MX2008007981A - Inhibitors of ccr9 activity - Google Patents

Abstract

N-(benzenesulphonyl)-2,3-dihydro-1H-indols, wherein the indol is substituted by cyano, carboxy or alkylcarbonyloxy and their use as therapeutical agents.

Description

INHIBITORS OF CCR9 ACTIVITY The present invention relates to inhibitors of CCR9 activity The chemokine ligand CC 25 (CCL25), originally described as chemokine expressed by the thymus (TECK), plays a crucial role in the initiation of T cells to the small intestine by means of signaling through the chemokine receptor CC 9 (CCR9) CCL25 is expressed constitutively within the small intestine, especially in the epithelial crypts, while it is weakly or not at all in the colon and on other mucosal surfaces CCR9 is the only receptor known for TECK / CCL25 The expression of CCR9 strongly correlates with the ability of peripheral T-lymphocytes to start in the small intestine Most intestinal intraepithelial lymphocytes (IEL) and T-nuclides of lamina proppa ( LPL) with CCR9 +, while a much lower percentage of T-cells circulating in the blood are CCR9 + T-cells CCR9 + in the peripheral blood exhibit c thus exclusively the receptor of intestinal initiation a4ß7 The blockade of CCR9 with the antibody against TECK / CCL25 significantly inhibits the initiation of T-hnfocytes in the small intestine In addition, there is a strict location of TECK / CCL25 and LPL CCR9 + in the small intestine instead of being in the large intestine, suggesting a distinctive mechanism of lymphocyte recruitment in different segments of the gastrointestinal tract Studies have also suggested a role of TECK / CCL25 in the interaction of T-endothelium nphocytes in the inflamed intestinal mucosa. There is an increase in TECK / CCL25 expression and a better adhesion of LPL to the mucosa of the small intestine after stimulation. of TNFa Desensitization of CCR9 or anti-TECK / CCL25 could attenuate the recruitment of nphocytes in microvessels of the small intestine Therefore, targeted blockade of CCL25-CCR9 interactions can provide effective therapeutic treatment in immune diseases. mediated, for example, intestinal disorders, such as autoimmune and inflammatory diseases or conditions. The infiltration of T-cells (T-cells) in the small intestine and colon has been specifically related to the pathogenesis of certain diseases, allergies to food, rheumatoid arthritis, human inflammatory bowel diseases (IBD), which include Crohn's disease and colitis ulcerative, for example including ulcerative proctitis Diseases that are also described as being mediated by CCR9, for example, include allergic diseases, sopasis, atopic dermatitis, asthma, fibrotic diseases, disorders and diseases that originate or that are mediated by transplantation, for example graft rejection, and cancer, such as leukemia (acute nphocytic leukemia), solid tumor, thymoma, thymic carcinoma Now, new compounds have been found that show surprising activity as inhibitors of CCR9 In one aspect, the present invention provides a compound of the Formula wherein Ri is hydrogen, alkyl, such as alkyl (of 1 to 6 carbon atoms), for example, terbutyl, haloalkyl, such as haloalkyl (of 1 to 4 carbon atoms), alkoxy, such as alkoxy (from 1 to 4 carbon atoms), haloalkyloxy, such as haloalkoxy (of 1 to 4 carbon atoms), or halogen, for example, F, Cl, Br, preferably R, is alkyl (of 1 to 6 carbon atoms), for example, terbutyl; R2 is substituted or unsubstituted phenyl, for example, phenyl substituted by one or more of alkyl, such as alkyl (of 1 to 6 carbon atoms), for example, terbutyl, haloalkyl, such as haloalkyl (from 1 to 4 carbon atoms), alkoxy, such as alkoxy (from 1 to 4 carbon atoms), haloalkyloxy, such as haloalkoxy (from 1 to 4 carbon atoms), or halogen, preferably R2 is unsubstituted phenyl or phenyl substituted by halogen, and R3 is carboxyl (-COOH), alkoxycarbonyl, such as alkoxy (1 to 4 carbon atoms) -carbonyl, eg, methoxycarbonyl, or cyano In a compound of formula I, each individual defined substituyeme can be a preferred substituent, example, a substitueme defined independently of one another In another aspect, the present invention provides a compound selected from the group consisting of methyl ester of 1- (4-tert-butyl-1-benzenesulfonyl) -2, 3-Hydro-1H-β-ddol-2-carboxylic acid, 1- (4-tert-butyl-1-benzenesulfonyl) -2,3-d? H? Dro-1 H- indo I-2-carboxylic acid, 5-bromo-meth-l-ester of 1 - (4-tert-butyl-l-benzenesulfonyl) -2,3-d? h? dro-1 H-? ndol-2 -carboxyl alcohol, and 5-bromo-1 - (4-tert-butyl-1-benzenesulfonyl) -2,3-d? -hydro-1 H-β-dol-2-carboxylic acid The compounds provided by the present invention are hereinafter referred to as the "compounds of (in accordance with) the present invention" A compound of the present invention includes a compound in any form, for example in free form, in the form of a salt, in the form of a solvate, and in the form of a salt and a solvate. In another aspect, the present invention provides a compound of the present invention in the form of a salt. These salts preferably include salts pharmaceutically acceptable, although pharmaceutically unacceptable salts are included, for example, for preparation / isolation / pupilization purposes The present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture. The present invention also includes tautomers. of a compound provided by the present invention, wherein tautomers may exist In another aspect the present invention provides a process for the production of a compound of Formula I, which comprises the steps of reacting a compound of the Formula wherein Ri and R3 are as defined above, with a compound of the formula Cl-S02-R2 III wherein R2 is as defined above, and b isolating a compound of the formula I obtained from the reaction mixture In a intermediary of Formula II or Formula III (starting materials), functional groups, if present, optionally they may be in a protected form or in the form of a salt, if a salt-forming group is present. Protective groups, optionally present, may be removed at an appropriate stage, for example in accordance with, for example in an analogous manner. a, a conventional method A compound of the present invention thus obtained can be converted into another compound of the present invention, for example a compound of the present invention obtained in free form can be converted into a salt of a compound of the present invention, and vice versa. The above reaction is an amine sulfonylation reaction, and may be carried out as appropriate, for example in a manner analogous to a conventional method, or as described herein. Intermediates (starting materials) of the Formula II and Formula III are known or can be prepared according to, for example in a manner analogous to, a conventional method, or as described. Any of the compounds described herein, for example a compound of the present invention and the intermediates of Formulas II and III, may be prepared as appropriate, for example in accordance with, for example, in a manner analogous to, a conventional method, for example, or as specified herein. For example, in the case that phenyl in a compound of the Formula I is substituted by carboxyl, it may be an option to protect this caboxyl group in a compound of formula II, for example, by esterification, to obtain a corresponding alkoxycarbonyl derivative The compound of formula II wherein aplo is substituted by alkylcarbonyloxy, it can be reacted with a compound of formula III, to obtain a compound of formula I, wherein the alkyl is substituted by alkoxycarbonyl, and the carboxylic acid ester obtained in this way can to be saponified, to obtain a corresponding compound of formula I, wherein aplo is substituted by carboxyl. The compounds of the present invention exhibit pharmacological activity and, consequently, are useful as pharmaceuticals. The compounds of the present invention show an inhibition-dependent inhibition. the dose in the Proximity Test of scintillation (ENSAYO SPA), ESSAY of the Eu-GTP binding, Test of m calcium mobilization (FLIPR ESSAY), for example, under conventional conditions, for example under the conditions described herein, for example in the nanomolar IC50 up to the low micromolar range The activity in the treatment of inflammatory bowel disease is determined, by example, in a SCID mouse model of inflammatory bowel disease.

Scintillation Proximity Test (SPA) The Principle of SPA Chemokines mediate their actions through seven transmembrane extension-G-protein-coupled receptors (GPCR) on target cells Ligand binding with GPCRs stimulates the GTP / interval GDP in heterotpmépcas G proteins, composed of the subunit of a, ß, yy The GPCR linked to the agonist initiates the guanine nucleotide cycle by catalyzing the dissociation of GDP from the subunit-a, allowing the binding of the endogenous GTP, and the dissociation of the β-complex The Ga-GTP and Gßy subunits can each activate the effectors, such as the adenyla cyclase, the phospho-pass C, and the ion channels (see, for example, Neer EJ, Cell, 80249-57 (1995 )) Ga-GTP is inactivated by an intrinsic activity of GTPase, which hydrates GTP up to GDP, subsequently, the G-protein containing GDP is ready for the next activation cycle. This process can be monitored in vitro by measuring the binding of GTP analogs resistant to hydrolysis, such as 5'-0- (3- [35S] -t? -osphate ([35S] -GTP? S), with the membranes Cells containing the receptor of interest It is shown that a GTPyS scintillation proximity assay (SPA) is a functional assay useful for monitoring the activation of CCR9 by TECK SPA is a homogeneous and versatile assay technology for fast and sensitive assay of a large number of processes Biological The assay format does not require separation steps, and is susceptible to automation. The membranes carrying the receptor are coupled via the glycoprotein fraction to the beads coated with fluorescent wheat germ agglutinin (Amersham Bioscience, #RNPQ 0001) Once immobilized, the receptor is close enough to the bead that, if the GPCR linked to the agonist initiates the guanine nucleotide cycle, [35S] -GTP? S (Amersham Bioscience, # SJ1308) binds to the membrane The radioactive molecule will be kept in close enough proximity so that the decaying particles stimulate the sparkle inside the bead to emit light, which is then detected by a PMT-based emulation counter. The unlinked radiohunger is too distant from the pearl to transfer energy, and therefore, goes undetected Cells and Cell Culture Pre-B mouse cells are grown 300-19 t ransfected with the human CCR9 receptor in suspension in cell culture flasks (100 milliliters of cell suspension in a 162 square centimeter cell culture flask) at 37 ° C in a humidified atmosphere containing 5 percent C02 in an RPMI medium 1640 supplemented with penicillin (100 International Units / milliliter), streptomycin (0 1 milligrams / milliliter), L-glutamine (up to a final concentration of 45 nM), 10 percent fetal bovine serum, 1 mM sodium pyruvate, 2- mercapto-ethanol 005 μM, 1 5 micrograms / milligram of puromycin, and 20 mM Hepes Cells can be used for approximately 12 steps for membrane preparation (ie, the density of the CCR9 receptor is acceptably high enough) The expression of CCR9 is monitored by FACS analysis using Human CCR9 antibody conjugated to Fluor 647 Alexa The expression of CCR9 should not be less than 50 percent positive cells by means of FACS in relation to the control of the fluorine isotype Alexa As an approximation, a 10 x culture can be divided 105 cells / milliliter, using a dilution of 1.30 to 1.50, and reach the initial cell density after 2 to 3 days (approximately 4 to 5 days for a centrifuge flask culture). Cells are harvested at a density of 8 to 10 x 105 cells / milliliter by centrifugation at 300-100 g for 10 minutes. In general terms, the cells are cultured and expanded to result in approximately 1 x 1010 cells. The combined cell granule is washed once in cold phosphate buffered serum (without calcium or magnesium), resuspended by pipette in the cold membrane regulator at approximately 2 x 108 cells / milliliter, freeze on dry ice, and store at -80 ° C Membrane Regulator Membrane regulator, pH = 7.5 (1000 milliliters) Tris 75 mM, MgCI2 125 mM, EDTA 0.3 mM, EGTA 1 mM, sucrose 250 mM, filtrate sterile, and stored at + 4 ° C Homogenization regulator (50 milliliters) Membrane regulator, 45 milliliters + 10 percent glycerol Membrane Preparation Pipette the cell suspension solution into strong tubes, and homogenize each solution. The homogenates are transferred to centrifuge tubes, and centrifuge for 10 minutes at 1,000 g. The supernatants are collected. 