MX2008007980A - Inhibitors of ccr9 activity - Google Patents

Abstract

Compounds of formula (I), in which R1and R2are independently a substituted phenyl group, where the substituents are as defined in the claims and with the proviso that at least one of the substituents is a cyano, carboxy or (C1-4)alkoxycarbonyl group, are inhibitors of CCR9 activity useful for therapeutic treatment, particularly of irritable bowel disease.

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 constitutively expressed 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 known receptor for TECK / CCL25. The expression of CCR9 strongly correlates with the ability of peripheral T-lymphocytes to start in the small intestine. Most intraepitehal intestinal lymphocytes (IEL) and T-lymphocytes of the lamina proppa (LPL) with CCR9 +, while that a much lower percentage of T-cells circulating in the blood are CCR9P T-cells CCR9 + in the peripheral blood almost exclusively exhibit the intestinal initiation receptor at ß7 The blocking of CCR9 with the antibody against TECK / CCL25 inhibits a Significantly, the start of T-lymphocytes in the small intestine In addition, there is a strict localization 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-endoteho lymphocytes 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 ant? -TECK / CCL25 could attenuate the recruitment of hnfocytes 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 diseases or autoimmune and inflammatory conditions The infiltration of T-lymphocytes (T-cells) in the small intestine and in the colon has been specifically related to the pathogenesis of the diseases cehacas, allergies to food, rheumatoid arthritis, human inflammatory bowel diseases (IBD), which include Crohn's disease and coli ulcerative tis 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, thymus, thymic carcinoma New compounds have been found that show surprising activity as inhibitors of CCR9 In one aspect, the present invention provides a compound of Formula O II R. - N- S- R_ I ° where R? and R2 are independently phenyl, for example including unsubstituted phenyl, and phenyl substituted by one or more of alkyl, such as alkyl (of 1 to 6 carbon atoms), for example methyl, tert-butyl, halo-alkyl, such as halo-alkyl (from 1 to 4 carbon atoms), for example CF 3, cycloalkyl (from 3 to 12 carbon atoms), for example cyclohexyl, adamantyl, -alkoxyl, such as alkoxy (from 1 to 4 carbon atoms), for example, methoxy, apl-alkyloxy, such as aplo (of 6 to 18 carbon atoms) -alkylloxyl (of 1 to 4 carbon atoms), for example benzyloxy, -haloalkoxy, such as haloalkoxy (from 1 to 4 carbon atoms), for example OCF3, cyano, halogen, for example fluorine, chlorine, bromine, with the proviso that at least one of Ri and R2 is phenyl substituted with cyano, and with the proviso that it is excluded he compound of N- (2-c? ano-phen? l) -4-tr? uoro-met? l -benzenesulfonamide In another aspect the present invention provides a compound of the formula I, wherein R, and R 2 independently of one another are cyano-phenyl, for example, 2-c? ano-phenol, 3-c? ano-phenol, (c? an) - (met? l) -fen? lo, for example, 2-met? l-4-c? ano-phenyl, 2-c? ano-5-met? l-fen? lo, (c? an) - (chloro) -fen? it, for example, 2-c? ano-4-chloro-phenyl, 2-c? ano-5-chloro-phenol, 3-chloro-4-c? ano-phenol, (c? an) - (tr? fluoro-methoxy?) - phenol, for example, 2-tr? fluoro-methox? -4-c? an-phenol, methyl phenyl, for example, 4-met? l-phen It is terbutyl-f-enyl, for example, 4-terbutyl-phenol, (methylene) - (methoxyl) -phenol, for example, 2-methox-4-methyl- phenyl, t-fluoro-methyl-phenyl, including bis-t-fluoro-methyl-phenyl, for example, 4-tr? uoro-met? l-phenol, 3,5-b? s-tr? fluoro-met? l- phenyl, chloro-phenyl, for example, including dichloro-phenyl, such as 4-chloro-phenol, 2,3-d-chloro-phenol, 2,4-d-chloro-phenol, trifluoro- methoxy phenyl, for example, 4-tr? fluoro-methox? -phenyl, bromo-phenyl, for example, 4-bromo-phenol, methoxy-phenyl, for example, including dimethoxy-phenyl, for example, 2, 4-d? Methox? -fe only, benzyloxy-phenyl, for example, 4-benzyl-phenyl, cyclohexyl-phenyl, for example, 