(m, IH), 2.14 (m, IH '</td><td>), 1.90 (m,</td><td>IH), 1.16 (d,</td>

J = 7.2 Hz, 3H).

EXAMPLE 2 (resolution)

Bis - [(l-Benzyl-4-methylpiperidin-3-yl) methylamine di-p-toluoyl-L-tartrate

33 1 of 2 N sodium hydroxide was added to a solution of 9.5 kg of (l-benzyl-4-methylpiperidin-3-yl) methylamine bishydrochloride in 16 1 of water. Solids precipitated from the mixture. The suspension was diluted with 43 1 of isopropanol and 11 1 of methanol to redissolve the solids. Di-p-toluoyl-L-tartaric acid (6.3 kg) was added, with precipitation of solids. The suspension was heated to reflux to redissolve the solids, then slowly cooled to 72 ° C. Di - p-toluoyl-L-tartrate seeds of bis - [(l-bencii-4-methylpiperidin-3-yl) methylamine] (180 g) were added, and the veiled solution was slowly cooled to 15 ° C. The solids were filtered and washed with isopropanol to provide 5.9 kg of bis- [(1-benzyl-4-methylpiperidin-3-yl) methylamine] di-p-toluoyl-L-tartrate] in 44% yield. NMR-^¡H (CD₃OD, 400 MHz): δ 8.04 (d, J = 8.4 Hz,

<td>2H),</td><td>7.30 (m,</td><td>7H), 5.86 (s, IH)</td><td> , 4,</td><td>, 91 (s,</td><td>3H)</td><td> , 3</td><td>, 64 (d, J =</td>

<td> 12,8</td><td>Hz, IH),</td><td>3.41 (d, J = 12.8</td><td>Hz,</td><td>IH), 3,</td><td> 09</td><td>(s,</td><td>IH), 2.90</td>

<td>(m,</td><td>2H), 2.40</td><td>(s, 3H), 2.22 (m.</td><td>2H)</td><td> , 1,92</td><td>(m,</td><td>IH)</td><td>, 1.57 (m,</td>

2H), 1.03 (d, J = 7.2 Hz, 3H).

EXAMPLE 3 (resolution of the fencifos)

7.57 g of (+) phenyl (31.3 mmol) were added to a solution of 6.83 g (31.3 mmol) in 250 ml of IPA and 10 ml of water, and the mixture was heated to reflux to Get a transparent solution. Sowing crystals were added at a temperature of approximately 65 ° C with an ee of 90%. The crystallization began after one hour and the mixture was allowed to reach room temperature overnight. The isolation provided 6.85 g (47%) with a 99% ee. The filtrate was concentrated, TBME, water and K were added.₂CO₃, and the phases were separated. The organic phase was dried (Na₂SW₄) and the solvent was evaporated. The resulting oil (3.99 g) was dissolved in 200 ml of IPA and 10 ml of water and 4.4 g of (-) fencifos were added. The mixture was heated to reflux and allowed to cool to room temperature overnight. This provided 6 g (41%) of salt with an ee of 99.9 +%. The analyzes were performed on the free amine. The free amine was obtained by treating the salt with TBME, water and K₂CO₃.

The procedures of examples 1 to 3 are schematically illustrated below (Bn being defined as benzyl (-CH₂-C₆H₅) ) :

CHaHN υί

HCl, water, ethanol

HE HAS,

CH, HN

Racemic racemic ζκα

ÁJ®n '

CHiHN

1) NaOH

2) di-p4oluyl-L-tartrate HA »zx

2HG IPO, MeOH (I ί ·· —i— ·

CH.HN 'racemic COOH

99%··

HE HAS,

2HCI

CHjHN^-'

2) Η0Λ

CH₃KN '

IIV, Ι ^, ΝΒη

<img file="CU23337B7_D0016.tif" />

93% ee

V

Vo

EXAMPLE 4

A racemic mixture of the compound of formula was resolved

III:

<img file="CU23337B7_D0017.tif" />

lil

Sample Processing:

A compound of formula III was filtered through a 0.2 pm nylon 66 filter disc.

