MXPA00012853A

MXPA00012853A - PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS

Info

Publication number: MXPA00012853A
Application number: MXPA/A/2000/012853A
Authority: MX
Inventors: Matthew Frank Brown; Todd Andrew Blumenkopf; Mark Edward Flanagan; Paul Steven Changelian
Original assignee: Pfizer Products Inc
Priority date: 1998-06-19
Filing date: 2000-12-19
Publication date: 2001-09-07

Abstract

A compound of formula (I) wherein R1, R2 and R3 are as defined in the formula which are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppresive agents for organ transplants, lupus, multiple sclesoris, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases.

Description

COMPOUNDS OF PIRRÓLO r2,3-d1PIRIMlDINA BACKGROUND OF THE INVENTION The present invention relates to pyrrolo [2,3-d] pyrimidine compounds which are inhibitors of tyrosine kinase proteins such as the enzyme Janus Kinase 3 (hereinafter referred to as JAK3) and as such, are a useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and others indications in which immunosuppression may be desirable. This invention also relates to a method for using such compounds in the treatment of the above indications in mammals, especially in humans, and to pharmaceutical compositions useful therefor. JAK3 is a member of the Janus family of protein tyrosine kinases. Although the remaining members of this family are expressed essentially by all tissues, JAK3 expression is limited to hematopoietic cells. This is consistent with its essential function in the signaling of IL-2, IL-4, IL-7, IL-9 and IL-15 through the receptors through a non-covalent association of JAK3 with the gamma chain common to these multichannel receptors. . The populations of XSCID patients have been identified with fairly low levels of the JAK3 protein or with genetic defects with respect to the gamma common chain, suggesting that immunosuppression would be the result of the blocking of JAK3 signaling. Animal studies have suggested that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but that JAK3 is constitutively required to maintain the function of T cells. The modulation of immune activity by this new mechanism can be useful in the treatment of proliferative disorders of T cells such as the rejection of transplants and autoimmune diseases.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula or their pharmaceutically acceptable salts, wherein R 1 is a group of formula in which the broken line represents optional double links; m is 0, 1. 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8; A and E are each CR7R8; and R6 is selected from the group consisting of hydrogen, C-Cß alkyl, trifluoromethyl, trifluoromethyl (Ci-Cß alkyl), (C alqu-C alqu alkyl) (difluoromethylene), (CrC 3 alkyl) (difluoromethylene) (C 1 -C 3 alkyl), ( C6 alkoxy) (CrC6 acyl), (CrC6 alkyl) amino (Ct-Cß acyl), (C6 alkyl) 2-amino (Ci-Cß acyl), C-C-aryl, C5-C9 heteroaryl, (aryl) C C-C-ioXalkyl Ci-Cβ), (C5-C9 heteroaryl) (Ci-Cß alkyl), (C6-C? Aryl) (C6-C? Ar aryl), (C6-C? 0 aryl) (aryl C6-C? 0) (CrC6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (CrC6 alkyl), hydroxy (C2-C6 alkyl), (acyloxy d-C6) (C2-C6 alkyl), (alkoxy) CrC6) (C2-C6 alkyl), piperazinyl (Ci-Cß alkyl), (C 1 -C 6 acyl) amino (CI-CT alkyl), (C 1 -C 6 -alioxy Ci-CßXalkyl Ci-Cß alkyl), (C 5 heteroaryl -C9) (C 1 -C 6 alkoxy-C 1 -C 6 alkyl), (C 1 -C 6 alkyl) thio (Ci-Cß alkyl), (C 6 -C 6 aryl) thio (C Cß alkyl), (CrC 6 alkyl) sulfinyl (CI- alkyl) CT), (aryl CQ-C? O) sulfinil (C? -C6 alkyl), (C? -C6 alkyl) sulfonyl (CrC6 alkyl), (C6-C-? O alkylsulfonyl) (CrC6 alkyl) , C Cβ aminoalkyl, (C 1 -C 6 alkyl) amino (C 6 alkyl), (C 1 -C 6 alkyl) 2amino (CrC 6 alkyl), R 13 CO (CrC 6 alkyl), where R 13 is R 20 O or R 20 R 21 N, R 20 and R 21 being selected each independently of the group consisting of hydrogen, Ci-Cß alkyl, (C 1 -C 6 aryloxy C 1 -C 6 alkyl) or (C 5 -C 9 heteroaryl) (C 6 -C 6 alkyl); or R14 (C2-C6 alkyl), wherein R14 is (C6 acyl) pperazino, (C6-C6 aryl) piperazino, (C5-C9 heteroaryl) piperazino, (C6 alkyl) piperazino, (C6-aryl) C? 0) (CrC6 alkyl) piperazin, (C5-C9 heteroaryl) (C6 alkyl) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C? -Ce alkyl) pipehdyl, (C6-C aryl? 0) piperidyl, (C5-C9 heteroaryl) piperidyl, (C6-C6alkyl) (CrC6 alkyl) piperidyl, (C5-C9 heteroaryl) (alkyl CrCe) piperidyl, (C-C6-alkoxy) acyl, (CrCe alkyl) aminoalpha (alkyl or (acyl C-C-p-piperidyl); R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, C-Cß alkyl, amino, hydroxy, C?-C6 alkoxy, (C alqu-C6 alkyl) amino, (C alqu-C6 alkyl) 2-amino, (acyl) C? -C6) amino, (C 1 -C 6 acyl) (C 1 -C 6 alkyl) amino, carboxy, (C 1 -Ce) acyl acyl, (C 1 -Ce) aminoacyl alkyl, (Cr C 1 aminoacyl alkyl, aminoacyl, trifluoromethyl, trifluoromethyl (C -Cß alkyl), (C 1 -Ce alkyl) (difluoromethylene), (C 1 -C 3 alkyl) difluoromethylene- (C 1 -C 3 alkyl), aryl CT-C 10, C 5 -C 9 heteroaryl, (aryl) C6-C? O) (CrC6 alkyl), (C5-C9 heteroaryl) (C6 alkyl), (C6-C6 aryl) (C6-C6 aryl), (C6-C6 aryl) (aryl C6-C? 0) (C6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (CrC6 alkyl), hydroxy (C? -C6 alkyl), (C? -Ce acyloxy) (C C? Alkyl), (CrCβXalkyl C Cß alkoxy), piperazinyl (C CC alquilo alkyl), (Cil-C6acyl) amyno (C Cß alkyl), piperidyl, (Ci-Cß-piperidyl alkyl, (C ar-C? aryl) (C alco-alkoxy? -C6) (C-Cß alkyl), (Cs-C9 heteroaryl) (C alco-C6-CßXalkyl), (C alqu-C6alkyl) thio (CrC6 alkyl), (a C6-C? 0) thio (C6-alkyl), (C6-alkyl) sulfinyl (C-C-alkyl), (C6-C? o) aryl sulfinyl (C-C-alkyl), (C-C6-alkyl) sulfonyl (C-alkyl) Cß), (C6-C6 aryl) sulfonyl (C-Cd alkyl), amino (C -Cß alkyl), (C alqu-C6 alkyl) amino (C?-C6 alkyl), (CrC 6 alkyl) 2-amino (C alquilo alkyl? -C6), R13CO (C6 alkyl) or R13CO (C3-C10 cycloalkyl), where R13 is R20O or R20R21N, each of R20 and R21 being independently selected from the group consisting of hydrogen, C1-C6 alkyl, (aryl C6-C) 0) (C 1 β alkyl) or (C 5 -C 9 heteroaryl) (C 1 -C 6 alkyl); R14, R14-CrC6 alkyl or R14-C3-C10 cycloalkyl, with R14 (acyl C? -C6) piperazino, (aryl C6-C? 0) piperazino, (heteroaryl C5-Cg) piperazino, (CrC? Jpiperazino alkyl, (aryl C? -CioXalkyl CrCßJpiperazino, (C5-C9 heteroaryl) (Ci-Cdjpiperazino alkyl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl (Ci-Cβ-piperidyl alkyl, (C 1 -C-cyclopiperidyl, aryl (C5-C9 heteroaryl) piperidyl, (aryl C6-C) o) (Ci-Ci-piperidyl alkyl, (heteroaryl Cs-CgXalkylC1-Cejptperidyl or (acylC?-C6) p¡peridyl; or a group of formula O chtíff Z wherein p is 0, 1, 2 or 3; and Z is hydroxy, Ci-Cß alkoxy or NR1R2, each of R1 and R2 being independently selected from the group consisting of hydrogen, C-Cß alkyl, piperidyl. (C 1 -C 6 -alkyl) piperidyl, (C 1 -Cy-cycloaliphenyl aryl, (C 5 -C 6 heteroaryl) piperidyl, (C 6 -C 10 aryl) (Ci-C 1 -piperidyl alkyl, (C 5 -C 6 heteroaryl) (C 1 -piβperidyl alkyl, (acyl C ? -C6) piperidyl, aryl CT-CIO, heteroaryl Cs-Cg, (aryl C? -C?) (Alkyl CrC6), (heteroaryl C5-C9? Alkyl C6), (aryl C6-C? 0) (aryl C6-C? O) (aryl C6-C? 0) (C? -C6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (Cr C6 alkyl), C? -C6 reakyl), (CrC5 alkyl) (CHR 5) (C 1 -C 6 alkyl), where R 5 is hydroxy, C 1 -C 7 acyloxy, C C β alkoxy, piperazino, (C 1 -C 6 acyl) amino, (CrC 6 alkyl) thio, (C 6 -C 6 aryl) thio , (C 1 -C 6 alkyl) sulfinyl, (C 6 -C 6 aryl) sulfinyl, (C 1 -C 7 alkylsulfoxyl, (C 6 -C 6 aryl sulfoxy), amino (C 6 alkyl) amino, (CrC 6 alkyl) 2 amino, (acyl d-Cβ-piperazino, (CrCßJpiperazino alkyl, (C 1 -C 6 -alkylC 6 alkyl aryl) piperazino, (C 5 -C 9 heteroaryl) (C 1 -C 6 alkyl) piperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C 1 -C 6 alkyl) ), (C 1 -C 5 alkyl) (CHR 6) (C 6 alkyl), where R 6 is piperidyl, (C 1 -C 6 alkyl) idyl, (aryl C6-C? o) piperidyl, (aryl C6-C? o) (alkyl d-C?) piperidyl, (heteroaryl Cs-Cgjpiperidyl or (heteroaryl C5-Cg) (Ci-C?] piperidyl alkyl; or when n is at least 1, D and E, or D and X are each CR7R8, the adjacent R7 groups can be taken, together with the carbon atoms to which they are attached, forming groups of the formulas V VI in which the dashed lines represent optional double links; a is 0, 1 or 2; m, A, B and X are as defined above; and G, J, L and M are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above; or when n is 1, D and E are each CR7R8 and m is 1, A and B are each CR7R8, the respective adjacent R7 groups can be taken, together with the carbon atoms to which they are attached, forming a group of formula wherein the discontinuous link represents optional double bonds; a, G, J, L and M are as defined above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, alkenyl C2-C6, C2-C6 alkynyl, trifluoromethyl, trifluoromethoxy, Ci-Cß alkyl, Cr-alkoxy C6, the alkyl or alkoxy groups being optionally substituted with one or three groups selected from halo, hydroxy, carboxy, amino (C-Cß-alkyl, (C d-Cß-alkyl, C (-C6 alkyl) 2-amino, C5-C9 heteroaryl, ( C2-Cg heterocycle) C3-C alkyl, C3-C cycloalkyl or Ce-Cio aryl; or each of R2 and R3 is independently C3-C10 cycloalkyl, C3-C10 cycloalkoxy, (C6-C6 alkyl) amino, (CrC6 alkyl) 2-amino, ( aryl C6-C ?o) amino, (C CßJtio alkyl, (C C-C? 0 ar) thioaryl, (C Ci-Cß-sulphonyl) alkyl, (C ar-C? o) alkylsulfinyl, (C alqu-C6 alkyl) sulfonyl, C6-C6 alkylsulfonyl, C6-C6 acyl, C6-alkoxy) -CO-NH-, (CrC6 alkyl) amino-CO-, C5-C9 heteroaryl, (C2-Cg heterocycle) C6 alkyl or aryl -C? O, the heteroaryl, heterocycloalkyl and aryl groups being optionally substituted by one to three halo, C? -C6 alkyl, (C? -C6 alkyl) -CO-NH-, (CrC6 alkoxy) -CO-NH- , (CrC6 alkyl) -CO-NH- (CrC6 alkyl), (C6-alkoxy) -CO-NH- (C6 alkyl), (C6-alkoxy) -CO-NH- (C-C alco alkoxy), carboxy, carboxy (C1-C6 alkyl), carbox i (alkoxy CI-CT), benzyloxycarbonyl (alkoxy CI-CT), (alkoxy CrC6) carbonyl (alkoxy CrC6), aryl C6-C? or, amino, amino (C-C-alkyl), (C-C6-alkoxy) carbonylamino , (aryl Ce-Cι) (C-Cß alkoxy) carbonylamino, (Ci-Cß-amino alkyl, (C C-C6 alkyl) 2-amino, (CrC6 alkyl) amino (C-Cß alkyl), (CrC 6 alkyl) 2-amino (CrC 6 alkyl), hydroxy, alkoxy CrC6, carboxy, carboxy (C-C-alkyl), (C-C-J-carbonyl-alkoxy, (C-C6-alkoxy) carbonyl (C-C6-alkyl), (C-C6-alkoxy) -CO-NH-, (C 1 -C 6 alkyl) -CO-NH-, cyano, (Cs-C-akhakyl heterocycle, amino-CO-NH-, (C 1 -C 6 alkyl) amino-CO-NH-, (CrCe ^ amino-CO-NH alkyl -, (aryl C6-C? 0) amino-CO-NH, (heteroaryl C5-C9) amino-CO-NH-, (alkyl CrC6) amino-CO-NH- (alkyl C? -C6), (alkyl C C6) 2 amino-CO- NH- (CrC6 alkyl), (C6-C6 aryl) amino-CO-NH- (C6 alkyl), (C5-C9 heteroaryl) amino-CO-NH- (CrC6 alkyl), (CrC6 alkyl) sulfonyl, (C?-C6 alkyl) sulfonylamino, (C alqu-C6 alkyl) sulfonylamino (C?-C6 alkyl), (C 6 -C 6 aryl) sulfonyl, (C 6 -C 6 aryl) sulfonylamino , (C6-C6 aryl) sulfonylamino (d-Cß alkyl), (CrCßJsulfonylamino alkyl, (C?-C6 alkyl) sulfonylamino (C?-C6 alkyl), C5-C heteroaryl (C2-Cg heterocycle) alkyl; provided that when A, B or X, in formulas V or VI, are defined as NR6 or CR7R8, R2 and / or R3 must be halo; provided that when R2 and R3 are each independently hydrogen or CrC6 alkyl, R1 can not be unsubstituted piperidinyl; provided that when R2 and R3 are each hydrogen, R1 can not be unsubstituted morpholinyl or pyrrolidinyl; provided that when R2 and R3 are each hydrogen, R1 can not be piperazinyl and provided that the groups of formulas IV, V, VI or XII do not contain two or more oxygens, sulfur or combinations thereof at adjacent positions. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids which are used to prepare the pharmaceutically acceptable addition salts of the above-mentioned basic compounds of this invention are those which form salts by addition of non-toxic acids, ie, salts containing pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1 '-methylene-bis (2-hydroxy-3-naphthoate)]. The invention also relates to the addition salts of bases of formula I. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of formula I which are acidic in nature are those which form base salts. non-toxic with such compounds. Such salts of non-toxic bases include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium salts or addition of water-soluble amines such as N-methylglucamine (meglumine) and salts of (lower alkanol) ammonium and other pharmaceutically acceptable organic amines. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic radicals or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups in which "alkyl" is as defined above. The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.