20 milliliters of new membrane regulator are added to each granule, transferred to the original strong tubes, and homogenized and centrifuged once more. The supernatants are collected. The combined supernatants are centrifuged. at 40,000 g for 30 minutes. Each granule is resuspended in 3 milliliters of cold homogenization buffer with a Dounce homogenizer. The concentration of protein in the homogeneous suspension is determined (BIO RAD assay, reference for bovine serum albumin) Bradford method ( microassay procedure) As an approximation, 1 x 1010 cells give as result a membrane yield of 10 to 20 milligrams of protein Aliquots are stored at -80 ° C Optimized Regulators and Solutions for the Test of Regulatory Compounds HEPES / BSA 50 mM HEPES (pH of 74), 50 micrograms / ml of albumin of bovine serum Regulator of assay 25 X HEPES 50 mM, pH of 74, 50 micrograms / milli tro of bovine serum albumin, 25 mM MgCl 2, 25 μM GDP, 250 mM NaCl, 375 micrograms / milliliter of TECK saponin Dilutions of TECK are prepared with 0 1 percent bovine serum albumin in phosphate-buffered serum to provide a 20-fold TECK solution for the GTP binding assay. For the compound test, a 74 μM TECK concentration is used, to give a final concentration of 037 μM in the reaction. Dilution of compounds. The test compounds are dissolved. in dimethyl sulfoxide at 100 times the highest, the final concentration in the test are made in series of these compound solutions concentrated in dimethyl sulfoxide, which are diluted five times in HEPES / BASA regulator to generate solutions of the concentrated compounds 20 times, which contain a concentration of dimethyl sulfoxide of 20 percent (volume / volume) The final concentration of dimethyl sulfoxide in the tests is 1 per cent. nt (volume / volume) Membrane Dilution Before use, the membranes (24 milligrams / milliliter of supply, lot CCR9-1) are diluted in HEPES / BSA regulator, to give 60 micrograms / milliliter 50 microliters of this membrane are added to each well (Final test concentration of 3 micrograms / well for membrane lot CCR9-1) Final test condition for the 50 mM HEPES compound test, pH of 74, 50 micrograms / milliliter of albumin bovine serum, 100 mM NaCl, 10 mM MgCl 2, 10 μM GDP, 150 micrograms / milliliter of saponin, TECK 037 μM, and 3 micrograms / well of membrane Test Protocol The test is carried out in the zero time format, which involves the sequential addition of the test samples, membrane, radiohgando, and beads as separate additions without prior incubation. Briefly stated, the membranes are incubated in the presence of the agonist and the compound with [35S] GTP? S and the scintillation beads for 1 hour at room temperature in a vibrating mixer Using a liquid handling robot, the following reagents are dispensed in a White &Clear 96 well isoplate (Wallac, # 1450-515) in the following 40 microliter sequence. assay regulator (HEPES 20 mM, pH of 75, 100 mM NaCI 10 mM MgCl 2, 1 μM GDP, 10 micrograms / milliliter of saponin, 50 micrograms / ml of bovine serum albumin) 10 microliters of human TECK / CCL25 agonist, 25 micrograms / milliliter (R &D Systems, # 334-TK-025) 10 microliters of sample in 50 percent dimethyl sulfoxide 50 microliters of membranes, 60 micrograms / milliliter in assay buffer 50 microliters of [35S] GTP? S, 1 nM in assay buffer 40 microliters of bead suspension, 1875 milligrams / milliliter of assay regulator After incubation, the plates are centrifuged for 5 minutes at 1,000 xg, and counted in the MicroBeta Counter (EG &G Wallac) in counting mode. SPA ParaLux Data Analysis Data analysis is carried out with the software package Excel Fit 40 (Microsoft) In order to determine the amount of the experimental window of the test, the Z-factor is calculated, using only the data control (baseline values and stimulated values) For this test, Z 'is estimated with 073, which indicates a large separation band, and an excellent overall test quality. Eu-GTP LINK TEST The Principle of the EU LINK TEST -GTP A fluorometropic method resolved in time to measure the activation of G-protein, which uses a GTP analog labeled with non-hydrolysable, non-radioactive europium, Eu-GTP Materials RPMI 1640 medium (made of powder, Gibco # 074- 0180 0) Penicillin / streptomycin solution, liquid (Gibco # 15140-122) Fetal bovine serum (certified, obtained from Gibco [# 16000], and then inactivated by heat) Sodium pyruvate (Gibco # 11360-039) Puromycin (used as a selection marker, Sigma # P-8833) Complete protease inhibitor (Roche # 1697498) Mouse human anti-CCR9 antibody conjugated with Fluor 647 Alexa (Pharmingen # 557975) Isotype control IgG2a conjugated with Fluor 647 Alexa (BD Pharmingen 3557715) TECK (aa24-150-h? S6, Protein Database with BMP Tool # BTP04-005213, Aliquots of TECK supply solution (5 milligrams / milliliter, approximately 350 μM) stored at -80 ° C Bovine serum albumin (Roche Diagnostics GmbH # 775827) Eu -GTP (Perkin-Elmer Life Sciences, Wallac, Turku, Finland, product code AD0260), the kit contains the following components Eu-GTP (1 65 nanomoles) The Eu-GTP of 11 is reconstituted with distilled water to provide a Eu-GTP concentration of 10 μM The aliquots of the reconstituted Eu-GTP were stored at -20 ° C GDP (23 micromoles) The lyophilized GDP is reconstituted with distilled water to provide a GDP concentration of 2 mM The aliquots of the reconstituted GDP are stored at -20 ° C VICTOR2MR V Multilabel Counter (Perkm-Elmer Life Sciences, Wallac, Turku, Finland) MultiScreen vacuum manifold (Millipore #MAVM 096OR) Cells and Cell Culture To carry out lameness is described in the present under "Cells and cell culture" in the "Proximity test of scintillation (SPA) "Membrane Regulator and Homogenization Regulator To be carried out as described herein below "membrane regulator and homogenization regulator" in the "Scintillation Proximity Test (SPA)" Preparation of Membranes To be carried out as described herein below "Membrane preparation" in the "closeness test of scintillation (SPA)" Optimized Regulators and Solutions for Testing Compounds To be carried out as described herein below "optimized regulators and solutions for the test of the compounds" in the "proximity test of scintillation (SPA)" For Eu-GTP The Eu-GTP supply solution is diluted to 10 nM in HEPES / BSA regulator before being used Solution GTP Wash Solution 10X GTP Wash Solution is diluted to 1 10 with distilled water, and cooled on ice Eu-GTP Linkage Test Protocol for Testing Compounds The Eu-GTP binding assay is carried out in a final volume of 100 micro-hours on Acro-Well filter plates.

Test components are added to the wells in the following order 40 microliters of assay buffer (25X) are added to each well (wells B2 to G12) 5 microliters of TECK (7.4 μM) are added to the wells of columns 2 to 11, and the final concentration of TECK in the assay is 037 μM. 5 microliters of 0 1 percent bovine serum albumin are added to the wells of column 12, which serve as the baseline control. Add 5 micro-hours of each compound concentration (20 times of the final concentration in 20 percent dimethyl sulfoxide) in triplicate to columns 3 to 11 (ie, three wells per concentration). Add 5 microliters of dimethyl sulfoxide. 20 percent to the wells of columns 2 and 12, which are the stimulated and basal controls, respectively. The final dimethyl sulfoxide concentration in all the wells is 1 percent (volume / volume). 50 microhours of membranes (3 micrograms / sample) to all wells, and mixed for a short time at 800 revolutions per minute on a microtiter plate stirrer (MS1 Minishaker) The plate is incubated for 30 minutes with slow agitation at 300 revolutions per minute on an orbital plate shaker (MTS 2/4 digital microtiter agitator) 10 microliters of 100 nM Eu-GTP per well are added to provide a final concentration of 10 nM The plate is incubated a for another 30 minutes with slow agitation at 300 revolutions per minute on the orbital plate shaker The reaction is terminated by filtration vacuum, and the filter plate is washed twice by vacuum filtration with 300 microns of ice-cold GTP washing regulator per well. The Eu-GTP retained on the filter is measured with a VICTOR2MR V Multilabel Counter (excitation of 340 nanometers / emission of 615 nanometers, delay of 0.4 microseconds, window of 0.4 milliseconds) within 30 minutes after the wash step.

Table A (Unfolding the Plate) Data Analysis The actual Eu-GTP binding signal elicited by the agonist stimulus (= a) is compared to the basal link (= b), and the final result is calculated as a percentage on the basal link [percentage on the basal = (a / bx 100) - 100].

The dose response curves for the percentage of stimulus above the basal link calculated for each test compound are adjusted using the program added to Excel, XLf? TMR (ID Business Solutions, Guilford, Surrey, United Kingdom), for the equation four parameter logistics (Model 205) y = A + ((BA) / (1 + ((C / x) D))) where x are the concentration values, and is the percentage of the stimulus above the corresponding basal link to the values of The adjusted parameters are A Lower plane of the curve, B Upper plane of the curve, C Value of x to the middle of the curve (that is, between the upper and lower plains), D Tilt factor (also known as Hill coefficient) The IC50 is defined as the point at which Half of the path between the solvent control containing TECK, and the solvent control without stimulus The Z 'value is calculated using only the control data (6 basal values and 6 stimulated values) for each experiment Z varies between 056 and 079 in all assays In another aspect, the present invention provides for the use of the SPA assay, or the use of the Eu-GTP LINK TEST in a process for the identification of CCR9 inhibitors. The SPA and the Eu-GTP LINK TEST are used as described herein The CCR9 inhibitors that can be identify by using these assays include antibodies and chemical compounds, for example, low molecular weight compounds Calcium Mobilization Assay a) The Principle of the Calcium Mobilization Assay The chemokine receptors are the seven transmembrane receptors coupled with sensitive Gai protein to pertussis toxin (PTX) A number of studies have demonstrated the activation of different signaling pathways for most chemokines and in multiple cell types, including an elevation of intracellular cytosolic calcium concentration ([Ca2 +], ) This process can be monitored in vitro by measuring the levels of ([Ca2 +],) by calcium-sensitive fluorescent dyes, using a fluorometropic imaging plate reader (FLIPR). Mobilization of intracellular calcium, in MOLT-4 cells, as measured using FLIPR technology, is shown as a useful functional assay to monitor the activation of CCR9 by TECK b) Cells and Cell Culture The human T-cell leukemia line MOLT-4 was obtained from the American Type Culture Collection (ATCC, Manassas, Va.) MOLT-4 cells are grown in medium, which is RPMI 1640 supplemented with 10 percent fetal calf serum, 2 mM L-glutamma, 100 Units / milliliter of penicillin, and 100 micrograms / milliliter of streptomycin, at 37 ° C, with C02 at 5 One hundred percent human serum albumin (HSA) is obtained at ZLB Behring (Vienna, Austria) as a 20 percent solution c) Calcium Mobilization Assay Protocol The following solutions are prepared • HPSS 701 grams of NaCl, 04 grams of KCI, 02 grams of MgSO4 »7H20, 476 grams of HEPES, 2 grams of Glucose» H20 (in 1 liter) Processing regulator (WB) 600 milliliters of HPSS + 09 milliliters of CaCl2 1M + 12 milliliters of HEPES 1M • Percentage of BSA / WB 60 milliliters of WB + 006 grams of bovine serum albumin (BSA, Sigma A7906) • Probenicide supply solution 356 milligrams of probenicide + 25 milliliters of 1M NaOH + 25 milliliters of WB • Probenicidal buffer 350 milliliters of WB + 35 milliliters of probenicide supply solution • Fluo-4 solution 50 micrograms of Fluo-4, AM + 0025 milliliters of dimethyl sulfoxide + 0025 milliliters of Pluronic G-127 (Invitrogen / Molecular Probes # P3000MP, supplied as 20 percent in dimethyl sulfoxide) Dye solution 105 milliliters of the medium + 1 05 milliliters of probenicide supply solution + 2 1 milliliters of 1M HEPES + 021 milliliters of Fluoc-4 TECK solution Prepared in 0 1 percent bovine serum albumin / WB MOLT-4 cells are harvested and loaded with Fluo- 4 / acetox? -met? L-ester (Fluo-4 / AM) according to the manufacturer's instructions (Invitrogen / Molecular Probes, Eugene, OR). Briefly stated, the cells are incubated (1 x 10 7 cells per 3 milliliters) in the dye solution for 60 minutes at 37 ° C and at 5 percent C02. Subsequently, the cells are washed twice with the Probenicidal buffer, and pipetted into the 96-well assay plates (clear bottom black polystyrene plates - Corning Costar # 3603) at 2 x 10 5 cells and 0.075 milliliters per well, and then centrifuged at 1,200 revolutions per minute for 3 to 4 minutes, to evenly distribute the cells at the bottom of the plates. The plates are incubated for 60 minutes in the dark at room temperature (RT), to allow desestepfication of the intracellular AM esters. The test compounds are first dissolved in dimethyl sulfoxide, and 0.006 milliliters of these delivery solutions are diluted in dimethyl sulfoxide, in 0.194 milliliters of WB (+ HSA) before being injected into the cell plates (0.025 milliliters / well) After a 30-minute incubation in the dark at room temperature, mobilization of intracellular Ca2 + is monitored after injection of TECK (to give an almost maximum effective concentration of at least EC8o), using a FLIPR instrument (Molecular Devices, Ismaning / Munich, Germany). The baseline readings are collected (at 3.5 second intervals) for 25 seconds before the TECK injection (0.025 milliliters / well), followed by 1 second intervals during the 80 seconds after the TECK injection The fluorescence readings are carried out using the standard positions, and all data are normalized using the Formula d) Calcium Calculus Response = [Fmax - Fm? n] / Fm? N where Fmax represents the maximum fluorescence response, and Fmm the minimum fluorescence of the baseline. The dose response curves for the calcium response data for each test compound are adjusted using the program added to X Lf it MR (ID Business Solutions, Guilford, Surrey, United Kingdom), for the four parameter logistic equation (Model 205), to determine the IC 50 values The compounds of the present invention show activity in the assays described herein, and a compound of the present invention is susceptible to showing a therapeutic activity in the treatment of disorders that are mediated by CCR9 activity. all of which are susceptible to being successfully treated with a CCR9 inhibitor, for example, include disorders where CCR9 activity has a causal or contributing role, such as disorders associated with the binding of CCR9. CCR9 with CCL25, for example, disorders mediated by the initiation of CCR9-mediated leukocytes in a subject Disorders, as used herein, include diseases Disorders that are susceptible to being mediated by CCR9 activity, for example, include - Disorders associated with inflammation for example, including inflammatory (chronic) disorders, disorders related to inflammation of the bronchi, for example including bronchitis, cervix, for example including cervicitis, conjunctiva, for example conjunctivitis, esophagus, for example esophagitis, cardiac muscle, for example myocarditis, rectum, for example proctitis, sclera, for example scleptis, gums, involving bone , pulmonary inflammation (alveo tis), respiratory tract, for example asthma, such as bronchial asthma, acute respiratory distress syndrome (ARDS), inflammatory skin disorders such as hypersensitivity to contact, atopic dermatitis, fibrotic disease (e.g., fibrosis) pulmonary), encephalitis, inflammatory osteo sis, Disorders associated with conditions d the immune system, immune, such as autoimmune disorders, for example including Graves' disease, Hashimoto's disease (chronic thyroiditis), multiple sclerosis, rheumatoid arthritis, arthritis, gout, osteoartptis, scleroderma, lupus syndromes, systemic lupus erythematosus, Sjoegren, sopasis, inflammatory bowel disease, including Crohn's disease, colitis for example ulcerative colitis, sepsis, septic shock, autoimmune hemolytic anemia (AHA), urticaria triggered by autoantibodies, pemphigus, nephritis, glomerulonephritis, Goodpasture syndrome, ankylosing spondylitis, Reiter's syndrome, pohmiositis, dermatomyositis, cytokine-mediated toxicity, neurotoxicity-2, alopecia areata, uveitis, lichen planus, bullous pemphigoid, myasthenia gravis, diabetes mellitus type I, immuno-mediated infertility such as premature ovarian failure, glandular failure, hypothyroidism, pemphigo vulgaps, pemphigo 1 -ol acetyl, paraneoplastic pemphigus, autoimmune hepatitis including that associated with the hepatitis B virus (HBV), and with the hepatitis C virus (HCV), Addison's disease, autoimmune skin diseases, such as sopasis, dermatitis herpetiformis , epidermohysis bullosa, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, chronic bullous disease of childhood, pernicious anemia, heme anemia tica, vitiligo, autoimmune poland glandular syndromes type I, type II, and type III, autoimmune hypoparathyroidism, autoimmune hypofisis, autoimmune Oofoptis, autoimmune orchitis, gestational pemphigoid, cicatricial pemphigus, mixed essential cipoglobulinemia, immune thrombocytopenic purpura, Goodpasture syndrome, autoimmune neutropenia, Eaton-Lambert myasthenic syndrome of rigid man, encephalomyelitis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, cerebellar degeneration, retinopathy, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, gluten-sensitive enteropathy, reactive arthritides, polymyositis / dermatomyositis, mixed connective tissue disease, Bechet's syndrome, polyarteptis nodosa, allergic anguitis, and granulomatosis (Churg-Strauss disease), langi itis overlap syndrome (hypersensitivity), vasculitis, Wegener's granulomatosis , temporal arteptis, Kawasaki disease, sarcoidosis, cpopatias, cardiovascular disease, Disorders associated with cytokine-mediated toxicity, for example, including interleukin 2 toxicity, Disorders associated with bones, for example, including osteoporosis, osteoartptis, disorders associated with the brain and nerves, neurodegenerative disorders, for example including disorders of the central nervous system as well as disorders of the peripheral nervous system, for example disorders of the central nervous system which include central nervous infections, brain injuries, cerebrovascular disorders and their consequences, Parkinson's disease, corticobasal degeneration, motor neuron disease, dementia including ALS, multiple sclerosis, traumatic disorders, including trauma and inflammatory consequences of trauma, traumatic brain injury, embolism, post-embolism, post-traumatic brain injury, cerebrovascular disease of small vessels, disorders in eating, in addition to dementias, for example including Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, and Parkinsonism linked to chromosome 17, frontotemporal dementias, including Picks disease, progressive nuclear paralysis, corticobasal degeneration, Huntington's disease, thalamic degeneration, Creutzfeld Jakob's dementia, dementia due to HIV, schizophrenia with dementia, Korsakoff psychosis, cognitive-related disorders, such as mild cognitive impairment, memory impairment associated with age, cognitive decline related to age, vascular cognitive impairment, attention deficit disorders, disorders of hyperactivity with attention deficit, and alterations of memory in children with learning disabilities, conditions associated with the hypothalamic-pituitary-adrenal axis, - Neuronal disorders, for example including neuronal migration disorders, hypotonia (reduced muscle tone), weakness muscle, attacks, delay of development (difficulty of physical or mental development), mental retardation, growth failure, feeding difficulties, lymphedema, micro headache, symptoms affecting the head and brain, motor dysfunction, Disorders associated with the eyes, for example including uveo- ptinitis, vitreo-retinopathy, cornea disease, iritis, ipdocic tis, cataracts, uveitis, diabetic retinopathy retinitis pigmentosa, conjunctivitis, keratitis, Disorders related to the gastrointestinal tract, for example, including colitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peptic ulceration, gastritis, oseophagitis, Disorders associated with heart and vascular conditions for example, including cardiovascular disorders, for example including heart failure, cardiac infarction, cardiac hypertrophy, heart failure, for example including all forms of heart pumping failures, such as high output and low output, acute and chronic, right side or left side, systolic or diastolic, Regardless of the underlying cause, myocardial infarction (MI), myocardial infarction prophylaxis (primary and secondary prevention), acute treatment of myocardial infarction, prevention of complications, heart disorders, prophylactic vascular disorders, vasculitides, pol larteptis nodosa, inflammatory consequences of ischemia, disease ischemic heart disease, myocardial infarction, embolism, peripheral vascular disease, pulmonary hypertension, ischemic disorders, for example including myocardial ischemia, for example stable angina, unstable angina, angina pectoris, bronchitis, asymptomatic arrhythmias such as all forms of tachyarrhythmias Headphones and Ventpcula, atrial tachycardia, atrial flutter, atrial fibrillation, reentrant tachycardia auricular-ventpcular, pre-excitation syndrome, ventricular tachycardia, ventpcular fluid, ventpcular fibrillation, bradycardic forms of arrhythmias, arrhythmia, chronic obstructive pulmonary disease, hypertension, such as high blood pressure or high blood pressure, for example, essential and secondary hypertension, including vascular disorders of hypertension, such as primary arterial hypertension as well as all kinds of secondary hypertension, renal, endocrine, neurogenic, and others, peripheral vascular disorders where the arterial and / or venous flow is reduced, resulting in an imbalance between the blood supply and the oxygen demand of the tissues, for example, including atherosclerosis, chronic peripheral arterial occlusive disease (PAOD), acute arterial thrombosis and embolism, inflammatory vascular disorders, Raynaud's phenomenon and venous disorders, atherosclerosis, a disease where the wall is remodeled of the vessels, for example including accumulation of cells, both of smooth muscle cells and of inflammatory cells of monocytes / macrophages, in the intima of the wall of the vessels; hypotension, disorders associated with the liver and kidneys, for example including kidney disorders, kidney disorders, for example acute kidney failure, kidney disease acute, liver disorders, eg cirrhosis, hepatitis, liver failure, cholestasis, acute / chronic hepatitis, sclerosing cholangitis, primary biliary cirrhosis, water / chronic interstitial glomerulonephritis, granulomatous diseases, - Disorders associated with stomach or pancreas conditions, for example, including stomach disorders, eg, gastric ulcer, gastrointestinal ulcer, pancreatic disorders, pancreatic fatigue, - Disorders associated with the respiratory tract and lungs, for example, including lung disorders, chronic lung disease, acute respiratory distress syndrome ( of adults) (ARDS), asthma, bronchitis due to asthma, bronchiectasis, diffuse interstitial lung disorders, pneumoconiosis, fibrous alveolitis, pulmonary fibrosis, Disorders associated with skin and connective tissue conditions, for example, including eczema, atopic dermatitis, dermatitis by contact, sopasis, acne, der matomyositis, syndrome Sjoegren, Churg-Strauss syndrome, sunburn, skin cancer, wound healing, urticaria, toxic epidermal necrosis, disorders associated with allergic conditions, for example, including delayed-type hypersensitivity, allergic conjunctivitis, drug allergies, rhinitis rhinitis allergic, vascu tis, contact dermatitis, disorders associated with angiogenesis, for example, including insufficient capacity to recruit the blood supply, disorders characterized by angiogenesis hated, angiogenesis associated with tumor, disorders associated with cancer and cell over proliferation, for example , including pre-mahgnas conditions, hyperproliferative disorders, cancers either primary or metastatic, cervical and metastatic cancer, cancer that originates from uncontrolled cell proliferation, solid tumors, such as those described in International Publication Number WO02066019, including cancer non-microcellular pulmonary, cervical cancer, tumor growth, lymphoma, B-cell or T-cell lymphoma, benign tumors, benign disprophylactic disorders, renal carcinoma, esophageal cancer, stomach cancer, renal carcinoma, bladder cancer, breast cancer , colon cancer, lung cancer, melanoma, nasopharyngeal cancer, osteocarcinoma, ovarian cancer, uterine cancer, prostate cancer, skin cancer, leukemia, tumor neovascularization, angiomas, myelodysplastic disorders, lack of response to normal death-inducing signals (immortahzation), increased cellular mobility and invasiveness , genetic instability, poorly regulated gene expression, (neuro) endocrine (carcinoid) cancer, blood cancer, lymphocytic leukemia, neuroblastoma, soft tissue cancer, prevention of metastasis, disorders associated with diabetic conditions, for example, including diabetes (type I diabetes, type II diabetes), diabetic retinopathy, insulin-dependent diabetes, diabetes mellitus, gestational diabetes, insulin hyposecretion, obesity, disorders associated with endometriosis, Testicular dysfunctions, Disorders associated with infectious disorders, for example, with chronic infectious conditions, for example including bacterial disorders, otitis media, Lyme disease, thyroiditis, viral disorders, parasitic disorders, fungal disorders, malaria, eg, malaria anemia, sepsis , severe sepsis, septic shock, for example endotoxin-induced septic shock, toxic shock induced by exotoxin, infectious shock (truly septic), septic shock caused by gram-negative bacteria, pelvic inflammatory disease, AIDS, enteritis, pneumonia; meningitis, encephalitis, lymphatic filapal infection, - Disorders associated with myasthenia gravis, Disorders associated with nephritis, for example, including glomerulonephritis, interstitial nephritis, Wegener's granulomatosis, fibrosis, Disorders associated with pain, for example, associated with system disorders central nervous system, such as multiple sclerosis, spinal cord injury, sciatica, failed back surgery syndrome, traumatic brain injury, epilepsy, Parkinson's disease, post-embolism and vascular injuries in the brain and spinal cord (e.g. , infarction, hemorrhage, vascular malformation), non-central neuropathic pain, for example including that associated with pain after mastectomy, phantom sensation, reflex sympathetic dystrophy (RSD), neuralgia-trigeminal radioculopathy, post-surgical pain, HIV-related pain / AIDS, cancer pain, metabolic neuropathies (eg, diabetic neuropathy, vasculitic neuropathy secondary to connective tissue disease), paraneoplastic neuropathy associated, for example, with lung carcinoma, or leukemia or lymphoma, or prostate carcinoma, colon , or stomach, tpgeminal neuralgia, cranial neuralgia, and post-herpetic neuralgia; pain associated with peripheral nerve damage, central pain (that is, due to cerebral ischemia), and different chronic pains, ie, back pain, back pain (low back pain), inflammatory and / or rheumatic pain, headache (eg, migraine with aura, migraine without aura, and other migraine disorders), episodic and chronic stress type headache, tension type headache, cluster headache, and chronic paroxysmal hemicrania, pain visceral, such as pancreatitis, intestinal cystitis, dysmenorrhea, irritable bowel syndrome, Crohn's disease, biliary colic, ureteral colic, myocardial infarction, and pain syndromes of the pelvic cavity, for example, vulvodynia, orchialgia, urethral syndrome 15, and protatodynia, acute pain, for example post-operative pain, and pain after trauma, Disorders associated with rheumatic disorders, for example, including arthritis, rheumatoid arthritis, osteoartptis, sopatic arthritis, crystal arthropathies, gout, pseudo-gout, calcium pyrophosphate deposition disease, lupus syndromes, systemic lupus erythematosus, sclerosis, scleroderma, sclerosis multiple, atherosclerosis, arteriosclerosis, spondyloarthropathies, systemic sclerosis, reactive arthritis, Reiter's syndrome, ankylosing spondylitis, pohmiositis, Disorders associated with sarcoidosis, - Disorders associated with transplantation, for example, including transplant rejection crisis and other disorders following transplantation , such as rejection of (xeno) organ or tissue transplantation, for example for the treatment of recipients, for example, heart, lung, heart-lung combined, liver, kidney, pancreas, skin, corneal transplants, graft-versus-host disease, such as following bone marrow transplantation, Ischemic reperfusion, Birth control (by means of inhibition of ovulation).

Although inhibition of ovulation is not a disorder, birth control (by means of ovulation inhibition) is also intended to be encompassed by the definition of "disorders that are susceptible to being mediated by CCR9 activity" according to the present invention Disorders which are susceptible to being mediated by CCR9, for example, include preferably autoimmune disorders, inflammatory disorders, allergic disorders, disorders following transplantation, cancer, more preferably autoimmune disorders, inflammatory disorders, disorders following transplantation , such as celiac disease, food allergy, rheumatoid arthritis, inflammatory bowel diseases (IBD), Crohn's disease, ulcerative colitis, sopasis, atopic dermatitis, asthma, fibrotic diseases, diseases following transplantation, rejection of GVH, cancer, leukemia (acute nphocytic leukemia), solid tumors, carcinoids, thymoma, carcinoma Thymic oma, preferably inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, for example include ulcerative proctitis In another aspect, the present invention provides a compound of the present invention for use as a pharmaceutical product, the use of a compound of the present invention as a pharmaceutical product, the use of a compound of the present invention for the manufacture of a medicament. , for example for the treatment of disorders mediated by CCR9 activity, for example, a compound of the present invention for the treatment of disorders mediated by CCR9 activity, such as disorders associated with disruption of the CCR9 link with CCL25. , such as disorders mediated by the initiation of CCR9-mediated leukocytes in a subject, for the treatment of disorders mediated by CCR9 activity. In another aspect, the present invention provides a compound of the present invention for the manufacture of a medicament for the treatment of inflammatory bowel disease For pharmaceutical use, can be used Use one or more compounds of the present invention, for example, in combination of two or more compounds of the present invention, and preferably a compound of the present invention is used. A compound of the present invention can be used as a pharmaceutical product. in the form of a pharmaceutical composition In another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of the present invention in association with at least one pharmaceutically acceptable excipient, for example an appropriate vehicle and / or diluent, for example including fillers, binders, disintegrants, flow conditioners, lubricants, sugars or sweeteners, fragrances, preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating osmotic pressure, and / or pH regulators. In another aspect, the present invention provides a pharmaceutical composition. of the present invention for use in the treatment of disorders that are mediated by the activity of CCR9, the use of a pharmaceutical composition of the present invention for the treatment of disorders that are mediated by the activity of CCR9, the use of a pharmaceutical composition comprising a compound of the present invention, for the treatment of inflammatory bowel disease, - the use of a pharmaceutical composition comprising a compound of the present invention, for the treatment of disorders that are mediated by the activity of CCR9. The treatment of disorders (diseases), as used herein, includes prophylaxis (prevention) For this treatment, the appropriate dosage, of course, will vary depending, for example, on the chemical nature and pharmacokinetic data of a compound of the present invention used, the individual host, the mode of administration, and the nature and severity of the conditions being treated. However, in general, in order to have satisfactory results in higher mammals, for example in humans, an indicated daily dosage includes a range of about 0.0001 grams to about 1.5 grams, such as from 0001 grams to 1.5 grams, from about 0001 milligrams / kilogram of body weight to about 20 milligrams / kilogram of body weight, such as of 001 milligrams / kilogram of body weight at 20 milligrams / kilogram of body weight, of a compound of the present invention, for example, administered in divided doses up to four times a day A compound of the present invention can be administered to higher mammals, for example to humans, by modes of administration similar to those conventionally employed with other mediators, for example low inhibitors. Molecular Weight, of CCR9 Activity In a further aspect, the present invention provides a method for the treatment of disorders that are mediated by CCR9 activity, for example including the disorders specified above, which treatment comprises administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention, for example in the form of a pharmaceutical composition. In another aspect, the present invention provides. - a compound of the present invention for the manufacture of a medicament, the use of a compound of the present invention for the manufacture of a medicament, for example a pharmaceutical composition, for the treatment of disorders that are mediated by the activity of CCR9 In In a further aspect, the present invention provides a method for the treatment of inflammatory bowel disease, which treatment comprises administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention, for example in the form of a pharmaceutical composition A compound of the present invention can be administered by any conventional route, for example enterally, for example including nasal, buccal, rectal, or oral administration, parenterally, for example including intravenous, mtra-artepal, intramuscular, intracardiac, subcutaneous administration , by intraosseous infusion, trans rmica (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), or by inhalation, topically, e.g. including epicutaneous, intranasal, or intratracheal, intrapeptoneal administration (infusion or injection into the peptoneal cavity); epidural (pepdural) (injection or infusion in the epidural space), intrathecal (injection or infusion into the cerebrospinal fluid), intravitreous (administration by means of the eye), or by medical devices, for example, for local delivery, for example stents ( vascular implants), for example in the form of coated or uncoated tablets, capsules, solutions (injectables), solutions for infusion, solid solutions, suspensions, dispersions, solid dispersions, for example in the form of ampoules, flasks, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lipsticks, drops, sprays, or in the form of suppositories. For topical use, for example, including administration to the eyes, satisfactory results can be obtained with local administration of a concentration of from 5 to 10 percent, such as from 1 to 3 percent, of the active substance, several times a day. day, for example 2 to 5 times a day. A compound of the present invention can be administered in the form of a pharmaceutically acceptable salt, for example an acid addition salt or a metal salt, or in free form, optionally in the form of a solvate A compound of the present invention in the form of a salt exhibits the same order of activity as a compound of the present invention in free form, optionally in the form of a solvate A compound of the present invention can be used for any method or use as described herein, alone or in combination with one or more, at least one second drug substance differently. In another aspect, the present invention provides - a combination of a compound of the present invention with at least one second drug substance, a pharmaceutical combination, which comprises a compound of the present invention in combination with at least one second drug substance, - a pharmaceutical composition, which comprises a compound of the present invention in combination with at least one second drug substance, and one or more pharmaceutically acceptable excipients, a compound of the present invention, in combination with at least one second drug substance, for example in the form of a combination or pharmaceutical composition, for use in any method defined in present, for example, a combination, a pharmaceutical combination, or a pharmaceutical composition, which comprises a compound of the present invention and at least one second drug substance, to be used as a pharmaceutical, the use as a pharmaceutical product, of a compound of the present invention in combination with at least one second drug substance, for example in the form of a combination or pharmaceutical composition, the use of a compound of the present invention, for the manufacture of a medicament for use in combination with a second drug substance, for example, for any therapeutic treatment as indicated herein, - a method for the treatment of disorders mediated by the activity of CCR9 in a subject in need thereof, which comprises the co-administration, in a concomitant or sequential manner, of a therapeutically effective amount of a compound of the present invention and at least one second drug substance, by example, in the form of a combination or pharmaceutical composition, a compound of the present invention in combination with at least one second drug substance, for example in the form of a combination or pharmaceutical composition, for use in the preparation of a medicament for used in disorders mediated by CCR9 activity Combinations include fixed combinations, as of a compound of the present invention, and at least one second drug substance, are in the same formulation, kits, wherein a compound of the present invention and at least one second drug substance in separate formulations, are provided therein. package, for example with instructions for co-administration, and free combinations, wherein a compound of the present invention and at least one second drug substance, are packaged separately, but instructions are given for its concomitant or sequential administration In another aspect, the present invention provides. a pharmaceutical packet, which comprises a first drug substance which is a compound of the present invention, and at least one second drug substance, in addition to instructions for its combined administration, a pharmaceutical packet, which comprises a compound of the present invention invention, in addition to instructions for its administration in combination with at least one second drug substance, a pharmaceutical packet, which comprises at least one second drug substance, in addition to instructions for its administration in combination with a compound of the present invention. The treatment with the combinations according to the present invention can provide improvements compared to the individual treatment. In another aspect, the present invention provides. a pharmaceutical combination, which comprises an amount of a compound of the present invention, and an amount of a second drug substance, wherein the amounts are appropriate to produce a synergistic therapeutic effect; a method for improving the therapeutic utility of a compound of the present invention, which comprises co-administration, for example in a concomitant manner or in sequence, of a therapeutically effective amount of a compound of the present invention, and a second drug substance, a method of improving the therapeutic utility of a second drug substance, which comprises co-administration, for example, in a manner concomitantly or in sequence, a therapeutically effective amount of a compound of the present invention, and a second drug substance A combination of the present invention, and a second drug substance, as a combination component, can be administered by any route conventional, for example as stipulated above for a compound of the present invention A second drug can be administered in appropriate dosages, for example in dosage ranges that are similar to those used for individual treatment, or, for example, in case of synergism, even in dosing intervals below conventional ones The pharmaceutical compositions according to the present invention can be manufactured according to, for example in a manner analogous to, a conventional method, for example, by mixing, granulating, coating, dissolving, or lyophilizing processes. Unit dosage forms can be contain, for example, from about 0.1 milligrams to about 1,500 milligrams, such as from 1 milligram to about 1,000 milligrams Pharmaceutical compositions comprising a combination of the present invention, and pharmaceutical compositions comprising a second drug as described herein, may be provided as appropriate, for example in accordance with, for example in a manner analogous to, a conventional method, or as described herein for a pharmaceutical composition of the present invention The term "second drug substance" means a chemotherapeutic drug, especially any chemotherapeutic agent, other than an agent of the present invention. For example, a second drug substance, as used herein, includes - other CCR9 inhibitors other than a compound of the present invention, for example, including antibodies and low molecular weight compounds, anti-inflammatory drugs and / or immunomodulators, antiallergic drugs, - anti-cancer drugs, anesthetics drugs, drug s anti-diarrheal. For the treatment of inflammatory bowel disease, the term "second drug substance" is intended to include an anti-inflammatory and / or immunomodulatory drug, for example including a drug which is active in the prevention or treatment of inflammatory bowel disease, and / or which is active in the treatment of inflammatory bowel disease manifestations, for example of the symptoms of inflammatory bowel disease, such as an anesthetic drug or an anti-diarrheal drug. Anti-inflammatory and / or immunomodulatory drugs that are susceptible to be used in combination with a compound of the present invention include, for example. mediators, for example inhibitors, of mTOR activity, including the rapamycin of the Formula and rapamycin derivatives, for example, including. 