Procedure: (96% ethanol, 4% water as solvent)

0.8711 g of the compound of formula III, of the filtrate, was dissolved in 5.0 ml of ethanol / water 96: 4. 1,544 g of di-p-toluoyl-L-tartaric acid were added and the mixture was stirred to obtain a clear solution. The solution was allowed to stand at room temperature for approximately 4 hours. The resulting suspension was filtered through Whatman filter paper No. 2 and washed with 4.0 ml of ethanol / water 96: 4. The solids were air dried, yielding 0.488 g of the diastereoisomeric salt.

0.488 g of the diastereoisomeric salt was suspended in 50 ml of water, and then 50 ml of methylene chloride was added. The pH of the mixture was adjusted to approximately 9 using saturated sodium bicarbonate followed by 1.0 N sodium hydroxide. After completing the pH adjustment, the phases were separated and the methylene chloride phase was filtered through Whatman filter # 2. The solvents were then removed by evaporation under reduced pressure to provide a light orange oil. The weight was not determined. This oil was evaluated by gas chromatography.

Analytical test: 97.3% of the desired enantiomer per normalized percentage of area.

EXAMPLE 5

Process·. (100% ethanol as solvent)

0.8714 g of (l-benzyl-4-methyl-piperidin-3-yl) -methylamine was dissolved in 5.0 ml of ethanol with a graduation of 200, 1,544 g of di-p-toluoyl-L-tartaric acid were added and the mixture was stirred to obtain a clear solution. The solution was allowed to stand at room temperature for approximately 4 hours. The resulting suspension was filtered through Whatman filter paper No. 2 and washed with 4.0 ml of ethanol / water 96: 4. The solids were air dried, providing 0.628 g of the diastereoisomeric salt.

0.628 g of the diastereoisomeric salt was suspended in 50 ml of water, and then 5.0 ml of methylene chloride was added. The pH of the mixture was adjusted to approximately 9 using saturated sodium bicarbonate followed by 0.1 N sodium hydroxide. After completing the pH adjustment, the phases were separated and the methylene chloride phase was filtered through filter paper. Whatman n ° 2. The solvents were then removed by evaporation under reduced pressure to provide a light yellow oil. The weight was not determined. The oil evaluation provided the analytical test: 90.5% of the desired enantiomer per normalized percentage of area.

EXAMPLE 6

3 - {(3R, 4R) -4-Methyl-3-methyl- (7H-pyrrolo [2,3-d] pyrimidin-4yl) -amino] -piperidin-1-yl) -3-oxopropionitrile

Procedure A (3R, 4R) - (l-benzyl-4-methylpiperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

4-Chloropyrrolo [2,3-d] pyrimidine (5.37 grams, 34.9 mmol), prepared by the procedure of Davoll, J. Am. Chem. Soc. 82, 131 (1960), which is incorporated by reference in its entirety, the product of Example 2 (6 grams, 27.5 mmol) and potassium carbonate (11.4 grams, 82.5 mmol) in water (60 ml). The suspension was heated at reflux for 90 hours. The mixture was cooled to 90 ° C and toluene (60 ml) was added. The biphasic mixture was filtered through a filter aid and the layers were separated. The aqueous layer was extracted with toluene. The combined toluene layers were washed with 1 N NaOH, treated with activated carbon and filtered through a filter aid. The toluene was evaporated in vacuo and the residue was crystallized from a 1: 1 mixture of isopropyl acetate and hexanes, yielding 5 grams of an off-white solid; 54% yield. LRMS: 336.1 (M + l).

Procedure B

Methyl - ((3R, 4R) -4-methylpiperidin-3-yl) - (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amine

To the product of Procedure A (0.7 grams, 2.19 mmol) dissolved in 15 ml of ethanol, 1.5 ml of 2N hydrochloric acid was added and the reaction mixture was degassed by purging with nitrogen. Then, 0.5 grams of 20% palladium hydroxide on carbon (50% water) (Aldrich) was added to the reaction mixture and the resulting mixture was stirred (Parr stirrer) under an atmosphere of 344,737 kPa of hydrogen at room temperature for 2 days. The reaction mixture filtered with Celite was concentrated to dryness in vacuo and the residue was purified by flash column chromatography (silica; 5% methanol in dichloromethane), yielding 0.48 grams (90%) of the title compound. LRMS: 246.1 (M + 1).