4-c-clohexyl-phenol, adamantyl-phenyl, for example, 4-adamant? phenol, with the proviso that at least one of R, and R2 is phenyl substituted with cyano, and with the proviso that the compound of N- (2-c? ano-phen? l) -4- is excluded. tr? fluoro-met? l-benzenesulfonamide In another aspect the present invention provides a compound of formula I, wherein R is cyano-phenyl, for example, 2-c? ano-phenol, 3 -c? ano-phenol, - (c? an) - (met? l) -fen? lo, for example, 2-met? l-4-c? ano-phenyl, 2-c? ano-5 -met? l-phenol, (c? an) - (chloro) -phenol, for example, 2-c? ano-4-chloro-phenyl, 2-c? ano-5-chloro-phen? lo, 3-chloro-4-cyano-phenol, (cyano) - (bromo) -phenol, for example, 2-cyano-4-bromo-phenyl, or (cyano) ) - (tr? fluoro-methoxy?) - phenol, for example, 2-tr? fluoro-methox? -4-c? ano-phen? In another aspect the present invention provides a compound of formula I, where R? is as defined above, and R2 is methyl-phenyl, for example, 4-methyl-phenol, tert-butyl-enyl, for example, 4-terbutyl-phenol, trifluoro-methyl-phenyl including bis -tpfluoro-methyl-phenyl, for example, 4-tr? uoro-met? l-phenol, 3,5-b? s-tr? fluoro-met? l-phenyl, methoxy phenyl, for example, including dimethoxy phenyl, for example, 2,4-d? methox? -phenyl, tpfluoro-methoxy phenyl, for example, 4-tr? fluoro-methox? -phenyl, benzyloxy- phenyl, for example, 4-benzyl? -phenyl, chloro-phenyl, for example, including dichloro-phenyl, such as 4-chloro-phenol, 2,3-d? chloro-phenol, 2,4-d? Chloro-phenol, bromo-phenyl, for example, 4-bromo-phenol, (meth? L) - (methox?) - phenol, for example, 2-methox? - 4-methyl-phenyl, cyclohexyl-phenyl, for example, 4-c-clohexyl-phenol, adamantyl-tenyl, for example, 4-adamantyl-phenol Each cycloalkyl or aplo indicated herein may be unsubstituted or substituted by the aplo substituents stipulated for phenyl in the meaning of R.sub.2 or R.sub.2 In a compound of formula I, each individual defined substituent may be a preferred substituent, for example, a substituent defined independently of one another. In another aspect, the present invention provides a compound selected from the group consisting of 4-tert.-N- (4-chloro-2-c? ano-phen?) -benzenesulfonam? Da, 4-tert.-N- (5-chloro-2-c? ano-phen?) -benzenesulfonamide, N- (4-chloro-2-c? ano-phen?) -4- tr? fluoro-met? l-benzenesulfonamide, N- (5-chloro-2-c? Ano-phen? L) -4-tr? Uoro-met? L -benzenesulfonamide, 4-tert.-N- (2-c? Ano-phen? L) - benzenesulfonamide, N- (4-chloro-2-c? ano-phen?) -4-met? l-benzenesulfonamide, 2,4-d? chloro-N- (4-c) ? ano-2-tr? fluoro-methox? -fen? l) -benzenesulfonamide, 2,4-d? chloro-N- (5-chloro-2-c? ano-phen? l) -benzenesulfonam ? da, N- (4-chloro-2-c? ano-phen? l) -2,4-d? methox? -benzenesulfonamide, N- (4-chloro-2-c? ano-phen ?) -2-methox? -4-met? l-benzenesulfonamide, 4-tert.-N- (3-c? ano-phen?) -benzenesulfonamide, N- (5-chloro- 2-cyano-phenol) -4-methylene-benzenesulfonamide, N- (4-cyano-2-tr? Fluoro-methox? -phen?) -3,5- b? s-tr? fluoro-met? l-benzenesulfonamide, N- (3-chloro-4-c? ano-phen? l) -3,5-b? s-tr? fluoro-met? l- benzenesulfonamide, 2,4-d? chloro-N- (3-chloro-4-c? ano-phen? l) -benzenesulfonamide, N- (3-c? ano-phen? l) - 4-tr? Fluoro-methox? -benzenesulfonamide, 2,4-d? Chloro-N- (4-c? Ano-2-met? L-phen? L) -benzenesulfonamide, 4 -terbut? lN- (2-c? ano-5-met? l-phen? l) -benzenesulfonamide, and N- (4-c? ano-2-met? l-phen? l) - 3,5-b? S-tr? Fluoro-met? L-benzenesulfonamide The compounds provided by the present invention are designated herein as the "compound (s) 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. invention in the form of a salt These salts preferably include pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, for example, for purposes of preparation n / isolation / pupification 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 Formula R, -NH2 II wherein R? is as defined above, with a compound of the Formula Cl-S02-R2 MI wherein R2 is as defined above, and b isolating a compound of Formula I obtained from of the reaction mixture In an intermediate of Formula II or of Formula III (starting materials), the functional groups, if present, can optionally be in a