The compounds of the invention may contain double bonds. When such double bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. Unless indicated otherwise, the alkyl and alkenyl groups recited herein, as well as the alkyl radicals of other groups mentioned herein (eg, alkoxy) may be linear or branched, and may also be cyclic (eg, example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic radicals. Unless indicated otherwise, halogen includes fluorine, chlorine, bromine and iodine. C3-C10 cycloalkyl, when used herein, refers to cycloalkyl groups containing from zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo [3.2.1] octane, norbornyl and the like. (C2-Cg heterocycle) alkyl, when used herein, refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrorpyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1, 3 tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl and the like. One of ordinary skill in the art will understand that the connection of said rings (C2-C9 heterocycle) alkyl is through a carbon or a nitrogen heteroatom with sp3 hybridization. Heteroaryl C2-Cg, when used herein, refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1, 3,5-oxadiazolyl, 1, 2,4 -oxadiazolyl, 1,2,3-oxadiazolyl, 1, 3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,4-triazinyl , 1, 2,3-triazinyl, 1, 3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridyl, purinyl, 6,7-dihydro-5H- [1] pyridinyl, benzo [b] thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzoisoxazolyl, benzimidazolyl, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl and the like. One of ordinary skill in the art will understand that the connection of said rings (C2-C9 heterocycle) alkyl is through a carbon or a nitrogen heteroatom with sp3 hybridization. Aryl Ce-Cio, when used herein, refers to phenyl or naphthyl. The compounds of formula (I) can be administered in a pharmaceutically acceptable form alone or in combination with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents. These agents may include, but are not limited to, cyclosporin A (eg, Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxypergualin, mycophenolate (eg Cellcept®), azathioprine (eg Imuran®). ), daclizumab (for example Zenapax®), OKT3 (for example Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (for example, prednisolone or dexamethasone) These agents can be administered as part of the same or in separate forms, by the same or different administration routes, and with the same or different administration patterns according to conventional pharmaceutical practice The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) ) and all optical isomers of the compounds of formula I (for example enantiomers and diastereoisomers), as well as racemic, diastereomeric and another type of such isomers. This invention also includes all the rotamers of the compounds of formula I, as well as the scleramics. Preferred compounds of formula I include those in which R 1 is a group of formula in which dashed line represents optional double bonds: m is 0, 1, 2 or 3; n is 0, 1, 2, or 3; X, B and D are each independently oxygen S (O) d, where d is 0, 1 or 2, NR6 or CR7R8; A and E are each independently CR7R8 or NR6; or when n is 1, D and E are each CR7R8 and m is 1, A and B are each CR7R8, the respective adjacent R7 groups can be taken, together with the carbon atoms to which they are attached, forming a group of formula wherein the discontinuous link represents optional double bonds; a, G, J, L, and M are as defined above; r is 0 or 1; c is 0, 1 or 2; and r1, W, Y and S are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above; Other preferred compounds of formula I include those in which R2 and R3 are each independently selected from the group consisting of hydrogen, C-Cß alkyl, C?-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, (C2-Cg heterocycle) ) alkyl, heteroaryl Cs-Cg or aryl Ce-Cι- Specific compounds of formula I include the following: 5-Fluoro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 4-Piperidin-1-l-5-trifluoromethyl-7H-pyrrolo [2,3-d] -pyrmidin; 2-. { 3-Ethyl-4- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclopentyl} -propan-2-ol; 2-. { 3-Eti-4 - [(2-hydroxy-ethyl) - (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -amino] -cyclopentyl} -propan-2-ol; N, N-dimethyl-N, - [3- (4-piperidin-1-yl-7 H -pyrrolo [2,3-d] -pyrimidin-5-yl) benzyl] -ethane-1,2-diamine; 2- [1- (5-m-Tolyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -piperidin-4-yl] -ethanol; 5- (3-lsopropyl-phenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (3-Methyl-3H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d-pyrimidine; 5- (1-Methyl-1 H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d-pyrimidine; 5- (2-Methyl-pyridin-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5-Chloro-4-r-peridin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5-Chloro-4- (octahydro-indol-1-yl) -7H-pyrrolo [2,3-d] -pyrimidine; 5-Ethinyl-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] -pyrimidine; and 4- (3,3-Dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine. The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibit tyrosine kinases or Janus Kinase 3 (JAK3) proteins in a mammal, including a human , which comprises an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in said disorders or conditions and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibit tyrosine kinases or Janus Kinase 3 (JAK3) proteins in a mammal, including a human , comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with T cell or anti-inflammatory immunosuppressive agents, effective in said disorders or conditions and a pharmaceutically acceptable carrier. The present invention also relates to a method for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula I or one of its pharmaceutically acceptable salts. The present invention also relates to a method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective to treat said disorder. The present invention also relates to a method for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula I or one of its pharmaceutically acceptable salts, alone or in combination with T cell or anti-inflammatory immunosuppressive agents. The present invention also relates to a method for treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis. , autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being, which comprises administering to said mammal an amount of a compound of formula I or one of its salts pharmaceutically acceptable, alone or combined with immunosuppressive agents of T cells or anti-inflammatory, effective to treat said disorder.

DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless indicated otherwise, R1, R2, R3 and R9 in the following reaction and description schemes are as defined above.

SCHEME 1 SCHEME 2 SCHEME 3 15 SCHEME 4 III fifteen In reaction 1 of scheme 1, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVll is converted to the corresponding compound of formula XVI, where R is benzenesulfonyl or benzyl, treating XVll 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 of about 0 ° C to about 70 ° C, preferably about 30 ° C, for a period of about 1 hour to about 3 hours, preferably 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 a compound of formula R1H. The reaction is carried out in an alcohol as solvent, such as tert-butanol, methanol or ethanol, or other high-boiling organic solvent, such as dimethylformamide, 1,4-dioxane or 1,2-dichloroethane, at a temperature of about 60 ° C to about 120 ° C, preferably about 80 ° C. Typical reaction times vary from about 2 hours to about 48 hours, preferably about 16 hours. In reaction 3 of scheme 1, removal of the protecting group from the compound of formula XV, where R is benzenesulfonyl, to give the corresponding compound of formula I, is carried out by treating XV with an alkaline base, such as sodium hydroxide or potassium hydroxide. , in an alcohol as a 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 about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the protecting group of the compound of formula XV, where R is benzyl, is carried out by treating XV with sodium in ammonia at a temperature of about -78 ° C for a period of about 15 minutes to about 1 hour. In reaction 1 of scheme 2, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XXI, wherein R is hydrogen or benzenesulfonate, is converted into the 4-chloro-5-halopyrrolo compound [2 , 3-d] pyrimidine of formula XX, where Y is chlorine, bromine or iodine, by reacting XXI with N-chlorosuccinimide N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated to reflux in chloroform, for a period of from about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 of scheme 2, the compound of 4-chloropyrrolo [2,3-d] pyrimidine of formula XXI, where R is hydrogen, is converted to the compound 4-chloro-5-nitropyrrolo [2,3 -d] corresponding pyrimidine of formula XX, wherein Y is nitro, by reacting XXI with nitric acid in sulfuric acid at a temperature from about -10 ° C to about 10 ° C, preferably about 0 ° C, for a period of about 5 minutes to approximately 15 minutes, preferably approximately 10 minutes. The compound of formula XXI, where Y is nitro, is converted to the corresponding 4-chloro-5-aminopyrrolo [2,3-d-pyrimidine of formula XX, where Y is amino, by reacting XXI under a series of conditions known to an expert in the art, such as hydrogenolysis with palladium or tin (IV) chloride and hydrochloric acid. In reaction 2 of scheme 2, the 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of formula XX, where R is hydrogen, is converted to the corresponding compound of formula XIX, where R2 is CrC6 alkyl or benzyl, treating XX with N-butyllithium at a temperature of about -78 ° C, and reacting the dianion intermediate thus formed with an alkyl halide or benzyl halide at a temperature of about -78 ° C to room temperature, preferably room temperature. Alternatively, the dianion thus formed is reacted with molecular oxygen to form the corresponding 4-chloro-5-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XIX, where R 2 is hydroxy. The compound of formula XX, where Y is bromine or iodine and R is benzenesulfonate, is converted to the compound of formula XIX, where R2 is C6-Ci2 aryl or vinyl, treating 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 thus formed 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 of about 50 ° C to about 80 ° C, preferably about 70 ° C, for a period of about 1 hour to about 3 hours, preferably about 1 hour. In reaction 3 of scheme 2, the compound of formula XIX is converted to the corresponding compound of formula XVI by treating XIX with N-butyl lithium, lithium diisopropylamide or sodium hydride, at a temperature of about -78 ° C, in the presence of a polar aprotic solvent, such as tetrahydrofuran. The anionic intermediate thus formed is further reacted with (a) alkyl halide or benzyl halide, at a temperature of about -78 ° C to room temperature, preferably -78 ° C, when R3 is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature of about -78 ° C at room temperature, preferably -78 ° C, when R3 is alkoxy; and (c) zinc chloride, at a temperature of about -78 ° C to room temperature, preferably -78 ° C, and the corresponding organo-zinc intermediate thus formed is then reacted with aryl iodide or vinyl iodide in presence of a catalytic amount of palladium. The resulting reaction mixture is stirred at a temperature of about 50 ° C to about 80 ° C, preferably about 70 ° C, for a period of about 1 hour to about 3 hours, preferably 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, wherein R 3 is hydroxy. In reaction 1 of scheme 3, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XXI is converted into the corresponding compound of formula XXII, according to the procedure described above in reaction 3 of scheme 2. In the reaction 2 of scheme 3, the compound of formula XXII is converted to the corresponding compound of formula XVI, according to the procedures described above in reactions 1 and 2 of scheme 3. In the reaction of scheme 4, the compound of chloropyrrolo [2,3-d] pyrimidine of formula XX in the corresponding 4-aminopyrrolo [2,3-d] pyrimidine compound of formula XXIV, according to the procedure described before reaction 2 of scheme 1. In reaction 2 of Scheme 4, the 4-amino-5-halopyrrolo [2,3-d] pyrimidine compound of formula XXIV is converted, where R is benzenesulfonate and Z is bromine or iodine, into the corresponding compound of formula XXIII by reacting XXIV with (a) arylboronic acid, when R2 is aryl, in an aprotic solvent such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium (0) at a temperature of about 50 ° C to about 100 ° C, preferably about 70 ° C, for a period of about 2 hours to about 48 hours, preferably about 12 hours; (b) alkynes, when R2 is alkynyl, in the presence of a catalytic amount of copper (I) iodide and palladium (0), and a polar solvent, such as dimethylformamide, at room temperature for a period of about 1 hour to about 5 hours. hours, preferably 3 hours; and (c) alkenes or styrenes, when R2 is vinyl or styrenyl, in the presence of a catalytic amount of palladium in dimethylformamide, dioxane or tetrahydrofuran, at a temperature of about 80 ° C to about 100 ° C, preferably about 100 ° C, for a period of from about 2 hours to about 48 hours, preferably about 48 hours. In reaction 3 of scheme 4, the compound of formula XXIII is converted into the corresponding compound of formula XV, according to the procedure described above in reaction 3 of scheme 2. The compounds of the present invention which are basic in nature can form a wide range of different salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the above to the parent compound. free by treatment with an alkaline reagent, and subsequently converting the above free base to a salt by the addition of pharmaceutically acceptable acids. The acid addition salts of the basic compounds of this invention are readily prepared by treatment of 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 methanol or ethanol. After carefully evaporating the solvent, the desired salt is obtained. The salt of the desired acid can also be precipitated in 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 which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal and alkaline earth metal salts and in particular, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic salts with the acidic compounds of the present invention. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium and the like. These salts are readily 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, these can also be prepared by mixing solutions in lower alkanes of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of the reagents are preferably employed in order to ensure completion of the reaction and obtaining the maximum product yield. 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, sublingual, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal administration, or in a suitable form 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 can take the form, for example, of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form, for example, of solutions, syrups or suspensions, or these may be presented as a dry product for reconstitution with water or other suitable vehicle before use.

Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives as suspending agents (eg, sorbitol, syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (for example, lecithin or arabic range); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid) For sublingual administration, the composition may take the form of tablets or lozenges formulated in conventional manner. The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional characterization or infusion techniques. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of a preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation aids such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, 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, for example, containing 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 released in the form of a solution or suspension from a pump spray container that is compressed or pumped by the patient as an aerosol spray presentation from a container. under pressure or nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dose unit can be determined by providing the container with a valve that releases a measured quantity. The pressure pack or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or insufflator, which 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 sublingual administration to an average adult human for the treatment of the above-mentioned disorders (e.g., asthma) ranges from 0.1 to 1000 mg of active ingredient per unit dose that it could be administered, for example, 1 to 4 times a day. Aerosol formulations for the treatment of the above-mentioned disorders (e.g., rheumatoid arthritis) in an average adult human are preferably arranged so that each measured dose or aerosol "application" contains from 20 μg to 1000 μg of the compound of the invention. invention. The total daily dose with an aerosol will vary in the range of 0.1 mg to 1000 mg. The administration can be carried out several times a day, for example, 2, 3, 4 or 8 times, administering for example, 1, 2 or 3 doses each time. A compound of formula (I) is administered in a pharmaceutically acceptable form alone or by combining with one or more additional agents that modulate a mammalian immune system or with anti-inflammatory agents which may include, but are not limited to cyclosporin A (e.g., Sandimmune ® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxypergualin, mycophenolate (for example, Cellcept®), azathioprine (for example, Imuran®), daclizumab (for example, Zenapax®), OKT3 (for example, Orthocolone®, AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (for example, prednisolone or dexamethasone) and such agents can be administered as part of the same form or in separate forms, and with the same or different administration patterns according to conventional pharmaceutical practice. FK506 (Tacrolimus) is administered orally at 0.1-0.15 mg / kg of weight, every 12 hours, in the first 48 hours postoperatively. The dose is controlled by Tacrolimus valley serum levels. Cyclosporin A (oral or intravenous Sandimmune® formulation, or Neoral®, oral solution or capsules) is administered orally at 5 mg / kg of weight every 12 hours in the first 48 hours after surgery. The dose is controlled by the valley levels of Cyclosporin A in the blood. The active agents can be formulated for sustained release according to procedures well known to those skilled in the art. Examples of such formulations can be found in U.S. Patent Nos. 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, demonstrate their efficacy in treating disorders or conditions characterized by Janus Kinase 3 is shown by the following in vitro assays.

Biological test Enzymatic assay of ak3 (ih1: qst) The enzymatic assay of JAK3 kinase uses a protein expressed in SF9 cells infected with baculovirus (a fusion protein of GST and the catalytic domain of human JAK3) purified by affinity chromatography in glutathione- Sepharose The substrate for the reaction is poly-glutamic acid-tyrosine (PGT (4: 1), Sigma, catalog number P0275), coated on Nunc Maxi Sorp plates at 100 μg / ml overnight at 37 ° C. The morning after the coating, the plates are washed three times and JAK3 is added to the wells containing 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl 2) + 0.2 μM ATP + 1 mM sodium orthovandate ). The reaction proceeds for 30 minutes at room temperature and the plates are washed three more times. The level of tyrosine phosphorylated in a given well is quantified by standardized ELISA using an antiphosphotyrosine antibody (ICN PY20, catalog number 69-151-1).

Cellular assay dnd39 / il-4 for kinase inhibitors ak3 The DND 39 / IL-4 assay is designed to find inhibitors of JAK3 kinase activity that would be the main candidates for immunosuppression and / or allergy. The assay uses a B cell line called DND39 that has received the luciferase gene driven by the germ line IgE promoter stably integrated into one of the chromosomes. When these cells are stimulated with IL-4, the JAK3 kinase that is associated with the IL-4 receptor, phosphorylates the transducer of the STAT6 signal. STAT6 then binds to the germline IgE promoter and initiates transcription of the luciferase gene. Luciferase is measured in a lysate of these cells using the Promega luciferase assay reagent system. Note: DND 39 cells are reproduced in RMPI 1640 supplemented with 10% heat inactivated FCS, 2 mM L-glutamine and 100 units / ml Penicillin / streptomycin. The cells are maintained from 1 × 10 5 to 1 × 10 6 cells / ml. By dividing up to 1 x 105 on Friday, the cells will become 1 x 106 on Monday. Then divide 1: 2 during the week keeping 200 ml in a flask if necessary. DND 39 to 3 x 105 cells are seeded in 100 μl of RPMI 1640 supplemented with 1% heat-inactivated FCS, 2 mM L-glutamine and 100 units / ml of Penicillin / Streptomycin in a 96-well V-bottom plate. (Nunc) Compounds are serially diluted 1: 2 in DMSO, starting at 4 mM to 1.9 μM. In a 96-well polypropylene plate, the tips are changed after each dilution. Then 5 μl of each dilution is added to 500 μl of RPMI / 1% serum in a 96-tube rack. 125 μl of the dilutions of the compounds are added to the cells and incubated at 37 ° C, 5% CO2 for one hour. One hour later, 25 μl of 25 ng / ml IL-4 is added to the cells and mixed. The final concentration of IL-4 is 2.5 ng / ml and the final concentration of the compound varies from 20 μM to 156 nM. The cells are then incubated overnight 16-18 hours. The plate is then centrifuged at 2500-3000 rpm in a tabletop centrifuge for 5 minutes. The culture supernatant is carefully removed by aspiration with an 8-well collector. 100 μl of PBS with calcium and magnesium are added to the sedimented cells. The cells are resuspended in PBS and transferred to a Packard White OptiPlate plate. 100 μl of Packard LucLite reagent is added to the wells of the OptiPlate plate. The following examples illustrate the preparation of the compounds of the present invention although it is not limited to the details thereof. The melting points are uncorrected. The NMR data are expressed in parts per million (d) and are referenced to the deuterium stabilization signal of the sample solvent (deuterochloroform), unless otherwise indicated). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N, N-dimethylformamide. Low resolution mass spectra (LRMS) were recorded in a Hewlett Packard 5989®, using chemical ionization (ammonium) or in a platform of Atmospheric Chemical Ionization at Atmospheric Pressure (APCI) Fisons (or Micro Mass) using a 50 / mixture 50 acetonitrile / water with 0.1% formic acid as the ionization agent. Ambient temperature refers to 20-25 ° C.

EXAMPLE 1 Cyclohexyl-methyl- (7H-pyrrolof2,3-dlpyrimidin-4-yl) amine PROCEDURE A Cyclohexyl-methyl- (7H-pyrrolor-2,3-dlpyrimidin-4-yl) amine A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (prepared by the procedure of Davoll, J. Am. Chem. Soc. (1960), 82, 131 was stirred. ), the product of procedure A (589 mg / 521 mmol) and 3 ml of tert-butanol, in a sealed tube at 100 ° C for 24 hours. The reaction mixture was added to water, acidified to pH 1 with 1N hydrochloric acid (aqueous), washed twice with diethyl ether (ether) and basified to pH 14 with 1N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried under vacuum to obtain 263 mg (88%) of the title compound. P.f. 177-180 ° C 1 H NMR (400 MHz, CDCl 3) d 1.11-1.22 (m, 1 H), 1.43-163 (m, 4 H), 1.73 (d, broad, 1 H, J = 13.3 Hz), 1.83 -1.90 (m, 4H), 3.23 (s, 3H), 4.69 (width, 1 H), 6.53 (d, 1 H, J = 3.5 Hz), 7.03 (d, 1 H, J = 3.5 Hz), 8.30 (s, 1 H), 10.6 (width, 1 H). LRMS: 231 (m + 1). The title compounds of examples 2 to 51 were prepared by a procedure analogous to that described in example 1.

EXAMPLE 2 9- (7H-Pyrrolor-2,3-dlpyrimidin-yl) -2.3.4.4a, 9,9a-hexahydro-1 H-carbazole EXAMPLE 3 4- (6-Dimethyl-morpholin-4-yl) -7H-pyrrolof2.3-d1-pyrimidine 2,6-Dimethylmorpholine. LRMS: 233.3.

EXAMPLE 4 4-Morpholin-4-yl-7H-pyrrolof2,3-d1pyrimidine 4-Morpholine. LRMS: 205.

EXAMPLE 5 - (2,5-Dimethyl-pyrrolidin-1-yl) -7H-pyrroloyl-2,3-d-pyrimidine 2,5-Dimethylpyrrolidine. Melting point: 227-229 ° C; LRMS: 216.3.

EXAMPLE 6 4- (4-Benzyl-piperidin-1-yl) -7H-pyrrolof2,3-dlpyrimidine 4-Benzylpiperidine. Melting point: 188-190 ° C; LRMS: 292.4.

EXAMPLE 7 4-Phenyl-1-f7H-p8rrolof213-dlpyrimidin-4-yl) -piperidin-4-ol 4-Phenylpiperidin-4-ol. Melting point: 201 -202 ° C; LRMS: 294.4.

EXAMPLE 8 1 -p- (7H-Pirrolor2.3-dlpyrimidin-4-M) -piperidin-4-in-1,3-dihydrobenzoimidazol-2-one Piperidin-4-yl-1,3-dihydrobenzoimidazole. Melting point: 182-184 ° C; LRMS: 334.4.

EXAMPLE 9-Phenyl-8- (7H-pyrrolor-2,3-dlpyrimidin-4-yl) -1.3.8-triaza-spiror4.51decan-4- ona 1-Phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one. Melting point: 232-234X.

EXAMPLE 10 4- (3-Methyl-piperidin-1-yl) -7H-pyrrolor-2,3-d-pyrimidine 3-Methylpiperidine. Melting point: 176-178 ° C; LRMS: 217.1.

EXAMPLE 11 - (3,5-Dimethyl-piperidin-1-yl) -7H-pyrrolor-2,3-dlpyrimidine 3,5-Dimethylpiperidine. Melting point: 258-260 ° C; LRMS: 231.

EXAMPLE 12 4- (2-Met.l-p.per.din-1-yl) -7H-pyrrc'or-2,3-d.pyrimidine 2-Methyl-piperidine. Melting point: 144-146 ° C; LRMS: 217.1.

EXAMPLE 13 4- (2-Ethyl-piperidin-1-yl) -7H-pyrrolor-2,3-d-pyrimidine 2-Ethylpiperidine. Melting point: 112-144 ° C; LRMS: 231.

EXAMPLE 14 ri- (7H-Pyrrolor-2,3-d1-pyrimidin-4-yl) -piperidin-2-in-methanol Piperidine-2-yl-methanol. Melting point: 135-136 ° C; LRMS: 232.9.

EXAMPLE 15 1- (7H-pyrrolof2,3-dlpyrimidin-yl) -piperidine-3-carboxylic acid diethylamide Diethylamide of piperidine-3-carboxylic acid. LRMS: 302.1 EXAMPLE 16 2-p-7H-Pyrrolor-2,3-dlpyrimidin-4-in-piperidin-2-in-ethanol Piperidin-2-yl-ethanol. Melting point: 139-140 ° C.

EXAMPLE 17 4-Azocan-1-yl-7H-pyrrolof2,3-d1pyrimidine Azapano Melting point: 225-226 ° C; LRMS: 231.3.

EXAMPLE 18 1- (7H-Pyrrolor-2,3-dlpyrimidin-4-yl) -piperidine-3-carboxylic acid amide Amide of piperidine-3-carboxylic acid. Melting point: 283-285 ° C.

EXAMPLE 19 D1met1-f1- (7H-pyrrolof2.3-d1-pyrimidin-4-yl) -pyrrolidin-3-ylamine Dimethylpyrrolidin-3-yl-amine. Melting point: 210-212 ° C; LRMS: 232.2.

EXAMPLE 20 N-Ethyl-N-f1- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) pyrrolidin-3-in-acetamide N-Ethylpyrrolidin-3-yl-acetamide. Melting point: 197-199 ° C; LRMS: 274.3.

EXAMPLE 21 4- (2-Methoxymethyl-pyrrolidin-1-yl) -7H-pyrrolof2,3-dlpyrimidine 2-Methoxymethylpyrrolidine. Melting point: 134-135 ° C; LRMS: 233.2 EXAMPLE 22 f1- (7H-Pyrrolof2,3-d1-pyrimidin-4-yl) -pyrrolidin-2-n-methanol Pyrrolidin-2-yl-methanol. Melting point: 188-189 ° C; LRMS: 219.3 EXAMPLE 23 N-ri- (7H-Pyrrolor-2,3-d1-pyrimidin-4-yl) -pyrrolidin-3-in-acetamide Pyrrolidin-3-yl-acetamide. Melting point: 260-261 ° C; LRMS: 246.3.

EXAMPLE 24 4- (2-Propyl-piperidin-1-yl) -7H-pyrrolor-2,3-dlpyrimidine Propylpiperidine. Melting point: 106-107 ° C; LRMS: 245.3.

EXAMPLE 25 - (4-Methyl-piperazin-1-yl) -7H-pyrrolor-2,3-d-pyrimidine 4-Methylpiperazine. Melting point: 141-142 ° C.

EXAMPLE 26 4-Piperazin-1-yl-7H-pyrrolor-2,3-d-pyrimidine Piperazine Melting point: 164-166 ° C.

EXAMPLE 27 4-Azepan-1-yl-7H-pyrrolor-2,3-d1-pyridine Azapano Melting point: 210 ° C; LRMS: 217.3.

EXAMPLE 28 1- (7H-Pyrrolor-2,3-d1-pyrimidin-4-yl) -pyrrolidin-3-ol Pirrolidin-3-ol. Melting point: 220-225 ° C; LRMS: 205.2.

EXAMPLE 29 ri- (7H-Pyrrolof2,3-d1-pyrimidin-4-yl) -piperidin-3-n-methanol Piperidine-3-yl-methanol- Melting point: 161.5-163.5 ° C; LRMS: 234.3.

EXAMPLE 30 Ethyl 1- (7H-pyrrolof2,3-d1pyrimid-4-yl) -piperidine-4-carboxylic acid ethyl ester Ethyl ester of piperidine-4-carboxylic acid. Melting point: 139-141 ° C; LRMS: 275.3.

EXAMPLE 31 1- (7H-Pyrrolor2,3-d1-pyrimidin-4-yl) -piperidine-3-carboxylic acid ethyl ester Ethyl ester of piperidine-3-carboxylic acid. Melting point: 139.5-141.5 ° C; LRMS: 275.3.

EXAMPLE 32 2-f1- (7H-Pirrolor2,3-d1p¡r¡m¡din-4-in-p¡peridin-4-ill-ethanol Piperidin-4-yl-ethanol. Melting point: 129-131 ° C; LRMS: 265.3.

EXAMPLE 33 4- (4-Phenyl-piperidin-1-yl) -7H-pyrrolor-2,3-d-pyrimidine 4-Phenylpiperidine. Melting point: 195 ° C; LRMS: 279 EXAMPLE 34 - (4-Trifluoromethyl-piperidin-1-yl) -7H-pyrrolof2,3-d1-pyrimidine 4-Trifluoromethylpiperidine. Melting point: 198 ° C; LRMS: 271.

EXAMPLE 35 -r4- (3-Phenyl-propyl) -piperidin-1-yn-7H-pyrrolof2,3-d1-pyrimidine 4- (3-Phenylpropyl) piperidine. Melting point: 134X; LRMS: 321.

EXAMPLE 36 4-f3,3-D-methyl-piperidin-1-yl) -7H-pyrrolor-2,3-dlpyrimidine 3,3-Dimethylpiperidine. Melting point: 204 ° C; LRMS: 231.

EXAMPLE 37 1- (7H-Pyrrolor-2,3-d1-pyrimidin-4-yl) -piperidine-3-carboxylic acid Piperidine-3-carboxylic acid. Melting point: 159-160 ° C; LRMS: 307.3.

EXAMPLE 38 1 -Methyl-10-oxa-4-aza-tricichlor5.2.1.0% 2,6 &ldecano 1 - . 1 -Methyl-4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -10-oxa-4-aza-tricyclo [5.2.1] decane. Melting point: 251-252 ° C; LRMS: 271.3 EXAMPLE 39 1- (5-Chloro-7H-pyrrolor-2,3-d-pyrimidin-4-yl) -decahydro-quinoline Decahydroquinoline. Melting point: 190-192 ° C; LRMS: 291.8.

EXAMPLE 40 Ethyl ester of 3-ri-f7H-pyrrolof2.3-d1-pyrimidin-4-yl) piperidin-3-propionic acid Ethyl ester of piperidin-3-yl-propionic acid. Melting point: 101-103 ° C; LRMS: 303.4.

EXAMPLE 41 3-f1- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -piperidin-3-in-propionic acid Piperidin-3-yl-propionic acid. Melting point: 217-219X; LRMS: 275.3.

EXAMPLE 42 1- (7H-Pyrroloyl-2,3-dlpyrimidin-4-yl) -piperidin-3-ol Piperidin-3-ol. Melting point: 152-154 ° C; LRMS: 219.3 EXAMPLE 43 -l1- (7H-Pyrrolor-2,3-d1-pyrimidin-4-in) -piperidin-3-in-propionamide Piperidin-3-yl-propionamide. Melting point: 212 - 214 ° C; LRMS: 274.3.

EXAMPLE 44 4- (2,6-Dimethyl-piperidin-1-yl) -7H-pyrrolor-2,3-d-pyrimidine 2,6-Dimethylpiperidine. LRMS: 231.

EXAMPLE 45 2-ri- (7H-Pyrrolor-2,3-d1-pyrimidin-4-yl) -p -peridin-3-y-propan-2-ol Piperidin-3-yl-propan-2-ol. Melting point: 182.8-183.6X; LRMS: 261.

EXAMPLE 46 2-ri- (7H-Pyrrolof2.3-dlPyrimidin-4-yl) -piperidin-4-y-propan-2-ol Piperidin-4-yl-propan-2-ol. Melting point: 170.1-171.3 ° C; LRMS: 261.

EXAMPLE 47 4-Methyl-1- (7H-pyrrolof2,3-d1-pyrimidin-4-yl) -piperidin-4-ol 4-Methylpiperidin-4-ol. Melting point: 163.8-165.1 ° C; LRMS: 233.1.

EXAMPLE 48 -Methyl-8- (7H-pyrrolor2.3-dlpyridn-4-yl) - ^ - aza-biciclof3.2.11octan-3-ol 3-Methyl-8-aza-bicyclo [3.2.1] octan-3-ol. Melting point: 142.1-143.8 ° C; LRMS: 259.1.

EXAMPLE 49 -ri- (7H-Pirrolor2.3-dlpyrimidin-4-yl) -pyrrolidin-2-in-propan-2-ol Pyrrolidin-2-yl-propan-2-ol. Melting point: 173 ° (dec); LRMS: 247.1.

EXAMPLE 50 3-Methyl-1-f7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -pyrrolidin-3-ol 3-Methylpyrrolidin-3-ol. LRMS: 219.

EXAMPLE 51 4-Pyrazol-1-yl-7H-pyrrolor-2,3-dlpyrimidine Pyrazole LRMS: 186.2.

EXAMPLE 52 Cyclohexyl-methyl- (6-phenyl-7H-pyrrolof2,3-d1-pyrimidin-4-yl) -amine Cyclohexylmethylamine.

PROCEDURE B 7-Benzenesulfonyl-4-chloro-7H-pyrrolor-2,3-d-pyrimidine In a flame-dried flask under nitrogen, 780 mg of 60% sodium hydride (19.5 mmol) in mineral oil was added to 30 ml of dimethylformamide (DMF) and the resulting mixture was cooled to 0 ° C. A solution of 2.0 g (13.0 mmoles) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in 10 ml of DMF was added slowly over a period of 5 minutes. The reaction was stirred for 10 minutes, at which time the generation of hydrogen (H2) ceased. Benzenesulfonyl chloride (1.7 ml / 13.0 mmol) was added, the reaction was warmed to room temperature and stirred for 1 hour. Water was added and the resulting precipitate was filtered and dried in vacuo to obtain 3.4 g (89%) of the title compound as a crystalline solid, m.p. 163-167 ° C.

PROCEDURE C 7-Benzenesulfonyl-4-chloro-6-phenyl-7H-pyrrolor-2,3-dlpyrimidine In a flame-dried flask and under nitrogen, 0.53 ml (3.79 mmoles) of diisopropylamine was dissolved in 5 ml of tetrahydrofuran (THF) and the solution was cooled to -78 ° C. N-Butyl lithium (3.75 mmol as a 2.5 M solution in hexanes) was added and the resulting mixture was brought to 0 ° C with continuous stirring for 10 minutes. The reaction mixture was again cooled to -78 ° C and to this mixture a solution of 1.0 g (3.40 mmol) of the product of procedure B in 10 ml of THF was added over a period of 10 minutes. The reaction mixture was stirred for 1 hour at -78 ° C, at which time 8.2 ml (4.10 mmol) of a 0.5 M solution of zinc chloride in THF was added, the reaction mixture was brought to room temperature and stirred for 1 hour. Iodobenzene was added (0.46 ml / 4.11 mmol) and a suspension of 197 mg of tetrakis (triphenylphosphine) palladium in 2 ml of THF. The resulting mixture was stirred under reflux for 3 hours, cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was acidified with 1 N HCl and extracted twice with dichloromethane. The dichloromethane layers were combined, washed with 1N HCl and brine, dried over magnesium sulfate (MgSO4), filtered and concentrated in vacuo to obtain the title compound. LRMS: 370, 372 (M + 2).

PROCEDURE D 4-Chloro-6-phenyl-7H-pyrrolor-2,3-d-pyrimidine The product of procedure C was dissolved in 10 ml of THF and 5.0 ml of methanol and 1.0 g of NaOH were added to this solution. The reaction mixture was stirred for 15 minutes, concentrated in vacuo and partitioned between a saturated aqueous solution of ammonium chloride (NH4CI) and ethyl acetate. The resulting aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate: hexane 1: 5), obtaining 0.59 g (76%) of the title compound as a pale yellow solid, m.p. 145 ° C (dec.). LRMS 230, 232 (M + 2).

PROCEDURE E Cyclohexyl-methyl- (6-phenyl-7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amine The product of procedure D (50 mg / 0.218 mmol) was reacted with 0.12 ml of N-methylcyclohexyl amine (0.920 mmol) as described in procedure B. The reaction mixture was concentrated in vacuo, methanol was added and the resulting precipitate was filtered affording 7 mg (10%) of the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl 3) d: 1.18-1.25 (m, 1 H), 1.47-1.66 (m, 4 H), 1.75-1.90 (m, 5 H), 3.30 (s, 3 H), 4.74 (Width, 1 H), 6.79 (s, 1 H), 7.32-7.36 (m, 1 H), 7.47-7.51 (m, 2 H), 7.77 (d, 2 H, J = 7.9 Hz), 8.33 (s, 1 H) . LRMS: 307 (M + 1). The title compounds of Examples 53-58 were prepared by a procedure analogous to that described in Example 52.

EXAMPLE 53 - (6-Phenyl-7H-pyrrolof2,3-d1-pyrimidin-4-yl) -decahydro-quinoline Decahydroquinoline. LRMS: 333.4.

EXAMPLE 54 4- (2-Ethyl-piperidin-1-yl) -6-phenyl-7H-pyrrolor-2,3-dlpyrimidine 2-Ethylpiperidine. LRMS: 307.4.

EXAMPLE 55 - (3,3-Dimethyl-piperidin-1-yl) -6-phenyl-7H-pyrrolof2,3-dlpyrimidine 3,3-Dimethylpiperidine. LRMS: 307.4.

EXAMPLE 56 6-Phenyl-4-piperidin-1-yl-7H-pyrrolor-2,3-dlpyrimidine Piperidine LRMS: 279.4.

EXAMPLE 57 4-Piperidin-1-yl-6-thiophen-3-yl-7H-pyrroloF2,3-d1-pyrimidine Piperidine LRMS: 285.4. EXAMPLE 58 4-Piperidin-1-yl-6-thiophen-2-yl-7H-pyrrolof2,3-d1-pyrimidine Piperidine LRMS: 285.4.

EXAMPLE 59 Cyclohexyl-methyl- (6-methyl-7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amine Cyclohexylmethylamine.

PROCEDURE F 7-Benzenesulfonyl-4-chloro-6-methyl-7H-pyrrolor-2,3-d1-pyrimidine A 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 ml of dry THF were charged to a flame-dried flask under nitrogen. The solution was cooled to -78 ° C and 1.63 ml (4.08 mmol) of a 2.5 M solution of n-butyl lithium in hexanes was added. The resulting mixture was brought to 0 ° C and stirred for 10 minutes. After cooling the mixture back to -78 ° C, a solution of 1.0 g (3.40 mmol) of the crude product of procedure C in 10 ml of dry THF was added over a period of 10 minutes. The resulting mixture was stirred for 1 hour, at which time 0.28 ml (4.50 mmol) of iodomethane was added. The reaction mixture was stirred for 2 hours, quenched with saturated NH 4 Cl solution and warmed to room temperature. The mixture was stirred for 5 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO 4, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M + 2).

PROCEDURE G 4-Chloro-6-methyl-7H-pyrroloyl-2,3-d1-pyrimidine Process product F was deprotected as described in procedure E. The crude product was purified by trituration with hexanes and dichloromethane to obtain 250 mg (44%) of the title compound as a yellow solid. Fusion point 205 ° C (dec.). LRMS 168, 170 (M + 2).

PROCEDURE H Cyclohexyl-methyl- (6-methyl-7H-pyrrolof2,3-d1-pyrimidin-4-yl) -amine The product of procedure G (50 mg / 0.298 mmol) was reacted with 100 mg (0.883 mmol) of N-methylcyclohexyl amine as described in procedure A. The reaction mixture was treated as in procedure A except that ethyl acetate was used instead of ether. The title compound (42 mg, 58% yield) was obtained as a white solid. Fusion point 221 ° C (dec.). 1 H NMR (400 MHz, CDCl 3) d 1.15-1.25 (m, 1 H), 1.43-1.62 (m, 4H), 1.73 (broad s, 1 H, J = 13.7 Hz), 1.82-1.90 (m, 4H), 2.41 (d, 3H, J = 0.8 Hz), 3. 21 (s, 3H), 4.63 (s wide, 1 H), 6.20 (s, 1 H) "8.22 (s, 1 H), 10.1 (s wide, 1 H). LRMS 245 (M + 2). The title compound of Example 60 was prepared by a procedure analogous to that described in Example 59.

EXAMPLE 60 6-Methyl-4-piperidin-1-yl-7H-pyrrolof2,3-d1-pyrimidine Piperidine LRMS: 217.3.

EXAMPLE 61 5-Chloro-4-piperidin-1-yl-7H-pyrrolof2,3-d1-pyrimidine PROCEDURE I 4,5-Dichloro-7H-pyrrolor-2,3-dlpyrimidine 4-Chloro-7H-pyrrolo [2,3-d] pyrimidine (154 mg, 1.0 mmol) was suspended in 6.0 ml of dry dichloromethane in a flame-dried flask and N-chlorosuccinimide (147 mg, 1.1 mmol) in one portion. The resulting mixture was stirred at room temperature for 18 hours at which time the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration affording 137 mg (72%) of the title compound as a gray solid. Melting point 224-227 ° C (dec.). LRMS: 188 (M + 1) PROCEDURE J 5-Chloro-4-piperidin-1-yl-7H-pyrrolor-2,3-dlpyrimidine The product of procedure I (57 mg, 0.3 mmol) was suspended in 3.0 ml of tert-butanol and piperidine (90 μl) was added to this mixture., 0.9 mmoles) and the resulting system was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and water (4.0 ml) was added. The solution was adjusted to pH 1 with 1 N HCl and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2N NaOH. the solution was then extracted with 2 x 15 ml of dichloromethane and the combined organic products were washed with water and then brine and dried over MgSO4. Work up the solvent gave 45 mg of a yellow solid which was purified by chromatography on silica gel (ethyl acetate: hexanes 3: 1), afforded 23 mg (32%) of the title compound as a light yellow solid. Melting point 170-172X. 1 H NMR (400 MHz, CDCl 3) 5: 1.67-1.74 (m, 6H), 6.35-6.37 (m, 4H), 7.10 (s, 1 H), 8.31 (s, 1 H). LRMS: 237 (M + 1). The title compounds of Examples 62-63 were prepared by a procedure analogous to that described in Example 61.

EXAMPLE 62 5-Chloro-4- (octahydro-indol-1-yl) -7H-pyrrolor-2,3-dlpyrimidine Octahydroindol. Melting point: 193 ° C; LRMS: 277.8.

EXAMPLE 63 1- (5-Chloro-7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -decahydro-quinoline Decahydroquinoline. Melting point: 190-192 ° C; LRMS: 291.8.

EXAMPLE 64 5-Phenyl-4-piperidin-1-yl-7H-pyrroloyl-2,3-d-pyrimidine PROCEDURE K 5-Bromo-4-chloro-7H-pyrrolof2,3-d1pyrimidine To a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (30 g / 0.02 mole) dissolved in 75 ml of chloroform was added 3.5 g (0.02 mole) of N-bromosuccinimide and the resulting mixture was led to reflux for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure to give 4.1 g (89%) of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 7.93 (d, 1 HJ = 2.8 Hz), 8.60 (s, 1 HOUR).

PROCEDURE L 7-Bencesulfonyl-5-bromo-4-chloro-7H-pyrrolof2.3-d1-pyrimidine 1.0 g (0.025 mole) of 60% sodium hydride in mineral oil was added to a suspension of the product of procedure K (4.1 g / 0.018 mole) in DMF (15 ml) and cooled to 0 ° C and the resulting mixture was stirred at 0 ° C for 15 minutes. Benzenesulfonyl chloride (3.2 g / 0.018 mol) was added, the reaction mixture was warmed to room temperature and stirred for 2 hours. Water (15 ml) was then added and the resulting solid was removed by filtration and dried under vacuum providing 5.9 g (89%) of the title compound.

PROCEDURE M 7-Benzenesulfonyl-5-bromo-4-piperidin-1-yl-7H-pyrrolof2,3-d1pyrimidine A mixture of 2.0 g (5.37 mmoles) of the product of procedure L and 1.1 g (13.4 mmoles) of piperidine in 10 ml of tert-butanol was heated at 60 ° C with 2 hour stirring. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (25 ml) and water (25 ml). The dichloromethane layer was dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 2.2 g (97%) of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 1.63-1.72 (m, 6 H), 3.54-3.57 (m, 4 H), 7.53 (t, 2 H, J = 2.0 Hz), 7.60 (s, 1 H), 7.61 (t, 1 H, J = 2.0 Hz), 8.17-8.20 (m, 2H), 8.43 (s, 1 H). LRMS: 422.7, 420.7 (M + 1).

PROCEDURE N 5-Phenyl-4-piperidin-1-yl-7H-pyrrolor2-3-dlpyrimidine 32 mg (0.261 mmoles) of phenylboronic acid and 75 mg (0.356 mmoles) of tribasic potassium phosphate were added, followed by 7 mg (0.006 mmoles) of tetrakis (triphenylphosphine) palladium, to a stirred solution of the product of procedure M (100 mg , 0.237 mmol) in 1.0 ml of dioxane. The resulting mixture was degassed with nitrogen and stirred at 100 ° C for 48 hours.

After cooling to room temperature, 1.0 ml of methanol was added, followed by 50 mg of NaOH and the new mixture was stirred at room temperature for 1 hour. The resulting mixture was then partitioned between dichloromethane and water, the dichloromethane layer was dried over MgSO 4 and concentrated to dryness in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate, hexanes 2: 1) to give 13 mg (20%) of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 1.33-1.34 (m, 4 H), 1.43-1.44 (m, 2 H), 3.26-3.28 (m, 4 H), 7.12 (s, 1 H), 7.27 (t , 1 H, J = 7.2 Hz), 7.38 (t, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 0.8 Hz), 8.42 (s, 1 H).

LRMS: 279.2 (M + 1). The title compounds of Examples 65-77 were prepared analogously to that described in Example 64.

EXAMPLE 65 -f3-Chloro-4-fluoro-phenyl) -4-piperidin-1-yl-7H-pyrrolor2.3-dlpyrimidine Piperidine LRMS: 331.8.

EXAMPLE 66 5- (4-Fluoro-phenyl) -4-piperidin-1-yl-7H-pyrrolor-2,3-dlpyrimidine Piperidine LRMS: 297.

EXAMPLE 67 5- (4-Chloro-phenyl) -4-piperidin-1-yl-7H-pyrrolor-2,3-d-pyrimidine Piperidine LRMS: 313.

EXAMPLE 68 Bis-trifluoromethyl-phenyl) -4-piperidin-1-yl-7H-pyrrolor-2,3-d-pyrimidine Piperidine LRMS: 415.4.

EXAMPLE 69 4-Piperidin-1-yl-5-o-tolyl-7H-pyrrolor-2,3-d-pyrimidine Piperidine LRMS: 293.4.

EXAMPLE 70 4-Piperidin-1-yl-5-p-tolyl-7H-pyrrolof2.3-d1-pyrimidine Piperidine LRMS: 293.4.

EXAMPLE 71 5-f4-Methoxy-phenyl) -4-piperidin-1-yl-7H-pyrrolor-2,3-d1-pyrimidine Piperidine LRMS: 309.4.

EXAMPLE 72 4-Piperidin-1-yl-5- (3-trifluoromethyl-phenyl) -7H-pyrrolor-2-d1-pyrimidine Piperidine LRMS: 347.4.

EXAMPLE 73 5- (3-Chloro-phenyl) -4-piperidin-1-yl-7H-pyrrolor-2,3-d1-pyrimidine Piperidine LRMS: 427.8.

EXAMPLE 74 Ethyl 3- (4-piperidin-1-yl-7H-pyrrolor-2,3-dlpyrimidin-5-yl) -benzoic acid ethyl ester Piperidine LRMS: 465.4.

EXAMPLE 75 2-r3- (4-Piperidin-1-yl-7H-pyrrolor-2,3-dlpyrimidin-5-yl) -phenill-propan-2-ol Piperidine LRMS: 451.4.

EXAMPLE 76 4- (2-Methyl-piperidin-1-yl) -5-m-tolyl-7H-pyrrolo [2,3-d1-pyrimidine] 2-methylpiperidine. LRMS: 307.2.

EXAMPLE 77 4-Azepan-1-yl-5-m-tolyl-7H-pyrrolor-2,3-d1pymidine Azepano. LRMS: 307.2.

EXAMPLE 78 4-Piperidin-1-yl-7H-pyrrolof2,3-dlpyrimidine-5-carbonitrile Piperidine (59 μL, 0.60 mmol) was added to a stirred solution of 4-chloro-7H-pyrrolo. { 2,3-d] pyrimidine-5-carbonitrile (54 mg, 0.3 mmol) (prepared by the method of Townsed, et al., J. Am. Chem. Soc, 1969, 9_, 2102), suspended in 3.0 ml of tert-butanol. The resulting mixture was then heated to reflux for 2.5 hours and after cooling to room temperature, it was transferred to a separatory funnel and diluted with ether (20 ml). The solution was extracted with 2 x 10 ml of 1 N HCl, the combined aqueous layers were adjusted to pH 7 with 2N potassium hydroxide solution (KOH) forming a precipitate which was collected by filtration, washed with water and dried under pressure reduced by providing 29 mg (42%) of the title compound as a colorless solid. Melting point 209-211 ° C; 1 H NMR (400 MHz) (acetone-d 6) d: 1.72-1.74 (m, 6H), 3.72-3.79 (m, 4H), 8.12 (s, 1 H), 8.29 (s, 1 H). LRMS: 228 (M + 1).

EXAMPLE 79 5-Ethinyl-4-p-perpentin-1-yl-7H-pyrrolor-2,3-d-pyrimidine PROCEDURE P 4-Chloro-5-vodo-7H-pyrrolor-2,3-dlpyrimidine 4.5 g (0.02 mole) of N-iodosuccinimide was added to a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (30 g, 0.02 mole) dissolved in 80 ml of chloroform and The resulting mixture was heated to reflux for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure to give 4.6 g (82%) of the title compound.

PROCEDURE Q 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolof2,3-d1-pyrimidine The title compound was prepared as described above in procedure L using the product of procedure O, yielding 5.4 g (80%) of material. LRMS: 419.6 (M + 1), 279.7.

PROCEDURE R 7-Benzenesulfonyl-5-vodo-4-piperidin-1-yl-7H-pyrrolof2,3-dlpyrimidine The title compound was prepared by the procedure described in procedure M using the product of procedure Q, yielding the title compound. LRMS: 469 (M + 1), 329.1.

PROCEDURE S 7-Benzenesulfonyl-4-piperidin-1-yl-5-triethylsilanylethynyl-7H-pyrrolor-2,3-dlpyrimidine 211 mg (0.5 mmol) of the product of procedure R, 19 mg (0.1 mmol) of copper iodide (I) and 58 mg (0.05 mmol) of tetrakis (triphenylphosphine) palladium were charged to a flame-dried flask under nitrogen. To this mixture were added 0.14 ml (1.0 mmol) of triethylamine and 0.27 ml (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 ml of dry DMF. The resulting mixture was stirred at room temperature for 3 hours, at which time 5.0 ml of water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over MgSO 4 and concentrated in vacuo. The resulting crude product was then purified by chromatography on silica gel (hexanes: ethyl acetate 7: 1) to give 194 mg (89%) of the title compound. LRMS: 481 (M + 1), 341.

PROCEDURE T 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolof2,3-dlpyrimidine 0.4 ml (0.4 mmol) of a 1M solution of tetrabutylammonium fluoride in THF was added dropwise to a stirred solution of the product of procedure S (194 mg, 0.40 mmol) dissolved in 2.0 ml of dry THF. The resulting mixture was stirred at room temperature for 10 minutes, then transferred to a methanolic solution (3.0 ml) containing 1 g of KOH, the new mixture was stirred at room temperature for 15 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, the ethyl acetate layer was washed with water and brine, dried over MgSO4 and concentrated to dryness in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate.hexanes 2: 1) to afford 72 mg (64%) of the title compound as a white crystalline solid. Melting point 179-181 ° C. 1 H NMR (400 MHz) (CDCl 3) d: 1.72 (broad s, 6H), 3.20 (s, 1 H), 3.82-3.83 (m, 4H), 7.47 (s, 1 H), 8.35 (s, 1 H). LRMS: 227 (M + 1).