Procedure C

- {(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4yl) -amino] -piperidin-l-yl} -3-oxo-propionitrile

To a stirred solution of the product of Procedure B (1.0 g) dissolved in 30 ml of ethanol was added 0.82 g of cyanoacetic acid 2,5-dioxo-pyrrolidin-l-yl ester and the resulting mixture stirred at room temperature for 2 h. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to dryness in vacuo, yielding 1.1 g (86%) of the title compound as a yellow foam. . LRMS:

313 (M + l).

Example 7 l - {(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4yl) -amino] -piperidin-l-yl) -ethanone

To a stirred solution of the product of Procedure B (0.03 grams, 0.114 mmol) dissolved in 5 ml of 10: 1 dichloromethane / pyridine was added (0.018 grams, 0.228 mmol) of acetyl chloride and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO₃). The organic layer was washed again with NaHCO₃ saturated, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane), yielding 0.005 g (15%) of the title compound as a colorless oil.

The title compounds of Examples 8-31 were prepared by a procedure analogous to that described in Example 7.

Example 8 (3R, 4R) - [1- (2-Aminoethanesulfonyl) -4-methylpiperidin-3-yl] methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 9 (3R, 4R) - (l-Etanosulfonyl-4-methylpiperidin-3-yl) -methyl62 (7Η-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 10 (3R, 4R) - [1- (Butane-l-sulfonyl) -4-methyl-piperidin-3-yl] methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 11

(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-l-carboxylic acid isobutyl ester

Example 12

N- (2- {(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] -piperidine-l-sulfonyl} -ethyl) propionamide

Example 13

(2 - {(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1sulfonyl} -ethyl) methyl ester - carbamic

Example 14

N- (2 - {(3R, 4R) -4-methyl-3 - [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] piperidine-1-sulfonyl} -ethyl) isobutyramide

Example 15 (3R, 4R) - (l-methanesulfonylpiperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 16 ((3R, 4R) -l-Etanosulfonylpiperidin-3-yl) -methyl- (7H63 pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 17 (3R, 4R) -Methyl- [1- (propane-1-sulfonyl) -piperidin-3-yl] (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 18 (3R, 4R) - [1- (Butane-1-sulfonyl) -piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 19

2,2-Dimethyl-N - ((3R, 4R) -2- &lt;4-methyl-3- [methyl- (7H10 pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1sulfonyl ) -ethyl) -propionamide

Example 20

(3 - {(3R, 4R) -4-methyl-3 [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin15 1-yl) tert-butyl ester -3-oxopropyl) -carbamic

Example 21

Methyl - [(3R-4R) -4-methyl-l- (propane-1-sulfonyl) -piperidin-3yl] - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

Example 22

0 3-Amino-1 - {(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] -piperidin-l-yl) -propan- canvas

Example 23

2-Methoxy-lf (3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] -piperidin-l-yl] -ethanone

Example 24

2-Dimethylamino-l - {(3R-4R) -4-methyl-3- [methyl- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} ethanone

Example 25

(3 - {(3R.4R) -4-methyl-3 [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-yl} - 3-oxopropyl) -carbamic

Example 26

3,3,3-Trifluoro-1 - ((3R, 4R) -4-methyl-3- [methyl- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl } propan-l-one

Example 27

N- (2 - {(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] -piperidin-l-yl} -2-oxo -ethyl) acetamide

Example 28

3-Ethoxy-1 - {(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -amino] -piperidin-l-yl} -propan- canvas

Example 29

(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methylamide

Example 30

(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-165 carboxylic acid diethylamide

Example 31 (3R, 4R) -Methyl- [4-methyl-l- (2-methylaminoethanesulfonyl) piperidin.-3-yl] - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine