Compositions containing pyrrolo 2,3-d pyrimidine derivatives

DescrfpUon .

Background of the Inventton [0001 ] Tha present invantion relates to pyrrolo[2,3-d]pyrímidine compounds whlch are inhibitors of pratein kinases, such as ttia anzyma Janus Kinasa 3 (harelnaftar alao raferred to as JAK3) and as such are usaful therapy as Immu-nosuppresslve agenta for organ transplanta, xeno translation, lupus, multiple sclerosis, rtieumatold arthritis, psorlasis,

Type I diabatas and oomplications from diabatas, cancar, asthma, atopic dermatrtis, autolmmuna thyrold dlsordere, ulceratlve colltls, Crohn'a disaase, Alzheimer’a dlsease, Leukamia and other Indications wtwre immunosuppression would be desirable, [0002] This invantlon also relates to a method of using such compounds in the treatment of the above indications In mammals, especially humans, and tbe phamaceutical compositions useful therefór.

[0003] JAK3 b a membar of the Janus family of proteln klnases. Although tha othar mambers of thls family are axpressad by essentially all tissuas, JAK3 axprasslon is limitad to hematopoetlc calls. Thla is consistent wilh its essantial rola in signaling thraugh the receptors for IL-2, IL-4, IL-7, IL-9 and IL-1S by non-covalant association of JAK3 witb the gamma chain common to thesa multichaln racaptora. XSCID patlent populations hava bean idantlflad wlth saverely reducad lavals of JAK3 protah or wlth genatic dafects to tha common gamma chain, suggestlng Ihat immunosuppras-sion should result from blocking slgnaling through the JAK3 pathway. Animal studias hava suggested that JAK3 not only plays a critkal role In B and T lymphocyta maturation, but that JAK3 is constitutivaly raquired to maintaln T call function. Modulation of immune aclivity through this noval meehanism can prove ueeful In the treatment of T cell pra-líferative disordars such as transplant rejection and autoimmuna disaasaa.

Summary of tha Invantlon [0004] The present invantion relatas to a compound of Iha lormula <img file="IS2173B_D0001.tif" /> w Uie pharmaceutically accaptable salt thereof; wharein

R’ ia a group of the formula <img file="IS2173B_D0002.tif" /> whereinyisO, 1 or2;

R⁴ Í8 selectad from tha group conslatlng of hydrogen, (C1-C6&gt;alky1. (C,-C6)alkylaulfonyl, (Cj-CgJalkanyl, (C2-C6) alkynyl wherein tha alkyl, alkanyl and alkynyl groupe are optionally subatituled by deuterium, hydroxy, amino, trifluor-omethyl, (C1-C4)alkoxy, (C^CgJacyloxy, (C, -Cg^lkylamino, ((C^CgJakyl^amino, cyano, nitro. (C^-Cgjalkanyt, (C2-CB) alkynyl or (C,-Cg)acylamino; or R⁴ la (Cj-C10)cycloalkyl wherein the cydoalkyl group is optlonally substituted by deu-tarium, hydrexy, amlno, trlfluoromalhyl, (C^CgJacyloxy, (Ci-Cgjalkylamino, (((^-Cgjalkylfeamlno, cyano, cyano(Ci-Cg) alkyl, trffluoromathyl^-CgJalkyl, nitro, nitrot^-Cglalkyl or (C^Cglacylamlno;

r5 |s pjparidlnyl subatltutad by ona to fiva carboxy, cyano, amlno, deuterium, hydraxy, (C_rC_e)aBcyl, (C^-Cgjalkoxy, halo, (Cf-Cejacyl, (C^CgJalkylamino, aminotC^CgJalkyl, (Cj-Cg^lkoxy-CO-NH, (C^gJalkylamino-CO-, (C₂-C₆)alka-nyl. (C₂-C_e) alkynyt, hydroxyíC^CgJalkyt, (CpCgblkoxy^-CgJalkyl, {^-CgJacyloxyfCpCglalkyt, nitro, cyano^-Cg) alkyl, hab(Ci-C_e)alkyl, nitrofCj-Cgialkyl, trffluoromethyl, trifluoramethyltCfCgJalkyl, (C^Cglacylamlno, (C₁-C_e)

<img file="IS2173B_D0003.tif" />

<img file="IS2173B_D0004.tif" />

acylamino(C₁-C_e)alkyl, (C₁-C_B)alkoxy(C₁-C₆)acylamino, aminofCpCgJacyl, amlno(C₁-C₆)acyl(C₁-C_B)alkyl, (C,-C_B) alkylainino(Cj-C_B)acyl, ((Cf-CgJalkyl^aminoCCpCgiacyl, R¹⁵R'⁸N-CO-O-, R^R^N-CO-tC^CgJalkyl, (C,-C6)alkyl-S (O)n, R¹⁵R¹⁸NS(O)m, R¹⁵R¹⁶NS(O)m (CvCgJalkyl, R¹⁵S(O)m R^1BN, Ri5S(O)mR’⁸N(C,-Ce)alkyl wherein m is 0,1 or 2 and R¹⁵ and R¹⁶ ara each indepandently selactad from hydragan or (C₁-C_B)alkyl; or a graup of the formula <img file="IS2173B_D0005.tif" /> whareinaisO, 1,2,3or4;

b, c, a, f and g are eaeh indapandantly 0 or 1;

d Í8 0,1,2,or3;

X is S(O)„ wherein n is 0,1 or2; oxygan, carbonyj or -C(=N-cyano)-,'

Y is S(O)_n whereln n ie 0,1 or 2; or cartwnyl; and

Z is carbonyl, C(O)O-, C(O)NR- or S(O)_n whsrein n is 0,1 or 2;

R⁶, R⁷, R⁸, R⁸, R¹⁰ and R¹¹ are aach Indapandently salected from the group consbting of hydrogen or (0,-Cg) alkyl optionally aubstltuted by deutarium, hydroxy, amino, trifluoromathyl, (Cf-Cgjacyloxy, (C, -C_B)alky1amino, ((C,-C_B) alkylfeamino, cyano, cyanolC^CgJalkyl, trffluoromethyl^-CgJalkyl, nitro, nltrolCj-CgJalkyl or (C_rCg)acylamino;