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or their pharmaceutically acceptable salts, wherein R 1 is a group of formula in which the broken line represents optional double links; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8; A and E are each CR7R8; and R6 is selected from the group consisting of hydrogen, C? -C6 alkyl, trifluoromethyl, trifluoromethyl (CrC6 alkyl), (CrC6 alkyl) (difluoromethylene), (C3 alkyl) (difluoromethylene) (CrC3 alkyl), (CrC6 alkoxy) ( acyl CrC6), (C 1 -CJamino alkyl (C Cß acyl), (C 6 alkyl) 2amino (Ci-Cß acyl), C 6 -C 0 aryl, C 5 -C 6 heteroaryl, (C 6 -C 6 aryl) (CrC 6 alkyl ), (C5-Cg heteroaryl) (C6-alkyl), (C6-C6-aryl) (C6-C10-aryl), (C6-C10-aryl) (C6-C6-aryl) (C6-C6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (C-C-alkyl), hydroxy (C2-C6-alkyl), (Ci-C-acyloxy) (C2-C6-alkyl), (C-C6-alkoxy) (C2-C6-alkyl) ), piperazinyl (CrC 6 alkyl), (C 1 -C 6 acyl) amino (CrC 6 alkyl), (C 6 -C aryl) (C 6 alkoxy) (CrC 6 alkyl), (C 5 -C 6 heteroaryl) (C 1 alkoxy) C6) (CrC6 alkyl), (CrC6 alkyl) thio (C6 alkyl), (C6-C6 aryl) thio (C6 alkyl), (C6 alkyl) sulfinyl (C6 alkyl), (aryl Ce-Cio) sulfinyl (C? -C6 alkyl), (C? -C6 alkyl) sulfonyl (C? -C6 alkyl), (C6-C? o aryl) sulfonyl (Ci-C? alkyl), aminoalkyl C Ce, (C 1 -C 6 alkyl) amino (d-C 6 alkyl), (C 1 -C 6 alkyl), R 13 CO (C 6 alkyl), wherein R 13 is R 20 O or R 20 R 21 N, R 20 and R 21 being selected each independently from the group consisting of hydrogen, C? -C6 alkyl (aryl Ce-Cio) (C6 alkyl) or (C5-C9 heteroaryl) (C6 alkyl); or R14 (C2-C6 alkyl), where R4 is (acyl C Cjjpiperazino, (aryl C6-C? 0) piperazino, (heteroaryl C5-Cg) piperazino, (alkyl Cr Cjjpiperazino, (aryl C6-C? o) ( C 1-J-piperazino alkyl, (C 5 -Cg heteroaryl) (Ci-C 1 -piperazino alkyl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 alkyl) piperidyl, (C 6 -C 6 aryl) piperidyl, (C 5 heteroaryl) C9) piperidyl, (aryl Ce-Cι) (Ci-Cß-piperidyl alkyl, (Cs-C9 heteroaryl) (C 1 -C 6 alkyl) piperidyl, (CrCßJacyl alkoxy, (CrCßJaminoaryl alkyl, (alkyl or (C 1 -C 6) piperidyl) R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, C-Cß-amino-hydroxy alkyl, Cr-Cß-alkoxy, (CrC6-alkyl) amino, (C-C6-alkyl) 2-amino, (C 1 -C 6) amino, ( acyl CrC6) (C alqu-C6 alkyl) amino, carboxy, (C?-C6 alkoxy) acyl, (C CßJaminoacyl alkyl, (C?-C6 alkyl) 2aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl (d-Cß alkyl), ( alkyl C? -C6) (difluoromethylene), (C? -C3 alkyl) difluoromethylene- (alkyl dC3) , aryl C6-C? 0, heteroaryl C5-Cg, (aryl C6-C? 0) (C? -C6 alkyl), (heteroaryl Cs-Cg) (C6 alkyl), (aryl C6-C? 0) ( aryl C6-C? 0), (aryl C? -C? 0) (aryl C6-C? 0) (CrC6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (d-C6 alkyl), hydroxy (alkyl) d-Cß), (acyloxy CrC6) (C? -C6 alkyl), (C? -C6 alkoxy) (C? -C6 alkyl), piperazinyl (C? -C6 alkyl), (C? -C6 acyl) amino ( alkyl d-C6), piperidyl, (alkyl d-C6) piperidyl, (aryl C6-C? 0) (alkoxy CrC6) (C6 alkyl), (heteroaryl C5-Cg) (C6 alkoxy) (alkyl d-C6) ), (alkyl d-C6) thio (d-C6 alkyl). (aryl C6-C? 0) thio (C? -C6 alkyl), (C? -C6 alkyl) sulfinyl (C? -C6 alkyl), (C6-C? o aryl) sulfinyl (d-C6 alkyl), ( alkyl CrC6) sulfonyl (d-Cß alkyl), (aryl Ce-Cι) sulfonyl (d-Cß alkyl), amino (Ci-Cß alkyl), (CrCßJamino alkyl (d-Cß alkyl), (d-C6 alkyl) 2amino (alkyl d-C6), R13CO (C6 alkyl) or R13CO (C3-C6 cycloalkyl), where R13 is R20O or R20R21N, each being selected from R20 and R21 independently of the group consisting of hydrogen, C -Cß alkyl, (aryl Cedo) ) (alkyl d-C6) or (C5-C9 heteroaryl) (C6-alkyl); R14, R14-d6-C6 alkyl or R14-C3-C10 cycloalkyl, with R14 (acyl C? -C6) piperazino, (aryl) Cß-C? O) piperazino, (C5-C9 heteroaryl) piperazino, (CrC6 alkyl) piperazino, (aryl Cedo) (C? -C6 alkyl) piperazino, (Cs-C9 heteroaryl) (C? C6) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 alkyl) piperidyl, (C 6 -C 6 aryl) piperidyl, (C 5 -Cg heteroaryl) piperidyl, (aryl C 6 -do) (alkyl d) -CßJpiperidyl, (heteroaryl Cs-C9) (alkyl) Ci-Cβ-piperidyl or (acyl CrC 6) piperidyl; or a group of formula where p is O, 1, 2 or 3; and Z is hydroxy, d-C6 alkoxy or NR1R2, each of R1 and R2 being independently selected from the group consisting of hydrogen, C? -C6 alkyl, piperidyl, (C? -C6 alkyl) piperidyl, (C6-C? ) piperidyl, (C5-C9 heteroaryl) piperidyl, (aryl Ce-Cι) (C 1 -C 6 alkyl) piperidyl, (C 5 -C 6 heteroaryl) (C 1 -C 6 alkyl) piperidyl, (C 1 -piperidyl acyl, aryl Ce) Cι, heteroaryl C 5 -Cg, (aryl C 6 -C 0) (alkyl CrC 6), (heteroaryl C 5 -Cg) (C 1 -C 6 alkyl), (aryl C 6 -C 0) (aryl C 6 -C 0) , (aryl Ce-Cío) (aril Ce-Cío) (alkyl d-Ce), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (C? -C6 alkyl), R5 (Ci-Ce alkyl), (C1 alkyl) -C5) (CHR5) (C? -C6 alkyl), where R5 is hydroxy, C? -C6 acyloxy, CrC6 alkoxy, piperazino, (acyl C? -Ce) amino, (C? -Ce) alkyl, (aryl C6) - C? O) thio, (C1-C-sulphonyl) alkyl, (C6-C6-alkylaryl) sulfinyl, (CrCSis-sulfoxyl alkyl, (C6-C6-aryl) sulfoxy, amino, (C6-alkyl) amino, (C-alkyl) ? -C6) 2amino, (acyl C? -C6) piperazino, (alkyl C? -Ce) piperazino, (aryl Ce-Cio) (alkyl C? -Ce) piperazinc (heter oaril C5-Cg) (C 1 -C 6 alkyl) piperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (alkyl d-Ce), (C 5 alkyl) (CHR 6) (C 1 -C 6 alkyl), where R 6 is piperidyl, (C 1 -C 6 alkyl) piperidyl, (C 6 -C 6 aryl) piperidyl, (C 6 -C 6 aryl) 0) (alkyl d-Cβ-piperidyl, (C5-Cg heteroaryl) piperidyl or (heteroaryl Cs-Cg) (alkyl d-Ce) piperidyl; or when n is at least 1, D and E, or D and X are each one CR7R8, the adjacent R7 groups can be taken together with the carbon atoms to which they are attached, forming groups of the formulas VI in which the broken lines represent optional double bonds, a is 0, 1 or 2; m, A, B and X are as defined above, and G, J, L and M are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 as defined above, or when n is 1, D and E are each CR7R8 and m is 1, A and B are each CR7R8, the respective adjacent R7 groups can be taken together with the carbon atoms to which they are attached. united, forming a group of formula wherein the discontinuous link represents optional double bonds; a, G, J, L and M are as defined above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S (O) d, where de is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, trifluoromethoxy, C-Cß alkyl, C C-C alco alkoxy, alkyl or alkoxy groups optionally substituted with one to three groups selected from halo, hydroxy, carboxy, amino (C 1 -C 6 alkyl) thio, (C 1 -Cyamino alkyl, C 1 -C 6 alkyl) amine, C 5 -C 6 heteroaryl , (C2-Cg heterocycle) alkyl, C3-C6 cycloalkyl or C6-C6 aryl or each of R2 and R3 is independently C3-C10 cycloalkyl, C3-C10 cycloalkoxy, (C? -C6 alkyl) amino, ( C6 alkyl) 2amino, (C6-C6alkylamino), (d6alkyl) thio, (C6-C6alloy) thio, (alkyl d-Ce) sulfinyl, (C6-C6alkylaryl) sulfinyl, (C 1 -C 6 alkyl) sulfonyl, (C 6 -C 6 aryl) sulfonyl, C Cß acyl, (CrC 6 alkoxy) -CO-NH-, (d-C 6 alkyl) amino-CO-, C 5 -C 9 heteroaryl , (C2-C9 heterocycle) C6-C6 alkyl or aryl, or the heteroaryl, heterocycloalkyl and aryl groups being optionally substituted with u not to three halo, alkyl d-Cß, (alkyl d. C6) -CO-NH-, (alkoxy Ci-CeJ-CO-NH-, (alkyl d.C6) -CO-NH- (alkyl d.Ce), (alkoxy C? .C6) -CO-NH- ( alkyl Ci.Ce), (alkoxy C? .C6) -CO-NH- (alkoxy Ci.Ce), carboxy, carboxy (alkyl d.C.sub.β), carboxy (C.sub.1 -C.sub.beta.-alkoxy), benzyloxycarbonyl (C.sub.2 -alkoxy) .C6), (C1-C6 alkoxy) carbonyl (d-Cß alkoxy), Ce-Cio aryl, amino, amino (Ci.Ce alkyl), (C? -C6 alkoxy) carbonylamino, (aryl Ce-Cio) (C 1 -C 4) alkoxycarbonylamino, (C 1 -C 4 alkyl) amino, (C 1 -C 6 alkyl) 2amino, (C 1 -C 4 alkyl C 1-6C), C 1 -C 6 alkyl 2 amino (C 1 alkyl) C6), hydroxy, d-C alco alkoxy, carboxy, carboxy (C?-C6 alkyl), (C?. C6 alkoxy) carbonyl, (C alco.Ce) alkoxycarbonyl (C?-C6 alkyl)(alkoxy Ci-Cei-CO-NH-, (alkyl d.C6) -CO-NH-, cyano, (C5-Cg heterocycle) alkyl, amino-CO-NH-, (C? -C6 alkyl) amino- CO-NH-, (Ci-Cekamino-CO-NH- alkyl, (C6-C? 0 aryl) -CO-NH-, (C5.C9 heteroaryl) amino-CO-NH-, (C6 alkyl) amino -CO-NH- (C. C6 alkyl), (C? .C6 alkyl) 2 amino-CO- NH- (C? -C6 alkyl), (C6-C10 aryl) amino-CO-NH- (Ci.Ce alkyl) ), (C5-C9 heteroaryl) amino-CO-NH (dC alkyl), (Ci-Cs-sulphonyl alkyl, (dCe) alkylphonylamino, (dC6 alkyl) sulfonylamino (C? C6 alkyl), (aryl) C6-C ?o) sulfonyl, (C 6 -C 6 aryl) sulfonylamino, (C 6 -C 10 aryl) sulfonylamino (C 1 -C 6 alkyl), (C 1 -C 4 alkyl) sulfonylamino, (C 1 alkyl) sulfonylamino (dC alkyl), heteroaryl Cs-Cg or (C2-C9 heterocycle) alkyl; provided that when A, B or X, in formulas V or VI, are defined as NR6 or CR7R8, R2 and / or R3 must be halo; provided that when R2 and R3 are each independently hydrogen or d-Cß alkyl, R1 can not be unsubstituted piperidinyl; provided that when R2 and R3 are each hydrogen, R1 can not be morpholino or unsubstituted pyrrolidinyl; provided that when R2 and R3 are each hydrogen, R1 can not be piperazinyl and provided that the groups of formulas IV, V, VI or XIII do not contain two or more oxygens, sulfur or combinations thereof at adjacent positions.

2. The compound according to claim 1, wherein R1 is a group of formula in which the broken line represents optional double links; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8; A and E are each independently CR7R8 or NR6; or when n is 1, D and E are each CR7R8 and m is 1, A and B are each CR7R8, the respective adjacent R7 groups can be taken, together with the carbon atoms to which they are attached, forming a group of formula wherein the discontinuous link represents optional double bonds; a, G, J, L and M are as defined above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above.

3. The compound according to claim 1, wherein R2 and R3 are each independently selected from the group consisting of hydrogen, d-Cß alkyl, Ci.Ce alkoxy, C3-C10 cycloalkyl, C3 cycloalkoxy. C10, (C2-Cg heterocycle) alkyl, Cs-Cg heteroaryl or Ce-Cio aryl.

4. The compound according to claim 1, wherein said compound is selected from the group consisting of: 5-fluoro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 4-piperidin-1-yl-5-trifluoromethyl-7H-pyrrolo [2,3-d] -pyrimidine; 2-. { 3-ethyl-4- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclopenti} -propan-2-ol; 2-. { 3-ethyl-4 - [(2-hydroxy-ethyl) - (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -amino] -cyclopentyl} -propan-2-ol; N, N-dimethyl-N '- [3- (4-piperidin-1-yl-7H-pyrrolo [2,3-d] -pyrimidin-5-yl) benzyl] -ethane-1,2-diamia; 2- [1 - (5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -piperidin-4-yl] -ethanol; 5- (3-isopropyl-phenyl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (3-methyl-3H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (1-methyl-1 H-imidazol-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5- (2-methyl-pyridin-4-yl) -4-piperidin-1-yl-7H-pyrrolo [2,3-d-pyrimidine; 5-chloro-4-piperidin-1-yl-7H-pyrrolo [2,3-d] pyrimidine; 5-chloro-4- (octahydro-indol-1-yl) -7H-pyrrolo [2,3-d] -pyrimidine; 5-ethynyl-4-piperidin-1-I-7H-pyrrolo [2,3-d] pyrimidine; 4-piperidin-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] pyrimidine; and 4- (3,3-Dimethyl-piperidin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine.

5. The pharmaceutical composition for (a) treating or preventing the disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis , autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibit the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human being, comprising a The amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, effective in said disorders or conditions and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition for (a) treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis , autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibit the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human being, comprising a The amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents, effective in said disorders or conditions and a pharmaceutically acceptable carrier. .

7. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human being.

8. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, sclerosis Multiple, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being.

9. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, alone or combined with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents for manufacturing of a medicament for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human.

10. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents for manufacturing of a medication to treat or prevent a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being.