40-O-alkyl? -rapam? c? na derivatives, such as derivatives of 40-Oh? Drox? -alqu? L-rapam? C? Na, such as 40-O- (2-h? Drox?) - et? L-rapamycin (everolimus), derivatives of 32-deoxo-rapam? C ? na and derivatives of 32-hydrox? -rapamycin, such as 32-deoxo-rapam? c? na, 16-O-sust? rapamycin derivatives, such as 16-pent-2? n? lox? -32-deoxo-rapam? c? na, 16-pent-2-? n? lox? -32- (S or R) -d? h? dro-rapam? c? na, 16-pent-2 -? n? lox? -32- (S or R) -d? h? dro-40-O- (2-h? drox? -et? l) -rapam? c? na, rapamycin derivatives that are acylated in the oxygen group at position 40, for example 40- [3-h? drox? -2- (h? drox? -met? l) -2-met? l-propanoate] -rapam? c? na ( also known as CCI779), rapamycin derivatives which are substituted at position 40 by heterocyclyl, for example 40-ep? - (tetrazole?) -rapam? cina (also known as ABT578), the so-called rapalogs, by example as disclosed in International Publications Nos. WO9802441, WO0114387 and WO0364383, such as AP23573, and the compounds disclosed under the name of TAFA- 93, AP23464, AP23675, AP23841, and biolimus (for example, biolimus A9), mediators, for example inhibitors, of calcineupna, for example ciclospopna A, FK 506, ascomycins that have immunosuppressive properties, for example ABT-281, ASM981 , - corticosteroids, cyclophosphamide, azathioprene, leflunomide, mizopine, mycophenolic acid or a salt, for example, sodium, mycophenolate-mofetil, 15-deoxyribose, or a homologue, analog, or immunosuppressant derivative thereof, mediators, eg inhibitors, of the activity of tyrosma bcr-abl kinase, mediators, for example inhibitors of the c-kit receptor tyrosine kinase activity, - mediators, eg inhibitors, of the activity of the tyrosine kinase receptor of the platelet-derived growth factor, for example Gleevec (imatimb), mediators, for example inhibitors, of MAP p38 kinase activity, - mediators, for example inhibitors, of the activity of vascular endothelial growth factor receptor tyrosome kinase, mediators, for example inhibitors , of the activity of protein kinase C, for example as disclosed in International Publications Nos. WO0238561 or WO0382859, for example the compound of Example 56 or 70, mediators, for example inh of the activity of JAK3 kinase, for example N-benzyl-3,4-d? h? drox? -benc? l? den-c? ano-acetamide ac? ano- (3,4-d? h? drox?) - [N-benc? lc? namam? da (Tirfostma AG 490), prodigiosin 25-C (PNU156804), [4- (4'-h? drox? -fen? l) -am? no - 6,7-d? Methox? -qu? Nazole? N] (WHI-P131), [4- (3'-bromo-4'-h? Drox? -fen? L) -am? No-6.7 -d? methox? -qu? nazol? na] (WHI-P154), [4- (3 ', 5'-d? bromo-4'-h? drox? -fen? l) -am? no-6 , 7-d? Methox? -qu? Nazol? Na] WHI-P97, KRX-211, 3-. { (3R, 4R) -4-met? L-3- [met? L- (7H-p? Rrolo- [2,3-d] -p? R? M? D? N-4-? L) - am? no] -p? per? d? n-1 -? l} -3-oxo-prop? Onyl, in free form in a pharmaceutically acceptable salt form, for example mono-citrate (also referred to as CP-690,550), or a compound as disclosed in the Publications International Numbers WO2004052359 or WO2005066156, - mediators, for example agonists or modulators of S1P receptor activity, for example FTY720 optionally phospho- pholated or an analogue thereof, for example 2-amino-2- [4- (3-benzyl? lox? -t? ofen? l) -2-chloro-phen? l] -et? -1,3-propanod? ol optionally phospho- pholated, or acid 1 -. { 4- [1 - (4-c? Clohex? I-3-tr? Fluoro-met? L-benz? Lox? -? M? No) -et? L] -2-et? L-benzyl} acetyl-3-carboxylic acid or its pharmaceutically acceptable salts, immunosuppressive monoclonal antibodies, for example monoclonal antibodies to leukocyte receptors, for example the Blys / BAFF receptor, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86, receiver IL-12, IL-17 receptor, IL-23 receptor, or its gandos, other immunomodulatory compounds, for example a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, by example at least one extracellular portion of CTLA4 or a mutant thereof, linked to a protein sequence other than CTLA4, for example CTLA4lg (eg, designated as ATCC 68629), or a mutant thereof, eg LEA29Y; mediators, for example inhibitors of the activities of the adhesion molecules, for example LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists, mediators, for example inhibitors, the activity of MIF, - 5-amino-salicylate (5-ASA) agents, such as sulfasalazine, Azulfidine®, Asacol®, Dipentum®, Pentasa®, Rowasa®, Canasa®, Colazal®, for example drugs containing mesalamine; for example, mesalazine in combination with heparin; - mediators, for example inhibitors, of the activity of TNF-alpha, for example including antibodies that bind TNF-alpha, for example infliximab (Remicade®), thalidomide, lenalidomide, nonsteroidal anti-inflammatory drugs (NSAIDs), nitric oxide releasers, for example including donor drugs of NO COX inhibitors (CINOD); phosphodiesterase, for example mediators, such as inhibitors of PDE4B activity, mediators, eg inhibitors, of caspase activity, mediators, for example agonists, of the GPBAR1 G-protein coupled receptor, mediators, eg inhibitors, of ceramide kinase activity, - "multi-functional anti-inflammatory drugs" (MFAIDs), for example phospholipase cytoshoxa A2 inhibitors (cPLA2), such as inhibitors of membrane anchored A2 phospho-linked with g cosaminoglycans, antibiotics, such as penicillins, cephalospopins, ephythmycins, tetracyclines, sulfonamides, such as sulfadiazine, sulfisoxazole, sulfones, such as dapsone, pleuromuthines, fluoro -quinolones, for example metronidazole, quinolones, such as ciprofloxacin, levofloxacin, probiotics and commensal bacteria, for example Lactobacillus, Lactobacillus reuten, - antiviral drugs, such as pbivipna, vidarabine, acyclovir, ganciclovir, zanamivir, oseltamivir phosphate, famciclovir, atazanavir, amantadine, didanosma, efavirenz, foscarnet, indinavir, lamivudine, nelfinavir, ptonavir, saqumavir, stavudine, val acyclovir, valganciclovir zidovudine Anti-allergic drugs that are susceptible to being useful in combination with a compound of the present invention include, for example, antihistamines (histamine-H1 antagonists), for example, bromopheniramine, chlorpheniramine, dexchlorpheniramine , tpprol idina, clemastma, difenhidramma, dif eni I pi ral i na, tppelenamina, hidroxizma, metdilazina, promethazma, tpmeprazina, azatadina, cyproheptadine, antazohna, pheniramine, piplamine, astemizole, terfenadine, loratadine, cetipzine, fexofenadine, descarbo-ethoxy-loratadine, and non-steroidal anti-asthmatics, such as agon-stas-ß2 (terbutaline, metaproterenol, fenoterol, isoetapna, albuterol, bitolte rol, salmeterol, and pirbuterol), theophylline, cromolyn-sodium, atropine, ipratropium bromide, leukotpene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), inhibitors of leucotpene biosynthesis (zileuton, BAY -1005), bronchodilators, anti-asthmatics (mast cell stabilizers) Anti-inflammatory drugs that are susceptible to being useful in combination with a compound of the present invention include, for example, non-steroidal anti-inflammatory agents (NSAIDs), as derivatives of propionic acid (aminoprofen, benoxaprofen, bucloxic acid, caprofen, fenbufen, fenprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozma, pirprofen, pranoprofen, suprofeno, thiaprofenic acid, and thioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanaco, diclofenac, fenclofenac, fenclózico acid, fentiazaco, furofenaco, ibufenaco, isoxepaco, oxpinaco, suhndaco, tiopinaco , tolmetin, zidometacin, and zomepiraco), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, mflumic acid, and tolfenamic acid), biphenyl carboxylic acid derivatives (dif lunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam, and tenoxicam), sa cilates (acetyl-sahthic acid, sulfasalazine), and pyrazolones (apazone, bezpipenlone, feprazone, mofebutazone, oxifenbutazone, phenyl-butazone), c-clo-oxygenase-2 inhibitors (COX-2) ), such as celecoxib; phosphodiesterase type IV (PDE-IV) inhibitors, chemokine receptor antagonists, especially CCR1, CCR2, and CCR3, cholesterol-lowering agents, such as HMG-CoA-reductase inhibitors (lovastatma, simvastatin, pravastatma, fluvastatma, atorvastatma, and other statmas), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibpco acid derivatives (gemfibrozil, clofibrate, fenofibrate, and benzafibrate), and probucol, anticancer agents, such as antimuscapnin antagonists (ipratropium bromide), other compounds, such as theophylline, sulfasalazm, and amino-sa cilates, for example 5-amino-salt-cylcocyclic acid, and pro-drugs thereof, anti-rheumatic The anti-cancer drugs that are susceptible to being useful as a combination component with a compound of the present invention, for example, include a steroid; for example prednisone n. An inhibitor of adenosine kinase, which directs, reduces, or inhibits the metabolism of nucleobase, nucleoside, nucleotide, and nucleic acid, such as 5-iodo-tuberc? D? Na, which is also known as 7H-p? rrolo- [2,3-d] -p? r? m? d? n-4-am? na, 5-iodo-7-ß-Dr? bofurans? ni ni An adjuvant; which improves the 5-FU-TS link, as well as a compound that directs, reduces, or inhibits alkaline phosphatase, such as leucovopna, levamisole iv An adrenal cortex antagonist, which directs, reduces, or inhibits the activity of the adrenal cortex, and changes the peripheral metabolism of corticosteroids , resulting in a decrease in 17-h? drox? -cort? coastal? des, such as mitotane v An inhibitor of the AKT pathway, such as a compound that directs, reduces, or inhibits AKT, also known as kinase Protein B (PKB), such as deguelma, which is also known as 3H-b? S [1] -benzop? Rano- [3,4-b 6 ', 5'-e] -p? Ran-7 ( 7aH) -one, 13,13a-d? H? Dro-9,10-d? Methox? -3,3-d? Met? L-, (7aS, 13aS), and tpci pbina, which is also known as 1, 4,5,6, 8-penta-aza-acenaft? Len-3-am? Na, 1,5-d? H? Dro-5-met? L-1-ß-Dr? Bofurans? An alkylating agent, which causes the alkylation of DNA, and results in breaks in DNA molecules, as well as cross-linking of the twin chains, thus interfering with DNA replication and RNA transcription, such as nitrogen mustards, for example chlorambucil, chlormetma, cyclophosphamide, ifosfamide, melphalan, estramustma (Emcit®), nitrosoureas, such as carmustma, fotemustma, lomustma, streptozocin (streptozotocin, STZ, Zanosar®), BCNU, Gliadel, dacarbazma , mechlorethamine, for example in the form of a hydrochloride, procarbazm, for example in the form of a hydrochloride, thiotepa, temozolomide (TEMODAR®), mitomycin, altretamine, busulfan, estramustine, uramustma Cyclophosphamide can be administered, for example, in the form as it is traded, for example the registered trademark CICLOSTIN®, and ifosfamide as HOLOXAN® vil An inhibitor of angiogenesis, which directs, reduces, or inhibits the production of new blood vessels, for example, which directs the amino-peptidase of met? on? na-2 (MetAP-2), the inflammatory protein of macrophages-1 (MIP-1alpha), CCL5, TGF-beta, lipoxygenase, cyclooxygenase, and topoisomerase, or indirectly directing the synthesis of p21, p53, CDK2, and collagen, for example include fumagillin, which is known as 2,4,6,8-decatetraenodioic acid, mono - [(3R, 4S, 5S, 6R) -5-methox? -4 - [(2R, 3R) -2-met? L-3- (3-met? L-2-buten? L) -ox? Ran? L] - 1-oxaesp? Ro- [25] -oct-6? L] -ester, (2E, 4E, 6E, 8E) - (9CI), shikonin, which is also known as 1,4-naphthalenedione, 5,8 -d? h? drox? -2 - [(1R) -1-h? drox? -4-met? l-3-penten? l] - (9CI), tranilast, which is also known as benzoic acid, - [[3- (3,4-d? Methox? -f in? l) -1 -oxo-2-propen? l] -am? no], ursolic acid, suramin, bengamide or a derivative thereof, ta domed, TNP-470 vui An anti-androgen, which blocks the action of androgens of adrenal and testicular origin, which stimulate the growth of normal and malignant prostatic tissue, such as nilutamide, bicalutamide (CASODEX®), which can be formulated, for example, as disclosed in the Patent of the States United States of America Number US4636505 ix An anti-estrogen, which antagonizes the effect of estrogens at the level of the estrogen receptor, for example including an aromatase inhibitor, which inhibits the production of estrogen, ie, the conversion of the substrates of androstenedione and testosterone to estrone and estradiol, respectively, for example including atamestane, exemestane, formestane, amino-glutethimide, rogletimide, pipdo-glutethimide, tplostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, letrozole, toremifene, bicalutamide, flutamide, tamoxifen, tamoxifen citrate , tamoxifen, fulvestrant, raloxifene, raloxifene hydrochloride Tamoxifen, for example, can be administered as commercially available, for example NOLVADEX®, and raloxifene hydrochloride is marketed as EVISTA®. Fulvestrant can be formulated as given to known in the US Pat. No. US4659516, and is marketed as FASLODEX® x An anti-hypercalcemia agent, which it is used to treat hypercalcemia, such as gallium nitrate hydrate (III), and pamidronate-disodium xi An antimetabolite, which inhibits or interrupts DNA synthesis that results in cell death, such as folic acid, for example methotrexate , pemetrexed ra trexed, pupnas, for example 6-mercapto-purine, cladpbma, clofarabine, fludarabine, thioguanine (thioguanine), 6-t? oguan? na, pentostatin (deoxy) coformicin), cytarabine, flexupdine, fluoro-uracil, 5-fluoro-uracil (5-FU), floxupdine (5-FUdR), capecitabine, gemcitabine, gemcitabine hydrochloride, hydroxyurea (for example, Hydrea®), DNA demethylating agents, such as 5-azac? t? d? na and decitabine, edatrexate Capecitabine and gemcitabma can be administered, for example, in the form as traded, such as XELODA® and GEMZAR® xn An inducer of apoptosis, which induces the normal series of events in a cell leading to its death, for example that selectively induces the X-linked mammalian inhibitor of the apoptosis protein XIAP, or, for example, decreases BCL-xL, such as ethanol, 2 - [[3- (2,3-d? chloropheno?) - prop? l] -am? no], gambogic acid, embehna, which is also known as 2.5-c? clohexad? eno-1,4-d? ona, 2,5-d? h? drox? -3-undec? lo- (9CI), arsenic trioxide xin An aurora kinase inhibitor, which directs, reduces, or inhibits the latter stages of the cell cycle from the checkpoint of G2 / M all the way to the point of mitotic verification and late mitosis, such as binuclein 2, which is also known as methanimidamide, N '- [1 - (3-chloro-4-fluoro-phenol) -4- c? ano-1H-p? razol-5-? l] -N, Nd? met? l- (9CI) xiv An inhibitor of Bruton's tyrosine kinase (BTK), which directs, reduces, or inhibits development of human B cells and mupno, such as terreic acid xv An inhibitor of calcmeupna, which directs, reduces, or inhibits the pathway of T-cell activation, such as cypermethrin, which is also known as 3- (2,2-d? chloro-ethen?) -2,2-d? met? lc? an (3-phenox) ? -fen? l) -met? l-ester of cyclopropane-carboxylic acid, deltametpna, which is also known as 3- (2,2-d? bromo-ethene) -2,2-d? met? l - (S) -c? An- (3-phenoxy? -fen? L) -met? L-ester of cyclopropane-carboxylic acid, (1R.3R), fenvalerate, which is also known as 4-chloro-a- (1-met? L-et? L) -c? Ano- (3-phenox? -fen? L) -met? L-ester of benzene-acetic acid, and Tirfostma 8; but excluding ciclospopna or FK506 xvi An inhibitor of CaM II kinase, which directs, reduces, or inhibits CaM kinases, which constitute a family of structurally related enzymes that include phosphoplase kinase, myocin light chain kinase, and CaM l-IV kinases, such as 4 - [(2S) -2 - [(5-? soqu? nol? n? l-sulfon? l) -met? l-am? no] -3-oxo-3- (4-phenol-1-p? Peraz? N? L) -prop? L] -phen? -ester of 5-? Soqu? Nol? N-sulfon? Co (9CI); N- [2 - [[[3- (4-Chloro-phenol) -2-propen? L] -met? L] -am? No] -met? L] -phen?] -N- ( 2-h? Drox? -et? L) -4-methox? -benzenesulfonamide? Xvi An inhibitor of CD45 tyrosome phosphatase; which directs, reduces, or inhibits the pTyr residues regulating the dephospholation on the tyrosm protein kinases of the Src family, which aid in the treatment of a variety of inflammatory and immune disorders; such as phosphonic acid, [[2- (4-bromo-phenoxy?) - 5-n? tro-phen? l] -h? drox? -met? lo] xvn A phosphatase inhibitor CDC25, which directs, reduces , or inhibits dephosphocyte-dependent cyclin dependent kinases expressed in tumors, such as 2,3-b? s - [(2-h? drox? -et? l) -t? o] -1,4-naphthalenedione xix A CHK kinase inhibitor, which directs, reduces , or inhibits the overexpression of the antiapoptotic protein Bcl-2, such as desbromo-imenialdisine Directs a kinase inhibitor CHK which is CHK1 and / or CHK2 xx A control agent to regulate the genistema, olomucin, and / or tirfostmas, such as daidzema, which is also known as 7-hydroxy? -3- (4-hydrox? -fen? l) -4H-1-benzop? ran-4-one, iso-olomucine, and Tirfostma 1 xxi A cyclooxygenase inhibitor, for example, including Cox-2 inhibitors, which direct, reduce, or inhibit the enzyme Cox-2 (c? Clo-ox? Genase-2), such as 1 - (4-chloro-benzoyl) -5-methox-2-met? N- (2-phenol-et? L) -1H-? Ndol-3-acetamide, 2-aryl acid -am? no-phenol-acetic substituted by 5-alkyl, and its derivatives, for example celecoxib (CELEBREX®), rofecoxib (VIOXX®), etopcoxib, valdecoxib, or an acid 5-alk-l-2 -ar? l-am? no-fen? l-acet? co, for example 5-met? l-2- (2'-chloro-6'-flu gold-an? l? no) -fen? l-acet? co, lumiracoxib, and celecoxib xxn A cRAF kinase inhibitor, which directs, reduces, or inhibits the increase of E-selectin and the vascular adhesion molecule -1, induced by TNF, such as 3- (3,5-d? Bromo-4-hydrox? -benzyl?) -5-iodo-1,3-d? H? Dro? Ndol -2-one, and 3- (d? Met? L-am? No) -N- [3 - [(4-h? Drox? -benzo? L) -am? No] -4-met? L- fen? l] -benzam? da RAF kinases play an important role as signaling regulatory kinases extracellular in cell differentiation, proliferation, and apoptosis A target of the cRAF kinase inhibitor includes, but is not limited to, RAF-1 xxni A cyclin-dependent kinase inhibitor, which directs, reduces, or inhibits the kinase-dependent kinase. cyclin which has a role in the regulation of the mammalian cell cycle, such as N9-isopropyl-olomucin, olomucin, purvalanol B, which is also known as benzoic acid, 2-chloro-4 - [[2 - [[(1 R ) -1 - (H? Drox? -met? L) -2-met? L-prop? L] -am? No] -9- (1 -met? L-et? L) -9H-pur? N -6 - ?!] - am? No] - (9CI), roascovitma, indirubin, which is also known as 3- (1, 3-d? H? Dro-3-oxo-2 H-? Ndol-2- ? I? Den) -1, 3-d? H? Dro-2H-? Ndol-2-one (9CI), quenpaullone, which is also known as 9-bromo-7,12-d? H? Dro? nololo- [3,2-d] [1] -benzazep? n-6 (5H) -one (9CI), purvalanol A, which is also known as 2 - [[6 - [(3-chloro-phenol ) -am? no] -9- (1-methyl-ethyl) -9H-pur? n-2-? l] -am? no] -3-met? l-1-butanol, (2R) - (9CI) ),? nd? rrub? na-3'-mono-oxime The progress of the cell cycle is regu side by a series of events in sequence that include the activation and subsequent inactivation of cyclic dependent kinases (Cdks), and the cyclins The cyclin dependent kinases are a group of sepna / threonine kinases that form active heterodimepcos complexes through their binding to their regulatory subunits, the cyclins. The examples of the objectives of a cyclin-dependent kinase inhibitor include, but are not limited to, CDK, AHR, CDK1, CDK2, CDK5, CDK4 / 6, GSKbeta, and ERK xxiv A cistern protease inhibitor, which directs, reduces, or inhibits cistern protease, which has a vital role in mammalian cellular change and apoptosis such as N - [(1 S) -3-fluoro-2-oxo-l- (2-phenol-et ?) -prop? l] -am? no] -2-oxo-1 - (phenol-met? l) -et? l] -morph? n-carboxamide xxv A DNA intercalator, which binds with DNA, and inhibits the synthesis of DNA, RNA, and protein, such as plicamycin, dactinomycin xxvi A DNA chain breaker, which causes the separation of the DNA strand, and results in the inhibition of DNA synthesis the inhibition of RNA and protein synthesis, such as bleomycin XXVII An E3 ligase inhibitor which directs, reduces, or inhibits E3 gauze, which inhibits the transfer of ubiquitme chains to proteins, marking them for degradation in the proteasome, such as N - ((3,3,3-tr? fluoro-2-tr? fluoro-met? l) -prop? on? l) -sulfanyl-amide xxvni An endocrine hormone, the which, by acting primarily on the pituitary gland, causes the supreme hormones in males, the net effect being a reduction of testosterone up to castration levels, in females, both estrogen of ovaries and synthesis of androgen are inhibited, such as leuprohda, megestrol, megestrol acetate xxix Compounds that direct, reduce, or inhibit the activity of the tyrosine kinase family of epidermal growth factor receptors (ErbB1, ErbB2, ErbB3 and ErbB4 as homo- or hetero-dimers), such as compounds, proteins, or antibodies that inhibit the members of the epidermal growth factor receptor tyrosome kinase family, for example the epidermal growth factor receptor, ErbB1, ErbB2, ErbB3, and ErbB4 , or which are linked to EGF or to ligands related to EGF, and are in particular the compounds, proteins, or generic monoclonal antibodies and specifically disclosed in International Publication Number WO 9702266, for example the compound of Example 39, in the Patent Numbers EP0564409, WO9903854, EP0520722, EP0566226, EP0787722, EP0837063, US5747498, WO9810767, WO9730034, W09749688, W09738983, and in particular WO9630347, for example a compound known as CP 358774, in International Publication Number WO9633980, for example a compound known as ZD 1839, and in International Publication No. WO 9503283 , for example a compound known as ZM105180, for example including the double-acting tyrosme kinase inhibitor (ErbB1 and ErbB2) lapatinib (GSK572016), for example lapatinib ditosylate, panituzumab, trastuzumab (HERCEPTIN®), cetuximab, iressa, OSI -774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E25, E62, E64, E2 11, E6.3 or E7.6.3, derivatives of 7H-pyrrolo- [2,3-d] -p? R? M? D? Na, which, for example, are disclosed in the Publication International Number WO03013541, erlotinib, gefitinib Erlotmib can be administered as commercially available, for example TARCEVA®, and gefitmib as IRESSA®, and monoclonal antibodies Humans against the epidermal growth factor receptor, including ABX-EGFR xxx A tyrosine kinase inhibitor EGFR, PDGFR, such as the EGFR kinase inhibitors, including tirfostma 23, tyrphostin 25, tirfostma 47, tirfostma 51, and tyrphostin AG 825 , 2-c? Ano-3- (3,4-d? H? Drox? -fen? L) -N-phen? L- (2E) -2-propenam? Da, tyrphostin Ag 1478, lavendustma A, a - [(3,5-d? Chlor-phen? L) -met? Len] -3-p? R? D? N-aceton? Tr? Lo, (aZ), an example of a tyrosine kinase inhibitor EGFR, PDGFR, for example, includes tyrphostin 46 The tyrosine kinase inhibitor PDGFR includes tyrphostin 46 The targets of a EGFR cmase inhibitor include guani cyclase (GC-C) HER2, EGFR, PTK, and tubuhna xxxi. farnesyl transferase, which directs, reduces, or inhibits the Ras protein, such as an α-hydroxy-farnesyl-phosphonic acid, 2 - [[(2S) -2 - [[(2S, 3S) -2 - [[ (2R) -2-am? No-3-mercapto-prop? L] -am? No] -3-met? L-pent? L] -ox?] - 1-oxo-3-phen? L-prop ? l] -am? no] -4- (methanol-sulfonyl) -1-methyl-ethyl-ester of buta acid noico, (2S), manumicin A, L-744,832, or DK8G557, tipifarnib (R115777), SCH66336 (lonafarnib), BMS-214662 xxxn A kinase inhibitor Flk-1, which directs, reduces, or inhibits the activity of the tyrosine kinase Flk-1, such as 2-propenamide, 2-c? ano-3- [4-h? drox? -3,5-b? s- (1 -met? l-et? l) -fen [I] -N- (3-phenol-propyl) - (2E) -2-propenamide A target of a kinase inhibitor Flk-1 includes, but is not limited to, KDR xxxni An inhibitor of Glycogen-3 synthase kinase (GSK3), which directs, reduces, or inhibits the glycogen-3 synthase kinase (GSK3), such as? nd? rrub? na-3'-mono-ox? ma Glycan-3 synthase kinase ( GSK-3, tau protein kinase I), a highly conserved and ubiquitously expressed septa / threonine protein kinase, is involved in signal transduction cascades of multiple cellular processes, which is a protein kinase that has been shown to be involved in the regulation of a diverse array of cellular functions, including protein synthesis, cell proliferation, cell differentiation, assembly / disassembly of microtubules, and apoptosis xxxiv A histone deacetylase inhibitor (HDAC), which inhibits histone deacetylase, and which possesses an anti-proliferative activity, such as the compounds disclosed in International Publication Number WO0222577, especially N-hydroxy-3- [4 - [[(2-hydrox? -et? l) - [2- (1H-? Ndol-3-? L) -et? L] -am? No] -met? L] -fen? L] -2E-2-propenamide, and Nh? drox? -3- [4 - [[2- (2-met? l-1 H-? ndol-3? l) -et? l] -am? no] -met? l] -fen? l ] -2E-2-propenamide, and the pharmaceutically acceptable salts thereof, suberoyl anilide hydroxamic acid (SAHA), p? R? D? N-3? -methyl-acid ester [ 4- (2-am? No-phen? L-carbamo? L) -benc? L] -carbam? Co, and its derivatives, butyric acid, piroxamide, tpcostatma A, oxamflatine, apicidin, depsipeptide, depudecin, trapoxin, toxin HC, which is also known as c? Clo- [L-alan? LD-alan? L- (aS, 2S) -a-a? No-b-oxo-ox? Ran-octane? LD-prohlo] (9CI ), sodium phenylbutyrate, suberoyl-bis-hydroxamic acid, Tpcostatma A, BMS-27275, pyroxamide, FR-901228, valproic acid xxxv An inhibitor of HSP90; which directs, reduces, or inhibits the intrinsic activity of HSP90 ATPase, degrades, directs, reduces, or inhibits HSP90 client proteins via the ubiquitase proteasome pathway. Compounds that direct, reduce, or inhibit intrinsic activity of ATPase HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, for example, 17-al? -am? no-17-demethox? -gludanamycin (17AAG), a derivative of geldanamycin , other compounds related to geldanamycin, radicicol and HDAC inhibitors Other examples of an HSP90 inhibitor include geldanamycin, 17-demethoxy? -17- (2-propen? l-amine) Potential indirect targets of an HSP90 inhibitor include FLT3, BCR-ABL, CHK1, CYP3A5 * 3 and / or NQ01 * 2 Nilotmib is an example of a tyrosine kinase inhibitor BCR-ABL xxxvi An inhibitor of l-kappa kinase B-alpha (IKK), which directs, reduces, or inhibits NF-kappaB, such as 2-propenon-tr? lo, 3 - [(4-met? l-phen? l) -sulfon? l] - (2E) X XXVII An insulin receptor tyrosine kinase inhibitor, which modulates the activities of the phosphatidyl-inositol 3 kinase, protein associated with microtubules, and S6 kinases, such as hydroxyl-2-naphthalene-1-met. lf osfonic, LY294002 xxxviii An inhibitor of N-terminal kinase kinase c-Jun (JNK); which directs, reduces, or inhibits the N-terminal kinase Jun, such as pyrazole-anthrone and / or epigallocatechin gallate The N-terminal kinase Jun (JNK), a protein kinase directed to the septa, is involved in the phosphorylation and activation of c-Jun and ATF2, and has a significant role in metabolism, growth, cell differentiation, and apoptosis. A target for a JNK kinase inhibitor includes, but is not limited to, DNMT xxxix. microtubule link, which acts by interrupting the microtubule network that is essential for mitotic and interphase cellular function, such as vinca alkaloids, for example vinblastma, vmblastin sulfate, vincpstine, vincpstine sulfate, vindesma, vinorelbine, taxanes, such as taxanes, for example docetaxel, pac taxel, discodermolysae, colchicine, epothilones and their derivatives, for example epothilone B or a derivative thereof The pac taxel is traded as TAXOL®, docetaxel as TAXOTERE®, vlastin sulfate as VINBLASTIN RP®, and vincpstma sulfate as FARMISTIN® Generic forms of paclitaxel are also included, as well as different dosage forms of paclitaxel Generic forms of paclitaxel include, but are not limited to, betaxolol hydrochloride Different dosage forms of paclitaxel include, but are not limited to, pachtaxel in albumin nanoparticles sold by ABRAXANE®, ONXOL ®, CYTOTAX® Discodermolide can be obtained, for example, as disclosed in the US Pat. No. US5010099 Also included are epothilone derivatives, which are disclosed in Patent Numbers US6194181, WO98 / 0121, W09825929, WO9808849, W09943653, W09822461 and WO0031247 Preferred especially Epo tona A and / or B xl A mitogen-activated protein kinase inhibitor (MAP), which directs, reduces, or inhibits the mitogen-activated protein, such as N- [2 - [[[3- ( 4-chloro-phen?) -2-propen? L] -met? L] -am? No] -met? L] -fen? L] -N- (2-hydrox? -et? L) -4-methox? -benzenesulfonamide The mitogen-activated protein kinases (MAPs) are a group of septa / threonine protein kinases, which are activated in response to a variety of extracellular stimuli, and mediate signal transduction. From the cell surface to the nucleus Various physiological and pathological cellular phenomena are regulated, including inflammation, apoptotic cell death, oncogenic transformation, invasion of tumor cells, and xli metastasis. An inhibitor of MDM2, which directs, reduces, or inhibits the interaction of MDM2 and the p53 tumor suppressor, such as trans-4-iodine, 4'-boran-l-chalcone. An inhibitor of MEK, which directs, reduces, or inhibits the kinase activity of the MAP MEK kinase, such as sorafenil, for example, Nexavar® (sorafenib tosylate), (b? s- [am? no- [2-am? No-phen? L) -t? O] -met? Len] -butane-d? N? Tr? Lo An objective of MEK includes, but is not limited to, ERK An indirect target of an inhibitor of MEK includes, but is not limited to, ciciina D1 xlni. A matrix metalloproteinase inhibitor (MMP), which directs, reduces, or inhibits a class of protease enzyme that selectively catalyzes the hydrolysis of peptide bonds, including the enzymes MMP-2 and MMP-9 that are involved in the promotion of the loss of tissue structure around the tumors, and that facilitate tumor growth, angiogenesis, and metastasis, such as actinonin, which is also known as N-4-h? drox? -N1 - [(1 S ) -1 - [[(2S) -2- (h? Drox? -met? L) -1-p? Rrol? D? N? L] -carbon? L] -2-met? L-prop? L ] -2-pentyl-butan-diamine, (2R) - (9CI), epigallocatechtolate, peptidomimetic and non-peptidomimetic inhibitors of collagen, tetracycline derivatives, for example the hydroxamate peptidomimetic inhibitor, batimastat, and its analog orally bioavailable mapmastate, ppnomastate, metastate, neovastate, tanomastate, TAA211, BMS-279251, BAY 12-9566, MMI270B or AAJ996 A target of an MMP inhibitor includes, but is not limited to, polypeptide deformylase xv A tyrosine kinase inhibitor NGFR, which directs, reduces, or inhibits the phosphorylation of nerve growth factor-dependent tyrosine p140c trk, such as tirfostma AG 879 Targets of a tyrosome kinase inhibitor NGFR include, but are not limited to, HER2, FLK1, FAK, TrkA, and / or TrkC An indirect target inhibits the expression of RAF1 xlv. A p38 MAP kinase inhibitor, which includes a SAPK2 / 38 kinase inhibitor, which directs, reduces, or inhibits p38-MAPK, which is a member of the MAPK family, such as 4- [4- (4-fluoro- fen? l) -5- (4-pi pdin 11) - 1 H-? m? dazol-2-? l] -phenol An example of a kinase inhibitor SAPK2 / p38 includes, but is not limited to, 3- (d? met? l-am? no) -N- [3 - [(4-h? drox? -benzo? l) -am? no] -4-met? l-phen? l] -benzam? da . A member of the MAPK family is a sepna / threonine kinase activated by Phosphorylation of tyrosine and threonine residues This kinase is phosphopel and activated by many cell tensions and inflammatory stimuli, which is thought to be involved in the regulation of important cellular responses, such as apoptosis and inflammatory reactions. xlvi A kinase inhibitor of tyrosma p56, which directs, reduces, or inhibits tyrosma kinase p56, which is an enzyme that is a tyrosine kinase of the src family specific for lymphoid critical for the development and activation of T-cells, such as damnacanth, which is also known as 9,10-d? h? dro-3-h? drox? -1-methox? o-9,10-d? oxo-2-anthracene-carboxaldehyde, Tirfostma 46. A goal of a p56 tyrosma kinase inhibitor includes, but is not limited to, Lck Lck is associated with the cytoplasmic domains of CD4, CD8, and the beta chain of the IL-2 receptor, and is thought to be involved in the steps Early T-cell activation mediated by TCR xlvn An inhibitor of tyrosine kinase PDGFR, which directs, reduces, or inhibits the activity of receptor tyrosome kinases C-kit (part of the PGDFR family), such as directing, reducing, or inhibiting the activity of the receptor tyrosome kinase family c-Kit, especially inhibiting the c-Kit receptor Examples of the targets of a tyrosome kinase inhibitor PDGFR include, but are not limited to, PDGFR, FLT3, and / or c-KIT, such as tirfostma AG 1296, tirfostma 9, 2-amino-4- (1H-? Ndol-5-? L) -1,3-butad? Ene-1,1,3-tr? -carbonitplo, a derivative of N-phen? -2- p? r? m? d? n-am? na, for example, imatinib, IRESSA® PDGF has a central role in the regulation of cell proliferation, chemotaxis, and survival in normal cells, as well as in different disease states, such as cancer, atherosclerosis, and fibrotic disease. The PDGF family is composed of dimepcas isoforms (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD), which exert their cellular effects by differential binding with two receptor tyrosine kinases PDGFR-a and PDGFR-β have molecular masses of approximately 170 and 180 kDa, respectively. inhibitor of phosphatid? d? l-? us? tol-3 kinase, which directs, reduces, or inhibits PI3 kinase, such as wortmanin, which is also known as 11- (acet? lox?) - l, 6b , 7, 8, 9a, 10,11, 11 b-octah? Dro-1 - (methox? -met? L) -9a, 11b-d? Met? L-3H-furo- [4,3,2- of] -? ndeno- [4,5-h] -2-benzop? ran-3,6,9-tr? ona, (1 S, 6bR, 9aS, 11R, 11bR) - (9CI), 8-phen ? l-2- (morpholin-4-? l) -chromen-4-one quercetma, quercetin dihydrate It has been shown that the activity of cmasa PI3 increases in response to a number of hormonal stimuli and growth factors, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and it has been implicated do in the processes related to cell growth and transformation An example of an objective of a phosphatidyl-mositol-3 kinase inhibitor includes, but is not limited to PI3K x x A phosphatase inhibitor, which directs, reduces, or inhibits Phosphatase, such as cantapdmic cantapdma, and L-leucinamide, N- [4- (2-carboxy-etheyl) -benzoyl] -gl? c? I-glutam? l- (E) Phosphatases remove the phospho-group, and restore the protein to its original dephospho- phated state. Therefore, the phospho- plation-dephospholation cycle can be considered as a molecular "on-off" switch. I Platinum agent, which contains platinum, and inhibits synthesis of DNA through the formation of cross-chain cross-linking and intra-chains of DNA molecules, such as carboplatin, cisplatma, oxa-platina, cisplatmo, satraplatin, and platinum agents, such as ZD0473, BBR3464 Carboplatin can be administered, example, in the way it is traded, for example CARBOPLAT®, and oxaliplatma as ELOXATIN® A protein phosphatase inhibitor, including an inhibitor of PP1 and PP2, and a tyrosine phosphatase inhibitor, which directs, reduces, or inhibits protein phosphatase Examples of an inhibitor of PP1 and PP2A include cantapidic acid and / or cantapdma Examples of a tyrosine phosphatase inhibitor include, but are not limited to, LP-bromo-tetramisole oxalate, 4-h? drox? -5- (h? drox) ? -met? l) -3- (1 -oxohexadec? l) -2 (5H) -furanone, (5R), and benzyl-phosphonic acid The term "an inhibitor of PP1 or PP2", as used herein , refers to a compound that directs, reduces, or inhibits Ser / Thr protein phosphatases. Type I phosphatases, which include PP1, can be inhibited by two stable proteins. heat known as inhibitor-1 (1-1) e? nh? b? dor-2 (I-2) Desfosfoplan preferentially a subunit of phospholase kinase Type II phosphatases are subdivided into classes of spontaneously active phosphatases (PP2A), Ca2 + Dependent (PP2B), and Mg2 + Dependent (PP2C) The term "tyrosine phosphatase inhibitor", as used herein, refers to compounds that direct, reduce, or inhibit tyrosine phosphatase. Phosphatases protein tyrosma (PTPs) are relatively recent additions to the phosphatase family Remove phosphate groups from tyrosine phosphoprotein residues of proteins PTPs exhibit diverse structural characteristics, and have important roles in the regulation of cell proliferation, differentiation, and adhesion and cell mobility, and in cytoskeletal function Examples of the targets of a tyrosine phosphatase inhibitor include, but are not limited to, alkaline phosphatase (ALP), heparanase, PTPase, and / or prostatic acid phosphatase ln A PKC inhibitor and a PKC delta kinase inhibitor The term "a PKC inhibitor", as used in present, refers to a compound that directs, reduces, or inhibits protein kinase C, as well as its isozymes Protein kinase C (PKC), a ubiquitous phospholipid-dependent enzyme, is involved in the signal transduction associated with the proliferation, differentiation, and cellular apoptosis Examples of a target of a PKC inhibitor include, but are not limited to, MAPK and / or NF- kappaB Examples of a PKC inhibitor include, but are not limited to, 3- [1 - [3- (d? met? l-am? no) -prop? l] -1 H-? ndol-3? l] -4- (1 H-? ndol-3-? l) -1 -H-pyrrolo-2,5-d-ona, bisindolyl-maleimide IX, sphingosine, which is known as 2-amino- 4-octadecene-1,3-d-ol, (2S, 3R, 4E) - (9CI), staurospopne, which is known as 9,13-epox? -1 H, 9H-d? -? Ndolo [1 , 2,3-gh 3 ', 2', 1 '-lm] -p? Rrolo- [3,4-j] [1, 7] -benzod? Azon? N-1 -one, derivatives of staurospopne, such as disclosed in European Patent Number EP0296110, for example midostaupna, 2,3,10,11, 12,13-hexahydro-10-methox? -9-met? l-1 l- (meth? -am? no) -, (9S, 10R, 11R.13R) - (9CI), tirfostma 51, and hipepcma, which is also known as 1, 3,4,6,8,13-hexah? drox? -10 , 11-dimethyl-phenanthro- [1, 10,9,8-opqra] -per? Leno-7,14-d? Ona, stereoisomer (6CI, 7CI, 8CI, 9CI), UCN-01, safmgol, BAI 43 -9006, bpostatma 1, pepfosma, ilmofosin, RO 318220 and RO 320432, GO 6976, Isis 3521, LI333531 / LI379196 The term "a PKC delta cmase inhibitor", as used in the pre This refers to a compound that directs, reduces, or inhibits the delta isozymes of PKC. Isozyme delta is a conventional PKC isozyme and is Ca2 + dependent. An example of a PKC delta kinase inhibitor includes, but is not limited to, Rottlepna. , which is also known as 1- [6 - [(3-acet? l-2,4,6-tr? h? drox? -5-met? l-phen? l) -met? l] -5 , 7-d? H? Drox? -2,2-d? Met? L-2H-1-benzop? Ran-8-? L] -3-phen? L-2-propen-1-one, (2E ) - (9CI) lui An inhibitor of the synthesis of po amine, which directs, reduces, or inhibits spermidine polyamines, such as DMFO, which is also known as (-) - 2-d? Fluoro-met? L -orn? t? na, N1.N12- diethyl-spermine 4HCI Spermidine and spermine polyamines are of vital importance for cell proliferation, although their precise mechanism of action is unclear. Tumor cells have an altered polyamine homeostasis reflected by increased activity of biosynthetic enzymes and protein reserves. high polyamine 11 v A proteasome inhibitor, which directs, reduces, or inhibits the proteasome, such as aclacinomycin A, g-otoxin, PS-341, MLN 341, bortezomib, velcade Examples of the targets of a proteasome inhibitor include, but are not limited to, NADPH oxidase generating 0 (2) (-), NF-kappaB, and / or farnesyl transferase, geranyl-transferase I Iv A PTP1B inhibitor, which directs, reduces, or inhibits PTP1B, an inhibitor of protein tyrosine kinase, such as N- [4- (2-carboxy-etheyl) -benzoyl] -gl? c? I-glutam? L-leuc? nam? da, (E) Ivi A tyrosine protein kinase inhibitor, including an inhibitor of the tyrosine kinase of the SRC family, an inh tyrosine kinase inhibitor Syk, and a tyrosine kinase inhibitor JAK-2 and / or JAK-3 The term "a protein tyrosine kinase inhibitor", as used herein, refers to a targeting compound, reduces, or inhibits tyrosine protein kinases Tyrosine protein kinases (PTKs) have a key role in the regulation of cell proliferation, differentiation, metabolism, migration, and survival They are classified as receiving PTKs and non-receptor PTKs The receiving PTKs contain a single chain of polypeptide with a transmembrane segment The extracellular end of this segment contains a high affinity ligand binding domain, while the cytoplasmic end comprises the catalytic core and the regulatory sequences. Examples of the targets of a tyrosine kinase inhibitor include, but are not limited to, EERK1, ERK2, Bruton tyrosine kinase (BTK), JAK2, ERK 1/2, PDGFR, and / or FLT3 Examples of indirect targets include, but are not limited to, TNFalpha, NO, PGE2, IRAK, iNOS, ICAM-1, and / or E-selectin Examples of a tyrosine kinase inhibitor include, but are not limited to, tirfostma AG 126, tyrphostin Ag 1288, tirfostma Ag 1295, geldanamycin, and genistein. Non-receptor tyrosome kinases include members of the Src, Tec, JAK, Fes, Abl, FAK, Csk, and Syk families located in the cytoplasm, as well as in the core. They exhibit different regulation, substrate phosphorylation, and kinase function. Poor regulation of these kinases has also been linked to several human diseases. The term "an inhibitor of tyrosine kinase of the SRC family", as used herein, is refers to a compound that directs, reduces, or inhibits SRC Examples of a tyrosine kinase inhibitor of the SRC family include, but are not limited to, PP1, which is also known as 1- (1, 1 -d? met? l-et? l) -3- (1-naphthalene? l) -1 H-pi razo lo- [3,4-d] -p? r? m? d? n-4-am ina (9CI ); and PP2, which is also known as 3- (4-chloro-phenol) -1 - (1,1-d? met? l-et? l) - 1 Hp? razolo- [3,4-d] -p? r? m? d? n-4-am? na, (9CI) The term "a tyrosine kinase inhibitor Syk", as used herein, refers to a compound that directs, reduces, or inhibits Syk. Examples of the objectives for a tyrosine kinase inhibitor Syk include, but are not limit to, Syk, STAT3, and / or STAT5 An example of a tyrosine kinase inhibitor Syk includes, but is not limited to, piceatanol, which is also known as 4 - [(1 E) -2- (3.5 -d? h? drox? -fen? l) -teten? -1,2-benzene? ol (9CI) The term "an inhibitor of tyrosine kinase Janus (JAK-2 and / or JAK-3)" as used herein, refers to a compound that directs, reduces, or inhibits the Janus tyrosine kinase. Janus tyrosine kinase inhibitors have been shown to be anti-leukemic agents with anti-thrombotic, anti-allergic, and immunosuppressants Targets of a tyrosome kinase inhibitor JAK-2 and / or JAK-3 include, but are not limited to, JAK-2, JAK-3, STAT3 An indirect target of a tyrosome kinase inhibitor JAK-2 and / or JAK-3 , includes, but is not limited to, CDK2 Examples of tyrosine kinase inhibitors JAK-2 and / or JAK-3 include, but are not limited to, Tyrphostin AG490, and 2-naft? lv? n? Ketone Compounds that direct, reduce, or inhibit the activity of members of the c-Abl family, and their gene fusion products, for example, include PD180970, AG957, or NSC 680410 Ivn A retmoid, which directs, reduces, or inhibits retinoid-dependent receptors, such as isotretinoin, tretinoin, alitretmoin, bexarotene Ivni An inhibitor of RNA II polymerase elongation, which directs, reduces, or inhibits the insulin-stimulated cytosolic and cytosolic kinase p70S6 in CHO cells, directs, reduces, or inhibits the transcription of RNA II polymerase, which may depend on the casein kinase II, and direct, reduce, or inhibit the breakdown of the germinal vesicle in bovine oocytes, such as 5,6-d-chloro-1-bet-Dr? bofurans? l-benc? midazole Ivix A septa / threonine kinase inhibitor, which inhibits septa / threonine kinases, such as 2-amιno-purine One example of a target of a septa / threonine kinase inhibitor includes, but is not limited to, the protein kinase dependent on dsRNA (PKR) Examples of indirect targets of a septa / threonine kinase inhibitor include, but are not limited to, MCP-1, NF-kappaB, elF2alpha, COX2 , RANTES, IL8, CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, eptropoietma, and / or CYP1A1 Ix An inhibitor of ester biosynthesis ol, which inhibits the biosynthesis of sterols, such as cholesterol, such as terbinadine Examples of the targets of a sterol biosynthesis inhibitor include, but are not limited to, squalene epoxidase, and CYP206 Ixi A topoisomerase inhibitor, including a topoisomerase I inhibitor and a topoisomerase II inhibitor Examples of a topoisomerase I inhibitor include, but are not limited to, topotecan, gimatecan, ipnotecan, camptotecan and its analogues, 9-n-tro-camptotecna, and the camptothecin conjugate macro- molecular PNU-166148 (compound A1 of International Publication Number WO9917804), 10-hydroxycamptotecna, for example the acetate salt, idarubicin, for example the hydrochloride, ipnotecan, for example the hydrochloride, etoposide, teniposide , topotecan, topotecan hydrochloride, doxorubicin, epirubicin, epirubicin hydrochloride, mitoxantrone, mitoxantrone, eg hydrochloride, daunorubicin, daunorubicin hydrochloride, valrubicin, dasatmib (BMS-354825) The ipnotecan can be administered, for example, in the form as is traded, for example under the trademark registered CAMPTOSAR® The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTIN® The term "topoisomerase II inhibitor", as used in the present, includes, but is not limited to, anthracyclines, such as doxorubicin, including the posomal formulation, for example CAELYX®, daunorubicin, including the posomal formulation, for example DUANOSOME®, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide The etoposide is marketed as ETOPOPHOS®, the teniposide as VM 26 -BRISTOL®, doxorubicin as ADRIBLASTIN® or ADRIAMYCIN®, epirubicism as FARMORUBICIN®, idarubicin as ZAVEDOS®, and mitoxantrone as NOVANTRON® Ixn VEGFR tyrosine kinase inhibitor, which directs, reduces, and / or inhibits angiogenic growth factors known and the cytokines involved in the modulation of nl and pathological angiogenesis The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosome kinases [VEGFR-1 (Flt-1 ), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] has a supreme and indispensable role in the regulation of multiple facets of angiogenic and lymphangiogenic processes. An example of a tyrosome kinase inhibitor VEGFR includes 3- (4-d? Met? L-am? No-benc? L? Den?) -2-? Ndolonone The compounds that direct, reduce, or inhibit the activity of VEGFR are especially compounds, proteins, or antibodies that inhibit the receptor tyrosine kinase of VEGF, which inhibit a VEGF receptor, or that bind to VEGF, and are in particular the compounds, proteins, or generic monoclonal antibodies and specifically disclosed in International Publication Number W09835958, for example, 1- (4-chloro-an? L? No) -4- (4-p? R? D? L-met? L) -ftalazine, or a pharmaceutically salt and acceptable thereof, for example succinate, or in Patent Numbers WO0009495, WO0027820, WO0059509, W09811223, WO0027819 and EP0769947, for example, which are described by M Prewett et al., in Cancer Research 59 (1999) 5209- 5218, by F Yuan et al, in Proc Nati Acad Sci USA, Volume 93, pages 14765-14770, December 1996, by Z Zhu et al, in Cancer Res 58, 1998, 3209-3214, and by J Mordenti et al. , in Toxicologic Pathology, Volume 27, Number 1 pages 14-21, 1999, in the International Publications Numbers WO0037502 and WO9410202, Angiostatma described by MS O'Reilly et al., Cell 79,1994,315-328, Endostatma described by MS O'Reilly et al., Cell 88, 1997, 277-285, anthramic acid amides, ZD4190 ZD6474 (vandetanib). , SU5416, SU6668, or anti-VEGF antibodies, or anti-VEGF receptor antibodies for example RhuMab (bevacizumab) Antibodies means intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies fd from at least two intact antibodies, and fragments of antibodies, as long as they exhibit the desired biological activity An example of a VEGF-R2 inhibitor, for example, includes axitmib Ixm A gonadotenoid agonists, such as abarelix, goserelin, goserelin acetate Ixiv A compound that induces the processes of cell differentiation, such as rheumatoid acid, alpha-, gamma-, or delta-tocopherol, or alpha-, gamma-, or delta-tocotpenol Ixv A bisphosphonate, for example including etpdonic, clodronic acid, tiludr onic, pamidronic, alendronic, ibandronic, psedronic, and zoledronic Ixvi A heparanase inhibitor, which prevents the degradation of heparan sulfate, for example PI-88 Ixvn A biological response modifier, preferably to nfocma or interferons, for example interferon-alpha IXVIII A telomerase inhibitor, for example telomestatma Ixix Mediators, such as catechol inhibitors or methyl- transferase, for example entacapone Ixx ispinesib, permetrexed (Ahmta®), sunitmib (SU11248), diethylstilbestrol (DES), BMS224818 (LEA29Y) Ixxi Somatostatin or a somatostatin analog, such as octeotpda (Sandostatin® or Sandostatin LAR®) Ixxn Growth hne receptor antagonists, such as pegvisomant, filgrastim, or pegfilgrastim, or interferon-alpha Ixxni Monoclonal antibodies, for example useful for the treatment of leukemia (AML), such as alemtuzumab (Campath®), ptuximab / Rituxan®), gemtuzumab, (ozogamicm, Mylotarg®), epratuzumab Ixxiv altretamine, amsacpna, asparaginase (Elspar®) , denileukin dif ti tox, masoprocol, pegaspargase Ixxv A phosphodiesterase inhibitor, for example anagreda (Agry n®, Xagpd®) Ixxvi A cancer vaccine, such as MDX-1379 The treatment of cancer with a compound, for example, or a CCR9 agent, of the present invention, optionally in combination with an anti-cancer drug, as indicated herein, may be associated with radiotherapy. Cancer treatment with a compound of the present invention, optionally in combination with a drug. against cancer, it can be a second-line treatment, for example immediately after treatment with another cancer drug or with another cancer therapy. The anesthetics that are likely to be useful as a Component of combination with a compound of the present invention include, for example, ethanol, bupivacaine, chloroprocaine, levobupivacaine, docaine, mepivacaine, procama, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marke Mepepdine, Methadone, Morphine, Oxycodone, Remifentanil, Sufentanyl, Butorphanol, Nalbuphine, Tramadol, Benzocaine, Dibucama, Linden Chloride, Xylocaine, and Phenazopipdma The anti-diarrheal drug substances that are likely to be useful as a combination component with an agent, or with an IBD agent, of the present invention, for example, include diphenoxylate, loperamide, codeine. If a compound of the present invention is administered in combination with other drug substances, the dosages of the second drug substance are -administered, of course, will vary depending on the type of co-drug used, the specific drug used, The condition being treated, as in the case of a compound of the present invention In general, dosages similar to those provided by the supplier of the second drug may be appropriate Chemical names of the compounds of the present invention, as they indicate in the present, they are copies of ISIS, version 2.2 (AutoNom 2000 Yam) The chemical names of the second substances of drug, or of other substances, can be derived from the Internet for example, by means of a program of search, such as SCI FINDER In the following Examples, all temperatures are in degrees Celsius The following abbreviations are used EtAc Ethyl acetate RT Ambient temperature Example 4-tert-butyl-N- (4-chloro-2-cyano-phenyl) - benzenesulfonamide A solution of 0 15 grams of 2-amino-5-chloro-benzonyl and 023 grams of 4-tert-butyl-benzenesulfonyl chloride is dissolved in 2 milliliters of NMP (N-met? L-2-p? Rrol? Dona), and the mixture obtained is cooled in an ice bath at 5 ° CA, adding 25 milliliters of a solution of potassium terbutylate (1N). in tetrahydrofuran), and the mixture obtained is stirred for 30 minutes, quenched with water, and the solvent obtained is evaporated from the obtained mixture. The evaporation residue is dissolved in EtAc, washed with a saturated solution of NaHCO 3, and dried The solvent is evaporated, and the residue of the evaporation is subjected to chromatography on a reversed phase column. The 4-tert.-N- (4-chloro-2-c? Ano-phen?) -benzenesulfonamide 1H is obtained -NRM (DMSO) 1 27 (s, 9 H), 706 (d, J = 85 Hz, 1H), 757-770 (m, 5 H), 799 (d, J = 2 Hz, 1H), 106 ( s broad, 1H, NH) In a manner analogous to the method described in the Example, but using the appropriate starting materials (intermediates), the compounds of the Formula are obtained wherein R1: R2 and R3 are as stipulated in the following Table 1, having a melting point p.f (° C) as defined in the following Table 1.

TABLE 1 CP "in Table 1 means" the compound number ".

Claims (2)

1. A compound of the formula: wherein: R is hydrogen, alkyl (of 1 to 6 carbon atoms), haloalkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), haloalkyloxy, or halogen, R2 is phenyl substituted by one or more of: alkyl (of 1 to 6 carbon atoms), haloalkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), halo-alkoxy (of 1 to 4 carbon atoms), or halogen; and R3 is carboxyl, alkoxy (1 to 4 carbon atoms) -carbonyl, or cyano.

2. A compound according to claim 1, wherein: R is alkyl (from 1 to 6 carbon atoms), R2 is unsubstituted phenyl or phenyl substituted by halogen, and R3 is alkoxy (from 1 to 4 carbon atoms) ) -carbonyl. A compound according to any of the claims 1 or 2, selected from the group consisting of methyl ester of the acid 1 - (4-tert.-l-benzenesulfonyl) -2,3-d? h? dro-1H-? ndol-2 -carboxyl, acid 1 - (4-tert.-l-benzenesulfonyl) -2,3-d? h? dro-1 H-? ndol-2-carboxylic acid, 5-bromo-met? l-ester of the acid 1 - (4-tert.-l-benzenesulfonyl) -2,3-d? h? d-1H-? ndol-2-carboxylic acid, and 5-bromo- 1- (4-tert.-l-benzenesulfonyl) -23-d? -hydro-1H-β-ddol-2-carboxylic acid 4 A compound according to any one of claims 1 to 3 , in the form of a salt A compound according to any of claims 1 to 4, for use as a pharmaceutical product 6 A pharmaceutical composition, which comprises a compound of any of claims 1 to 5, in association with when less a pharmaceutically acceptable excipient, The use of a compound according to any of claims 1 to 4, for the manufacture of a medicament for the treatment of disorders that are mediated by r the activity of CCR9 A pharmaceutical combination, which comprises a compound according to any of claims 1 to 4, or a pharmaceutical composition according to claim 6, and which also comprises a second drug substance. 9. A method for the treatment of disorders that are mediated by CCR9 activity, which treatment comprises administering to a subject in need of such treatment, a therapeutically effective amount of a compound according to any of claims 1 to 5, or a Pharmaceutical composition according to claim 6, optionally in combination with a second drug substance