R^1Z b carboxy, cyano, amino, oxo, deutarium, hydroxy, trifluoromethyl, (C3-Ce)alkyl, Irifluoromethyl^-Cgjalkyl, (C,-CB)alkoxy, halo, (C^-C^cyl, (CrCg)alkylamino, ((C^CgJalkyt^ amino, amlno^-CgJalkyl, (C,-C6)alkoxy-CO-NH, (Cf-Cgíalkylamino-CO-, (Cg-Cgjalkenyl, (C2-CB) alkynyl, hydraxyíC^CjJalkyl, (C1-C6)alkoxy(C1-CB)alkyl, (C,-C6)acy-loxy(C1-CQ)alkyl, nltro, cyano(C1-Ce)alky1, halo(C3-Ce)alkyl, nltro(C1-Ce)alkyl. (CrCs)acylamlno, (C1-Ce)acylamino (C1-Ce)alkyf. (CrCglBkoxytCj-Cgiacylamino, amlnofC^jJacyl, amlnofCrCglacyltCj-Cglalkyl, (C^CgJalkylamino (Cf-Cglacyl, ((C1-C6)alkyl)2amino(Cl-CB)acyll R’⁸R¹⁸N-CO-O-, R’W’N-CO-^-CgJalkyl, R1SC(O)NH, R¹⁸OC(O) NH, R¹⁵NHC(O)NH, (C^lkyl-SÍO)^ (C^eJalkyl-SJOUCrCgíalkyl, R¹⁸R^lBNS(O)m, RiSRWNSIO^ (C,-C_B) alkyl, R¹⁸S(O)m R¹⁸N, R’⁶S(O)mR’⁸N(C1-CB)alkyl wttarein m is 0,1 or 2 and R¹⁵ and R¹⁸ are each indapandently sdected fram hydrogen or (CrC_B)alkyl;

R² Is hydrogan, halogen or (CfCgXilkyl; and

R³ b hydrogan.

[0005] Tba praaant Invantlon also relatas lo tha phamacautícally accaptabla acid addltlon salts of compounda of the formula I. Tha adds whlch are uæd to prepara tha phamacautically aœaptable acid addlHon salts of tha aföra-mentionad base compounds of thb Invention are ttiosa which form non-toxlc acid addition salts, Le., salts containing pharmacologically acceptable anlone, such as the hydrochlorida, hydrobromlda, hydrobdlde, nltrata, aulfate, blsulfate, phosphata, add phosphate, acatata, lactata, dtrata, add cttrate, tartrata, bltartrata, aucdnata, malaata, fumarate, glu-eonata, aaccharate, benzoate, mathanasulfbnata, ettianaaulfonata, banzenesulfonata, p-tduanesulfonata and pamo-ata fl.e.. 1,r-methylene-bis-(24iydroxy-3-naphthoate)]8alb.

[0006] The invanlion alao ralates to baaa addition saltsofformiila I. The chamical bases that may be used as raagants io prapare pharmaceutically acceptable base salts of those compounds of fbrmula I that are acidic in natura are thosa that form non-toxic base salb with such compounds. Such non-toxlc base salts Includa, but are not limited to thosa derived lirom such pharmacologically accaptable catlons such as alkali matal catkms (a.g., potassium and sodium) and alkaline aarth metal cattons [e.g., calclum and magnasium), ammonhim or watersolubla amina addition salts such as N-mathylglucamina-(meglumina), and tha lowar alkanolammonium and othar basa salts of pharmacautically accepta-bla organlc amlnaa.

0007] The term ’alkyl', as used harain, unlass otharwisa Indicated, Indudes saturated monovalent hydracarbon radicab having stralght or branched moieties or combinations tharaof.

[0008] Tha tarm 'alkoxy*. as used herein, indudes O-alkyl groups wtiareln 'alkyl* Is dafinad abova.

Tha tarm ’hakf, as uaad harein, unlass otherwlaa Indlcatad, Indudas fluoro, chloro, bremo or lodo.

0009] The compounds of thls InvanUan may contaln doubla bonds. Whan such bonds are prasent, tha compounds of tha invantion axlat aa cb and trans oonfigurationa and aa mixturas tharaof.

<img file="IS2173B_D0006.tif" />

[0010] Unless otherwise Indlcated, the alkyl and alkenyl groups referred to hareln, as well as the alkyl moiafles of other groups rafarred to herein (e.g., alkoxy), may ba llnaar or branched, and thay may also be cycllc (e.g., cydopropyl, cyclobutyl, cydopantyl, cydohaxyl or cydohaptyl) or ba llnearor branchad and contain cydlc moieties. Unleas oíharwiaa indicated, halogen indudes fluorine, chlorine, bramirw, and iodlna.

[0011] Compounds of formula (I) may be adminlstared in a pharmacautically acceptable form either alone or in combination with one or more addilional agants whlcb modulate a mammalian immune system or wrth antiinflammatory agants. These agents may induda but are not llmited to cydosporin A (e.g. Sandimmuna® or Neora®, rapamycin, FK-506 (tacralimus), leflunomide, deoxyspergualin, mycophanolate (a.g. Cellcept®), azathioprine (e.g. Imuran®), da-dizumab (e.g. Zenapax®. OKT3 (a.g. Qrthodona®), AtGam, asplrin, acataminophen, ibuprofen, naproxen, piroxicam, and antllnflammatory steioids (e.g. prednisdone or dexamathasone). Thesa agents may be administered as pait of the sama or separate dosage forms, via the same or dlffarant routes of adminlstratlon, and on the same or differant adminlstration schedules according to standard pharmaceutical practica.

[0012] The compounds of thls inventkm Indude all conformational laomera (e.g., ds and trans iaomera. Tha com-pounda of tha preaent Invention hava asymmatric cantars and therefbre exist in dlflarsnt enantiomaric and diastaiw-merlc fdrma. Thls Invention relatea to the use &lt;rf all optieal isomars and stereolsomara of the compounds of tha presant invention, and mixturea thareof, and to all pharmacautical compositions and mathods of treatment that may amploy or contaln them. In this ragard, the Invantlon indudas both the E and Z conflguratlons. The compounds of formula I may alao axist as tautomara. This invention relatas to tha usa of all such tautomars and mlxtures thereof.

[0013] This invention also encompassee pharmaœutlcal composltlons contalnlng pradrugs of compounds of tha formula I. Thls inventlon also ancompassaa methods of treatlng or preventing dlaordere that can be traated or prevented by tha Inhibition of protein klnaeae, such as tha anzyme Janue Klnase 3 comprising administaring prodrugs of compounds of the formula I. Compounds of formula I havlng fraa amlno, amldo, hydraxy or carboxylic groups can ba converted Into prodrugs. Prodruge Induda compounds wherein an amino add resldua, or a polypeptlds chaln of two dr more (e.g„ two, three or four) amino add rasidues which are covalantly Joined through peptide bonds to free amino, hydroxy arcarboxylic acld groups ofcompounds of formula I. The amino acid residues indude tha 20 naturally occurríng amino acids commonly deslgnatad by thrae latter symbds and also Indude, 4-hydroxyprollne, hydroxylysine, demo-sine, iaodemoslne, 3-mathylhistidlna, norvlin, bata-alanina, gamma-aminobutyrlc add, citnilline, homocysteine, homo-aerlne, omittiine and malhioine sulfone, Prodrugs also indude compounds wharein cartxxiates, carbamataa, amidas and alkyl astars which ara covalantly bonded to the abova subsUtuante of fbrmula I through the carbonyl carbon prodrug sidachain.

[0014] Preferred compounds of fbrmula I indude thoae wharein a is 0; b is 1; X is carbonyl; c is 0; d is 0; β Is 0; f ia 0; and g is 0.

[0010] Other preferred compounds of formula I indude thoae whereln a is 0; b la 1; X ia carbonyl; c ia 0; d is 1; e ia 0; f le 0, and g is 0.

[0010] Other prefarrad compounds of formula I indude those whereln a is 0; b is 1; X Is carbonyl; c is 1; d Is 0; β is 0; f Is 0; and g Is 0.

[0017] Other prefarred compounda of formula I indude those wharain a is 0; b is 1; X Is -C(=N=cyano)-; c is 1; d is 0;eis0;fia0;andgb0.

[0010] Oflier prefwred compounde of formula I indude thosa wherain a Is 0; b Is 0: c ia 0; d is 0; e is 0; f Is 0; g is 1; andZla-0(0)-0-.

[0010] Other prafarred compounda of formiila I Induda Ihose wharein a Is 0; b Is 1; X is S(O)„; n is 2; c is 0; d is 0; ela0;fia0;andgis0.

[0020] Other prefarred compounda of forrnula I induda thoaa wharein a is 0; b is 1; X is S(O)„; n Is 2; c Is 0; d ia 2; β 18 0; f is 1; g is 1; and Z la carbonyl.

[0021] Olhar prefwred compounds of fbrmula I induda those wharein a is 0; b Is 1; X Is S(O)„; n is 2; c Is 0; d b 2; eia0;fte1;andgi80.

[0022] Othar preferred compounds of formula I indude Ihose wherein a is 0; b Is 1; X is carbonyl; c is 1; d is 0; β is 1; Y Í8 S(O)_n; n Is 2; f Is 0; and g is 0.

[0023] Othar prefarred compounds of formula I induda those wherein a is 0; b Is 1; X is S(O)„; n is 2; c is 1; d is 0; eia0;fte0; andglsO.

[0024] Other preferred compounds of formula I indude those wherein a ia 1; b is 1; X Is carbonyl; e is 1; d is 0; β ia 0; f is 0; andgisO.

[0020] Othar preferred compounds of formula I induda those whereln a ia 0; b is 1; X ie SfO^; c la 0; d is 1; β is 1;

Y Is S(O)„; n Is 2; f is 0; and g is 0.

[0020] Other preferred compounda of formula I indude thoae wherein a Is 0; b Is 1; X is S(O)n; c ia 0; d is 1; e Is 1;

Y Is S[O)„; n is 2; f Is 1; and g isO.

[0027] Othar preferred compounds of formula I Indude those whareln a ia 0; b Is 1; X Is oxygen; c la 0; d is 1; β Is 1;

Y is S(O)n; n Is 2; f ia 1; and g ia 0.

inozDj utner preiarraa compounas of tormuia i inciuaa tnosa wnarein a is 0; b ia 1; x is oxygan; c is o; d is 1; a β 1; Y is S(O)_n; π is 2; f is 0; and g Is 0.

[0029] Other prefarrad compounds of formula I induda thosa wherain a is 0; b is 1; X is carbonyl; c is 1; d Is 1; e is 1; Y is S(O)_n; f is 0; and g is 0.

[0030] Other prefarred compounds of formula I include those whereln a is 0; b Is 1; X is carbonyl; c is 1; d is 1; e Is 1; Y Is S(O)„; n is 2; f ie 1; and g te 0.

[0031] Other prefarrad compounds of formula I induda those wharein R¹² is cyano, trifluoromathyl, (C₁-C₆)alkyl, trifluoromeOiyltCf-CeJalkyl, (Cq-Cgjalkylamino, ((C^CgJalkytfeamino, (C₂-C₆)alkynyl. cyano^-CgJalkyl, (CvCgjalkyl-S(O)_m whereh m ia 0,1 or 2.

[0032] Spacific prafarrad compounds of fbrmula I induda thosa wherein said compound is selactad fram tha graup coneisting oft

Mathyl-[4-methy1-1-(prapane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;

4-Methyl-3-[mathyl-{7H-pyrTOlo[2,3-d]pyrlmldln-4-yl)-amino]-plperidlne-1-carboxylic add methyl ester; 3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrralo[2,3-d|pyrimldln-4-yl)-amino]-piperidln-1-yl}-propan-1-one;

4-Mathyl-3-[mathyl-(7H-pyrTDlo[2,3-d]pyrimidln-4-yl)-Bmino]-piparidina-1-cartx)xyllc acld dlmettiylamlde; ({4-Methyl-3-[methyl-(7H-pyndo[2,3-d]pyrimidin-4-yl)-amino]-piparidine-1-carbonyl}-amino)-acatic add athyl as-tar;

3-{4-Methyl-3-[methyl-(7H-pyrrolo[2_l3-d]pyrimidin-4-yl)-anfiino]-piparldin-1-yl}-3-oxo-propionitrile;

3_I3_l3-TriBuoro-144-methyl-3-[methyl-(5-methyl-7H'pynolo[2,3-d]pyrimidin-4-yl)-amino]-piperidln-1-yl)-propan1-ona;

1-{4-Melhyl-3-[mathyl-(7H-pyrrolo[2,3-d]pyrimidln-4-yl)-amlno}-plparldln-1-yl}-but-3-yn-1-one; 1-{34(5-Chloro-7H-pyrrolo|2_l3-d]pyrimldln-4-yl)-methyl-amino]-4-inethyl-plpei1dln-1-ylJ-propan-1-one; 1-{3-Í(5-Fluoro-7H-pyrralo[2_l3-d]pyrirnidin-4-yl)-methyl-amino]-4-m0ttiyt-piper1dln-1-yl}-propan-1-ona; N-cyano-4-melhyl-3-[methyl-{7H-pyrTOlo[2_l34]pyrlmidln4-yl)-ainino]-N^,-prapyl-plperldlne-1 -carboxamidine; and N-cyan»4,N',N^,-Triniathyl-3-[methyl-(7H-pyrrolop,3-d]pyrinnidln-4-yl)-amlno]-plpertdina-1-carboxamidina.

[0033] Tha present Invantlon also ralatae to a pharmacautlcal composltlon for (a) treating or preventlng a diswdar or condition selected firom organ transplant rejedbn, xeno transplation, lupus, mdtlpla scbrosis, rtieumatoid arthritis, psoriasis, Type I diabetes and complicatlons from diabetes, cancer, asttima, atopb darrnatitia, autoimmune thyrob disordars, ulcaratlva colltb, Crohn's diseasa, Alzheimar's disaasa, Leukamia, and other autoimmune disaasas or (b) ttia inhlbitíon of protein kinasas or Janus Kinase 3 (JAK3) In a mammal, Indudlng a human, comprislng an amount of a compound of formula I or a phannaceuOcally accaptabla salt tharaof, affactive In auch disordara or conditions and a phamnacauticaly accaptabla carrter.

[0034] Ήιβ present Invantion also ralates to a mathod for tha Inhlbttbn of protain typrosina kinasas or Janua Kinaae 3 (JAK3) In a mammal, bduding a human, comprialng admbilstaring to said mammal an affactlva amount of a compound of formula I or a pharmaceutloally accaptabla satt thareof.

[0030] Ήιβ present Inventlon also ralatas to a method Ibr treating or preventlng a disordar or condlUon selected from organ transplant rejacUon, xeno transplatbn, lupus, muKlpb sdarosis, rtiaumatoid arttiritis, psoriasla, Type I dlabetaa and oompHcatkn» from dlabetas, cancer, asthma, atopic darmatftis, autoimmune thyrold dbordare, ulcarative cdltia, Crahn's diseaae, Alzheimer'a diseaee, Leukamla, and other autoimmuna diaaasas in a mammal, Induding a human, compriaing adminlataring to said mammal an amount of a compound of formula I or a pharmaceutlcally acceptable salt theraof, affactlva in treatlng eudi a condltbn.

Detailed Descriptbn of the Invanttan [0030] The following reactlon Sdiames illuatrata tha praparation of the compounds of the present Inventlon. Unless otherwiM indlcatad R^z, R³, R⁴ and R^s in the reactlon Sdiamas and Ihe dlscussbn that fellow ara daflnad as abova,

PREPARATIONA [003η <img file="IS2173B_D0007.tif" />

<img file="IS2173B_D0008.tif" />

<img file="IS2173B_D0009.tif" />

<img file="IS2173B_D0010.tif" />

SCHEME3 <img file="IS2173B_D0011.tif" /> [0038] In reaction 1 of Preparation A, Iha 4-ctiloropyrrolo[2,3-d]pyrimldine compound of formula XXI, whareln R is hydrogen or a protectlng group such as benzaneaulfónyl or banzyl, is convarted to tha 4-chloro-5-halopyrrolo[2,3-d] pyrlmidlne compound of formula XX, whareln Y ia chloro, bromo or iodo, by reacting XXI wrth N-chloroauccinimide, N-bramoauccinimide or N-iodosucdnimide. Iha raaction mixture is heated to reflux, in chloroform, for a trma pertod be-twaen about 1 hour to about 3 hours, preferably about 1 hour.

[0038] In reacUon 2 of Praparation A, the 4-cblora-5-halopyrra)o[2,3-d]pyrimidina compound of formula XX, wharein R is hydrogan, ta convartad lo tha eorreapondlng compound of formula XIX, wherein R² is (C-,-C_e)alkyl, by traatlng XX with N-butyHlttilum, at a temperature of about -78°C, and raacting the dianion intermadiata so formad wlth an alkylhal ide at a temparature between about -78°C to room temparature, preferably room temperature.

[0040] InreactionlofSchamatthe4-chlorapyrrolo[2,34]pyrinnldinBcornpoundofformulaXVIIi8CX3nvertadtolhe correapondlng compound of formula XVI, wherein R la benzenesuHbnyl or banzyl, by treatlng XVII witti banzanasulfonyl chlorlde, benzylchlortde or benzylbromlde In tha presence of a base, such as sodlum hydride or potasaium cartjonate, and a polar aprotio solvent, such as dimethylformamide or tetrahydrafuran. Tha reaction mixlure Is stirred at a temperature betwaen about 0’C to about 70°C, prefarably aboul 30’C, for a tlme period between about 1 hour (o about 3 hours, preferably about 2 houre.

[0041] In reaction 2 of Scheme the 4-chloropyrrolo[2,3-d]pyrimidina compound of fórmula XVI Is convartad to the correapondlng 4-aminopyrroto[2,3-d]pyrimldina compound of fomula XV by coupling XVI wlth an amine of the formula HNR*R^e. The reactlon Is carried out in an alcohol solvant, auch as tert-butanol, mathanol or ethanol, or other high boiling organic solvants, auch as dimethytfornamlde, triethylamlne, 1,4-dtoxane or 1,2-dichloroethana, at a tampara-

<img file="IS2173B_D0012.tif" />

ture between about 60°C to aboul 120°C, preferably about 80°C. Typical raaciion times ara beiween about 2 hours to about 48 hours, preferably about 16 hours. When R³ Is a nrtrogen containing heterocydoalkyl graup, each nitrogen must be protected by a protecting group, such a benzyl. Removal of the R⁵ protecting graup Is carried out under cortditions appropríate for that particular protacting group in use which will not affect the R protecting group on the pyrrolo[2,3-d]pyrimidlne ring. Ramoval of iha R⁵ pretading group, when banzyl, Is carried out in an alcohol solvant, auch as ethanol, in tha presant of hydragen and a catalyst, such as palladlum hydroxkJa on carbon. The R⁵ nltrogen containing hatrocycloalkyl group so formad may ba furthar raactad with a variaty of dlfferent elactrophiles of förmula II. For urea formatton, electraphHas of formula II such as fsocyanates, carbamates and carbamoyl chloridea are reacted wltti tha R⁵ nltrogen of the hetarealkyl group h a eolvent, such as acetonitrila or dimathylformamide, in the presanca of a base, such aa sodium or potasalum carbonata, at a temperature batwaan about 20°C to about 100 ’C fbr a tlma pariod batween about 24 hours I» about 72 houre. Foramide and sulfonamlda formatlon, electrophiles of formula II, such aa acylchlorides and eulfonyl chtoridae, are raacled with the R⁵ nilrogan of tha hetaroalkyl graup In a solvant such as methylana chlorlde In tha presanca of a basa such as pyridlne at ambiant temperaturea for a time period between about 12 hours to about 24 hours. Amide formation may also be carried out by raading a carboxylic acid with the hateroalkyl group In the presenca of a carbodllmkle such as 1-(3-dimethylaminppropyl&gt;-3-alhylcarbodiimide In a solvent such as methylene chloride at amblent temperaturas for 12-24 hours. For alkyl formatlon, alectraphiles of fbrmula II, such as ο,β-unsaturated amides, aclds, nitriles, esters, and α-halo amides, are reacted with tha R⁵ nitrogan of the hetaroalkyl group in a solvant such as methanol at ambient temperatures fbr a time period between about 12 houra to about 1B hours. Alkyl formatton may also ba carriad out by reacting aldahydes with the heteroalkyl group in the presanca of a reduclng agant, such as sodium cyanoborohydride, In a solvent, such as methanol, at ambient temperature fbr a time period between about 12 houra to about 18 houre.

[0042] In reactlon 3 of Scheme 1, removal of the protecting group from the compound of fbrmula XV, wheraln R is benzenesulfonyl, to glve tha oorresponding compound of formula I, Is carried out by treating XV with an alkali basa, such ae sodium hydroxide or potasslum hydroxide, in an alcohol solvent, such as maOianol or ethanol, or mixed sol-vants, such as alcohd/tetrahydrofuran or alcohol/water. The reaction la carriad out at room temparature for a llma period between about 15 mlnutes to about 1 hour, praferably 30 mlnutas. Removal of the protecting group fram the compound crf formula XV, whereln R le benzyl, is conducted by traatlng XV with sodlum In ammonia at a tamperature of about -78°C fbr a tlme perbd befwean about 15 mlnufas to about 1 hour.

[0043] In raaction 1 of Schame 2, tha 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XX is convarted to tha corresponding 4-aminopyrrolo[2,3&lt;l]pyrimldine compound of formula XXIV, according to the procedure described above in reaction 2 of Scheme 1.

[0044] In raaction 1 of Scheme 3, tha compound of formula XVII Is convartad to tha corresponding compound of formula I, aeeordlng to Iha procedura daacribad above in raaction 2 of Sdieme 1.

[0045] The compounds of the present Invantlon that ara baslc ln natura are capable of formlng a wide varlety of different aalts wrth varioue inorganlc and organlc adds. Although such salts must be pharmacautically acceptabla for adminletratlon to anlmals, It is often deslrable in practice to inltlally Isolata the compound of tha present Invantlon from tha reacflon mbdure as a pharmacaulically unaccaptable salt and then simply convart tha latter back to Oia free base compound by treatmerrt with an alkallna reagent and subsaquenlly converl the lattar free base to a pfiarmacautically accaptable acld addltlon satt. The acid addition salts of tha basa compounds of thia Invention are readlly prepared by traatlng tha base compound with a substantially aquhzalant amount of the chosen mlneral or organic acld in an aqueous aolvant madlum or In a suitabla organlc solvant, auch as methanol or elhanol. Upon careful avaporation of the solvent, tha daalred solid salt la readlly obtalned. Tha deslred acid sall can also be precipítated from a solution of the free base in an organic solvent by addlng to the solutlon an apprapriata mlnaral or organic acid.

[0048] Thosa compounds of tha preaant Inventlon that are acidic in nature, are capable of forming baae salts wilh various pharmacologically acceptable cattons. Examplaa of auch salts feidude tha alkall melal or alkalina-aarth matal salts and particulariy, the sodium and potassium salts. These salts are all prepared by convantional techniques. The chamleal baaes which are used as reagante to prepare the pharmaceutically acceptable basa salts of this invantion are those whlch fbrm non-toxic base salts with tha acidio eompounds of tha preaant Inventlon. Sush non-toxic base salts Indude ttiose darived from such pharmacologlcally aeeeplable catkxis aa aodium, potaaelum caldum and mag-neslum, etc. Thasa satts can easlly be prepared by treating tha correspondlng acidic compounde wlth an aqueous solution contalnlng the desired pharmacdoglcally acceptabla catlons, and then evaporating tha resultlng solutlon to drynass, preferably under reducad pressure. Altematlvely, thay may also ba prepared by mlxlng lowar alkanolic solutions of the acidlc compounda and tha deaired alkall malal alkoxlde togaOiar, and then avaporating tha raaulting solution to drynesa in Ihe aama mannar as bafbre. In eKhar case, stoichlonnetric quantHlas of reagants are prefarably amployed In order to ansura completaness of readion and maxknum ylalds of the deslred final product.

[0047] The eompositlons of the preaant invantion may ba fbrmulated In a conventional manner using ona or more pharmaceutically accaptabla carrlers. Thus, Oia actlva compounds of tha invantion may be formulated fororal, buccal, intranasal, parentaral (e.g„ intravanoue, Intramuscular or aubcutanaous) or rectal administratlon or in a form suitable for adminístration by inhalalion or insufflation. The active compounds of The invention may also ba formulated Ibr sus-tainad delivary.

[0048] For oral admlnlatratlon, tha pharmacautlcal compositions may take the form of, for exampla, tablats or cap-sulas prepared by convantional means wtth pharmaceutlcally acceptable excipients such as binding agents (e.g., pregalatinized maiza starch, polyvinylpyrrolidone or hydroxypropyl mathylcallulosa); ffflers (a.g., lactose, microcryslal-line callulosa or calcium phosphate); lubrícants (e.g., magnasium staarata, talc or silica); disintegrants (e.g., potato starch or sodium alarch glycolata); or watting agants (e.g., sodium lauryl sulphate). The tablats may be coated by mattiods wall known in the art. Liquid preparations fororal admlnlstratlon may laka tha Ibm of, fbr example, aolutiona, symps or suspanslons, or they may be preaantad as a dry product for consUtution with watar or other suitable vehiele bafora usa. Sudi llquld preparatlons may be prepared by convantlonal maans wlth pharmacautlcally accaptable ad-dltives auch as suspanding agents (e.g., sorbitol syrup, mathyl cellulose or hydrogenatad edible fata); amulslfying agents (e.g., lecithin or acacia); non-aqueoua vahidas (e.g., almond oil, oily esters or ethyl alcohol); and presarvativea (e.g„ mathyl or propyl p-hydroxybenzoatas or sorbic add).

[0049] For buccal administration, the compoaition maytake the fbrm oftablets or lozengaa formulated in convantional mannar.

[0050] The activa compounds of the invantion may be fbrmulatad fbr paranteral admlnistration by injectlon, including uslng convantlonal cathatarlzation tachniquas or infusion. Formulattona for injadlon may ba presanted in unit dosage form, e.g., in ampules or in multi-dose containars, with an addad praaarvatlva. The compositions may take auch forms as susperwlora, solutlons or emulstons In oily or aqueous vehidas, and may contain formulating agants such as eus-pendlng, stabillzlng and/or disperalng agents. Altematively, tha active ingredient may ba in powder fomn for reconstitution with a suitable wehide, e.g., aterlle pyrogen-free watar, before usa.

[0051] Tha active compounds of the inventton may alao be formulated In redal compositjons auch as suppositoriea of ratantion anemas, a.q., contalning conventlonal suppoeltory baaaa auch as cocoa butter or othar glycarídes. [0052] For Intranaeal administration or admlnistratlon by Inhalatlon, tha acth/a compounds of tha InvenUon ara con-venlenUy delivered In tha form of a solution or suspension from a pump spray containar that is squeazed or pumped by the paUant or as an aerosol spray presantation from a prassurized container or a nabulizer, with tha use of a suitable propellant, e.g.. dichlorodifluoromethane, trichlorofluoromethana, dlchlorototrafluoFoeOiane, carbon dioxida or other suitable gaa. In tha caaa of a presaurtzad aarosol, tha dosaga unlt may ba datarminad by providing a valva to dallvar a metarad amount. The pressurizad contalnar or nabullzar may oantain a solulion or suspansion of tha adiva compound. Capeulea and cartridges (mada, for axampla, from gelatln) for uee In an inhalar or inaufflator may be formulated contalnlng a powder mlx of a compound of the InvanUon and a auitabla powdar basa such aa lactosa or starch. [0053] A prapoead dosa of tha activa compounds of tha Invention for oral, parantaral or buccal adminlstration to tha avaraga adult human for tha treatmant of the oondKlons rafarred to abova (e.g., rheumatold arthrltis) Is 0.1 to 1000 mg of tha active ingredlant per untt dose which could be admlnlatered, fbr axampla, 1 to 4 tlmaa per day.

[0054] Aaroaol formulations for trealment of the condltfona refarred to above (a.g., asthma) in tha avarage adult human ara prefarably arranged ao that each materad don or "puff* of aerosd contalns 20 pg to 1000 pg of tha compound of the Invenllon. Tha ovarall daily doaa wlth an aarosd wlll be wfthln tha range 0.1 mg to 1000 mg. Administration may be aaveral ttnea daly, for axampte 2,3,4 or 8 times, glvlng for exampla, 1,2 or 3 doses aach tima.

[0053] A compound offormula (I) administered In a pharmaceutically accaptable form elther alone or In combination with one or more addltional agants whlch modulata a mammlian immune systam or wlth antiinflammatory agents, agents which may include but are not llmitad to cydosporin A (a.g. Sandimmuna® or NaoraHS, rapamycin, FK-506 (taerolimus), laflunomide, daoxyspargualin, mycophandate (e.g. Cdlcapl®, azathioprina (e.g. Imuran®), dadizumab (a.g. Zanapax®), OKT3 (a.g. Orthocdone®), AtGam, asplrín, acctaminophen, ibuprofen, naproxan, plroxicam, and antHnflmmatory etarolde (e.g. predntedone or dexamethasona); and such agenls may be admlnletarad aa part of the sama or separata dosaga forms, vla Oia sama or dlflarent rautee of adminlstration, and on tha sama or different ad-mlnistratlon echedules accordlng to etandard pharmaceutical pradice.

[0050] FK506 (Tacrolimus) Is givan orally at 0.10-0.15 mg/kg body weight, every 12 hours, within first 45 hours post-oparatlve. Does ie monitored by sanim Tacrolimus trough levels.

10057] Cydosporfn A (Sand immuna oral or intravenous formulatlon, or Neoral®, oral solutlon or capsules) is glven orally at 5 mg/kg body weight, avery 12 houra withln 48 houra postoparatlva. Dose Ia monitored by blood Cyclosporln Atraugh levala.

[0058] The activa agents can be formulated tor suetalned dallvary accordlng to methode wall known to thosa of ordlnary aklll In the art. Examplaa of auch fbrmulations can ba found fn Unitad Statas Patants 3,538,214,4,060,598, 4,173,626,3,119,742, and 3,492,397.

[0059] Tha abllity of the compounds of formula I or thair pharmaceuticaHy accaptabla saHs to inhiblt Janus Kinasa 3 and, coneequently, demonatrete thair affactlvenass för treating dtaordere or conditions characterlzed by Janus Kinasa 3 Is shown by tha fdlowing In vltro aasay tests.

BiolOflical Aasay

JAK3 (JH1:GST) Enzymatic Aasay [0060] Tha JAK3 kinaae assay utilizes a protaln axpreased in baculovirus-infeclad SF9 cells (a fusion protain of GST and thacalalylicdomain of human JAK3) purifiad by afflnity ohromatography on glutathiona-Sapaharosa. The aubstrata fbr tha raactlon is pdy-Glutamic add-Tyrosíne (PGT (4:1), Sigma catalog # P0275), coatsd onto Nunc Maxi Sorp plates at 100 pg/ml ovemight at 37’C. Tha moming after coatlng, the platas are washad three times and JAK3 Is added to tha walls contalning 100 μί of kinasa buffer (50 mM HEPES, pH 7.3,125 mM NaCI, 24 mM MgCI2)+ 0.2 uM ATP +1 mM Na orthovanadata.) Tha reactlon procaada fbr 30 minutea at room tamperatura and tha plates Is washed threa more tlmas. The level of phosphorylatad tyrosina in a givan well is quantltatad by standard ELISA assay utilizing an anti-phosphotyroslna antibody (ICN PY20, cat. #69-151-1).

Inhibition of Human IL-2 Depandent T-Cell Blasl ProllferaUon [0061] Thls screen meaauras the inhibltory affaet of compounds on IL-2 dependant T-Cell blast prollferation In vllro. Sinca signaling through Ihe IL-2 receptor raquire8 JAK-3, cell actlve inhlbítors of JAK-3 ahould inhibil IL-2 dapandant T-CeU blast prollfaration.

[0062] Ttie cella for thla assay are isdatad from fresh human blood. Aftar aaparaUon of the mononuclaar cells uslng Accuapin Syalem-Histopaque-1077 (Sigma # A7054), primary human T-Cdle are leolatad by negaOva salactkxi uslng Lympho-Kwik T (One Lambda, Inc., Cat # LK-50T). T-Cells are culturad at 1-2 x 10®/ml ln Madla (RPMI * 10% haat-Inactivatad ffetal calf serum (Hyclona Cat # A-1111-L) +1% PenldlHn/Streptomydn (Gibco)) and induca to proliferata by tha addition of 10ug/ml PHA (Murex Diagnostk», Cat # HA16). Aftar 3 daya at 37°C In 5% CO₂, calls ara washed 3 flmas in Media, rasuapandad to a denaity of 1-2 x 10® cells/ml ln Medla plua 100 Unlts/ml of human recomblnant IL-2 (R&amp;D Systams, Cat # 202-IL). After 1 waek tha calla are IL-2 dapandant and can ba malntained fbr up to 3 weeks by feadlng twice weekly wtth equal volumea of Madia +100 Unlte/ml of IL-2.

[0063] To aaaay fbr a tast compounda ability to inniblt IL-2 dapenderrt T-Cdl prdlfarabon, IL-2 dapandent cells ara washad 3 timaa, resuspendad In madta and than plated (50,000 cella/wall/O.I ml) in a Flat-bottom 96-wall microlitar plata (Falcon # 353075). Fram a10 mM atock of teat compound In DMSO, sartal 2-fold dlutlons of compound are addad In triplicata wells atarting at 10 uM. After ona hour, 10 Unlla/ml of IL-2 ia added (o aach tast wall. Plates are then incubatad at 37°C, 5% CO₂ for 72 hours. Platas ara than pulsad wlth ’H-thymldlne (0.5 uCI/wall) (NEN Cat # NET-027A), and incubatad an addilional 18 hours. Culture platas are than harvastad wlth a 96-wall plala harvastar and tha amount of ³H-thymidina mcorporatad Into prdífarallng ceHs Is datermlned by counting on a Packard Top Count acin-tlllation counter. Data la analyzad by plotting tha % inhlbition of prolifaration varaas the concentratlon of taet compound. An ICjo value (uM) ia detaimkiad from ihla plot.

[0064] Tha föllowing Examplas llluBlrate tha praparation of the compounds of tha preaent Invantion but it ia not llmitad to the dataHa thareof. Malting polnts are uncorrected. NMR data are reportad In parts per mllllon (S) and are referenced to tha deutarium lock aignal from tha sample aolvanl (dauteriochlorofbrm unlraa otharwiaa spedfiad). Commerdal reaganta were uflllzed wtthout furthar purificatlon. TH F refars to tatrahydrofuran. DMF refare to N .N-dlmathylformamide. Low Resdution Maaa Spactra (LRMS) were racorded on elthar a Hawlatt Packard 5989®, utllizlng chamical ionizaOon (ammonbm), or a Flsona (or Micro Mass) Atmoepharic Prassura Chamlcal lonlzation (APCI) platform which uaaa a 50/50 mlxlure of acetonitrila/water wtth 0.1% fbrmlc add as tha lonlzlng agant Room or amblant tamparature refers to20-25°C.

Exampla 1

144-Methyl-3-[maHiyl-(7H-pyiTolo[2,3-dlpyriinldln-4-yl)-amlno]-pipflrtdln-1.vP-ethanona

HethodA (1-Bantyl-4-mathyl-plparidln-3-yl)-methy1-amlne [0065] To a stirred solutlon of 1-banzyl-4-mathyl-plperidln-3-one (2.3 grama, 11.5 mmol), prapared by tha methods of lorfo, Μ A. and Damla, G., Tetrahadran, 26,5519 (1970) and Griaco at ak, Joumal of the Araarican Chamlcal Sodaty, 107,1768 (1985), (modlflad uslng 5% malhanol as a co-solvant), botti rafarencaa are Incorporatad by referance in ttiak antlrety, dlaadved in 23 mL of 2 M mathylamlna In tatrahydroftiran was addad 1.4 mL (23 mmol) of acetic add and the resulting mlxture atirred In a aealed tube fbr 18 houra at room tamperature. Triacatoxy sodium borohydrida (4.9 grema. 23 mmol) was addad and the naw mfxturs allrrad at raom tamparature in a saalad tuba fbr 24 h, at wtilch time, the reaction was quenched upon addition of 1 N sodium hydroxida (50 mL). The raaction mixture was then extractad 3 x 80 mL with ether, tha combined ather layera dríed over sodium sulfate (Na₂SO₄) and concentrated to dryneas In vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1).

Mathod B (1-Benzyl-4-methyl-plparidln-3-yl)-niBthyl-(7H-pyrrolo[2,3-d]pyrlmldln-4-yl)-amliw [0066] A solution of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams, 15.9 mmol), prepared by the method of Davoll, J. Am. Chem. Soc., 82,131 (1960), which is incorporatad by refaranca in Ita entiraty, and tha product from Method A (1.7 grams, 7.95 mmol) dlssolvad In 2 aquivalants of triathylamina was heated In a aaaled tube at 100 °C for 3 daya. Following cooling to room temparatura and concantration under reduced preesure, the resldua waa purffled by flash chromatography (silica; 3% methanol In dichloromethana) affordlng 1.3 grams (50%) of tha title compound as a color-laaa o9. LRMS: 336.1 (M+1).

MethodC

Methyl-(4-methyl-plperidln-3-yl)-(7H-pyrrolo[2,3-d]pyi1mÍdln-4-yl)-amlne [0067] To the product from Method B (0.7 grams, 2.19 mmol) dissolved in 15 mL of eOianol was added 1.5 mL of 2 N hydrochlorie add and the reaction mixture degassed by nitrogan purge. To the raaction mixture was then added 0.5 grams of 20% palladium hydroxlde on carbon (50% water) (Aldrich) and tha resulting mlxture ahaken (Parr-Shaker) undar a 50 psi atmosphara of hydrogan at room tamparatura fbr 2 days. The Celíte filtared reaction mixlure was con-cantrated to dryneas in vacuo and the residua purlflad by tlaah chramatography (ailica; 5% melhanol In dichoromethane) affordlng 0.48 grama (90%) of the title oompound. LRMS: 246.1 (M+1).

MethodD

1-(4-MBthyl-3-[methyl-[7H-pyiTolo[2,3-d]pyrlinldln-4-yl)-amlnol-plparldln-1-yQ-ethanone [0068] To a atirred aolution of the product from Method C (0.03 grams, 0.114 mmol) diaaolved in 5 mL of 10:1 dichlo-romethane/pyridlna was addad (0.018 grams, 0.228 mmol) of acatylchlorida and the resulting mixture stlrred at room tamperature fbr 18 houra. Tha reaction mlxture was than partltionad batwwn dichloremathana and aaturated sodium blcarbonata (NaHCO₃). The organlc layar waa washad again with aaturaled NaHCO₃, dried over sodium sulfate and concantrated to dryneaa In vacuo. Tha resldue was purified by preparatwe thin layer chromatography (PTLC) (silica; 4% mathanol In dtehloromethane) affordlng 0.005 mg (15%) of the title compound aa a cotoriBae oil. LRMS: 288.1 (M+1). [0008] The title compounda for axamptaa 2-26 wara prepared by a mathod analogoua to that described in Example 1.

Example 2 [1-(2-Anilno-ettianeaulfdnyl)-4-methyl-plperidln-3-yl]-ni8thyl-f7H-pyrrolo[2,3-d]pyrimldln-4-yl)-amlne [0070] [1-(2-Amlno-ethane8ulfonyl)-4-melhyl-piperidin-3-yl]-methyl-amine. LRMS: 353.

Exampla 3 (1-Ethane8Ulfonyl-4-m8thyl-plperldln-3-yl)methyl-(7H-pyiTOlo[2,3-d]pyi1nildln-4-y1)-ainlne [0071] (1-E0ianasulfbnyl-4-malhyl-plperidin-3-yl)-melhyl-aniina. LRMS: 338.

Exampla4 [1-(Butane-1-auHbnyl)4-niethyl-plperidln-3-yl]-ffletbyl-(7H-pyrrolo[2,3-d]pyrlmldln-4-yl)-amlnB [0072] [1-(ButanM-sul1bnyl)4-mattiyl-piparidin-3-yl]-inettiyl-amlne. LRMS: 366.

Example 5

4-MBthyl-3-[iii9thyl-(7H-pyrrolo[2,3-&lt;l]pyrlmldin-4-yl)-anilno]-plparMlnB-1-carboxyllc add Isobutyl Mtar [0073] 4-Methy73-mathylainino-piperidlne-1-carboxylic acid isobulyl aster. LRMS: 346.

Example 0

N-(2-(4-MBthy1-3-[niethyH7H-pyiTolo[2,3-d]pyrlmldlii-4-yl)-arwlno]-plperidlne-1-8ulfonyl}-ethyl)-proplonamlde [0074] N-[2-(4-Methyl-3-methylaminO‘piperidine-1-sulfonyl)-eUiyl]-propionamide. LRMS: 409.

Example 7 (2-{4-M9thyl-3-(methyl-(7H-pyrrolo[2.3-d]pyr1mldln-4-yl)-ainlno]-plparidlna-1-Bulfonyl)-ethyl)-carbamlc acld methylBBtar [0075] [2-(4-Methyl-3-methylarnino-piperldlnB-1-sulfonyl)-ethyl]-carbamic aeid mathyl aster. LRMS: 411.

Example 8

N-(2-{4-MBthyl-3-(mBthy1-(7H-pyrrolo[2,3-dlpyrlmldln-4-vl)-amlno1-plperldlne-1-aulfonvO-e1hyl)-lBobutyramld8 [0076] N-[2-(4-Mettiyl-3-methylamino-plparidine-1-sulfonyl)-ethyl]-i8obutyramida. LRMS: 423.

Example 9 (1-Metbane«ulfonyl-plpBridln-3-yl)-mBtby1-(7H-pyrrolot2.3-d]pyrlmldln4-yl)-amlne [0077] (1-Methanasulfonyl-piperidin-3-yl)-methyl-amlne. LRMS: 310.

Example 10 |1-Ethan«ttilfonyl-plper1dln-3-yl)-ffiBthy1-(7H-pyrrolo[2,3-d]pyrlmldln-4-yl)-amln8 [0078] (1-ElhanesuHbnyl-plparidin-3-yl)-methyl-amine. LRMS: 324.

Example11

Methyl-[1-&lt;propBnB-1-Bulf6nyl)-Plperldln-3-ytH7H-pyrn&gt;lo[2,3-dlpyrlmldln-4-v1)-atnin8 [0070] (1-PrapylsuNiDnyl-piperMln-3-yl)-niethyl-amlne. LRMS: 335.

Example 12 [1-tBirtane-1-Bulfonyl)-plper1dln-3-yl]-mBthvl-(7H-pvrn)lo[2.3-d)pyrlmldln-4-y1)-amlne [0080] (1-Butyl8ulfonyl-plperidln-3-yl)-mathyl-amlne. LRMS: 352.

E«ampl« 13

2,2-DlmBthyl-N-(2-&lt;44nathyl-3-[m8thyl-(7H-pyrrolo[2.3-d]pyrlnildln-4-yl)-ainlno]-plperidin8-1-aulfonyl}-ethyl)proplonamlde [0081] 2,2-Dirnethyl-N-[2-(4-methyl-3-methylamino-piperidine-1-5ulfonyl)-ethyl]-prapionamida. LRMS: 437.

Example 14

3-{4-MBthyl-3-[inathyl-(7H-pynolo[2,3-d]pyi1mldln4-yl)ainlno]-plpBridln-1-yl)-3-oxo-proplonltflle [0082] 3-(4-Methyl-3-methylamlno-pjparidin-1 -yl)-3-oxo-propionitrila. LRMS: 313.

Example 15 (3-(4-Methyl-3-{mathyl-(7H-pynrolo[2,3-d]pyi1mldln4-yl)-amlno]-plp8fídin-1 -yl)-3-oxo-propyl)-cartoamle acld tart-butyl eatar [0083] [3-(4-Malhyl-3-methylamlno-pipBrldin-1-yl]-3-oxo-pn]pyl]-cart&gt;amlc acld tert-butyl ester. LRMS; 417.

Example 16

Mrthyl44-mathyl-1-(proparw-1-gulfonyl)-p&lt;pafÍdln-3-yl]-(7H-pyrrolo[2,3-d]pyrimldln4-yl)-amlnB [0084] Mathyl-[4-mathyH -(propana-1 -sulfbnyl)-piperidin-3-yl]-amine. LRM5:352.

Example 17

3-Amlno-H4-methyl-3-[mettiyl-(7H-pyrrolo[2.3Hapyrlmldln4-yl)-aiwlno]-plperidln-1-ylÍ-propan-1-ona [0085] 3-Amino-1-(4-metliyl-3-rTiethylamino-piperidin-1-yl&gt;propan-1-ona. LRMS: 317.

Example 18

2-Methoxy-1-(4-nwthyl-3-1mBthyl-(7H-pyrro1o[2,3-d1pyrlmldln4-v1)-amlno]-plperidln-1-yQ-athanon8 [0086] 2-Methoxy-1 -(4-methyl-3-methylamino-piperidin-1 -yl)-ethanone. LRMS: 318.

Exampla 18

2-Plmethylamlno-144-mathyl-3-[mathyl-(7H-pynro)oP,3-d]pyrlmldln4-yl)-amlno]-plpefldln-1-yl}-ethanone [0087] 2-Dlmathylaniino-1-(4-niethyl-3-methylamino-pipai1din-1-yl}-Bthanona. LRMS: 331.

Exampla 20 (3-{4-Methyl-3-{methyl-(7H-pyrrolo[2.3-d]pyr1mldln4-yl)-amlno]-plperidln-1-yl)-3-oxo-propyl)-carbanilc acld tert-buty I aster [0088] [3-(4-Methyl-3-methylarr8no-piparldln-1-yl]-3-oxo-prapyl]-carbamic acid tert-butyl aster. LRMS: 417.

Exampla 21

3,3,3-THfluoro-1-{4-methyl-34inettiyl-(7H-pyrTOlo[2,3-dlpyrlmldln4^yl)-ainlno]-plpei1dln-1-y&lt;}-propan-1-one [0088] 3,3,3-Trifluoro-1-(4-mathyl-3-inathylamino-plparldln-1-yl)-prepan-1-one.

Example22

N-{2-{4-Mettiy1-3-[inethy1-(7H-pyrTolo[2,3-d]pyr1mldln4-yl)-anilno]-plpar1din-1-yl)-2-oxo-ethyl)-acatamlda [0090] N-[2-(4-Me1hyl-3-mathylamlno-plparidln-1-yl)-2-oxo-athyq-acatamlda. LRMS: 345.

Exarnpte 23

3- Ethoxy-1-{4.melhyl-3-[methyl-(7H-pyrrolo[2,3-d1pyrimldln-4-yl)-amlno]-plparidln-1-yl}-prepan-1-ona [0091] 3-Ethaxy-1-(4-methyl-3-mattiylamino-piperidin-1-yl}-propan-1-one. LRMS:346.

Example 24

4- Methyl-3-lmethyH7H-pyrTOlo[2,3-d1pyrlmldln-4-yl)-amino]-plpertdlnB.1.carbaxylic acld mathylamlda [0092] 4-Methyl-3-methylamino-piperidina-1-carboxylic acid mathylamida. LRMS: 303.

Example 25

4-Mathyl-3-[niethyl-f7H-pyrrolo[2.3-dIpyr1mldln-4-yl)-amlnol-plperidlne-1-c«rboxvllcaclddl8thylamlde [0093] 4-MBthyl-3-methylamino-piperldine-1-cart»xyllc add dlathylamlde. LRMS: 345.

Exampla 26

MathyH4-methyl-1-(2-methylainlno-athanB8ulfonyl)-plpefldln-3-yl]-(7H-pyrrolo[2,3-d]pyrlmldln-4-yl)-amlne [0094] Methyl-[4-melhyl-1-(2-mathylamlno-ethanesuHbnyl)-piperldin-3-yl]-amlna. LRMS: 367.