protected form or in the form of a salt, if a salt-forming group The protecting groups, optionally present, can be removed in an appropriate step, for example according to, for example in a manner analogous to, 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 can 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 of Formula III, are known or can be prepared according to, for example in a manner analogous to, a conventional method, or as described herein. Any compound described herein, for example a compound of the present invention invention and the intermediaries of the Formulas II and III, can 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 The compounds of the present invention, for example including a compound of Formula I, exhibit pharmacological activity, and therefore, are useful as pharmaceuticals. For use as pharmaceuticals, they are found, according to the present invention, that the compounds of the formula I and the compound of N- (2-c? ano-phen? l) -4-tr? uoro-met? l -benzenesulfonamide are useful ( the compound of Example 13), for example, in free form, in the form of a salt and / or a solvate. For use as a pharmaceutical product, therefore, N- (2-c? An-phenol) -4-tpfluoro-methyl-benzenesulfonamide is included The compounds of formula I, and the N- compound ( 2-cyanophenol) -4-tr? Fluoro-met? L -benzenesulfonamide, for example, in free form, in salt form, and / or in the form of solvate, are also designated herein as the "Agents of (agreement with) the present invention". The agents of the present invention show dose-dependent inhibition in the Scintillation Proximity Assay (SPA ASSAY), Eu-GTP Assay Assay, Calcium Mobilization Assay (FLIPR ASSAY), for example, under conventional conditions, for example under the conditions described herein, for example in IC50 nanomolar up to the low micromolar interval Activity in the treatment of inflammatory bowel disease is determined, for example, in a SCID mouse model of inflammatory bowel disease. Proximity test of the scintillation (SPA) The Principle of SPA Chemokines mediate their actions through seven receptors coupled with transmembrane extension G-protein (GPCR) on the target cells Ligand binding with GPCRs stimulates the GTP / GDP range in the heterotipeptic G proteins, composed of the subunit of a, β, yy The GPCR bound to the agonist initiates the guanine nucleotide cycle by cata- lling the dissociation of GDP from the α-subunit, allowing the binding of the endogenous GTP, and the dissociation of the β-complex and the subunits Ga-GTP and Gßy they can each activate the effectors, such as adenylyl cyclase, phospho-pass C, and ion channels (see, for example, Neer E. J, Cell, 80249-57 (1995 )) Ga-GTP is inactivated by an intrinsic activity of GTPase, which hydroxies GTP up to GDP, subsequently, the G-protein containing GDP is ready for the next activation cycle. This process can be monitored m vitro by measuring the link of GTP analogs resistant to hydrolysis, such as 5'-O- (3- [35 S] -t? -osphate ([35 S] -GTP? S), with the cell membranes containing the receptor of interest It is shown that a proximity test of GTPyS (SPA) scintillation is a useful functional assay for monitoring the activation of CCR9 by TECK SPA is a homogeneous and versatile assay technology for rapid and sensitive testing of a large number of biological processes The assay format does not require separation steps, and is susceptible to automation The membranes carrying the receptor are coupled by means of the glycoprotein fraction to the beads coated with fluorescent wheat germ agglutinin (Amersham Bioscience, # RNPQ 0001) Once immobilized, the recipient is sufficiently close 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 remain in close enough proximity for the decaying particles to stimulate the scintillator inside the bead to emit light, which is then detected by a scintillation counter based on PMT. The unbonded radiohgando is too distant from the bead to transfer energy, and therefore, goes undetected. Cells and Cell Culture Pre-B mouse cells 300-19 transfected with the human CCR9 receptor in suspension are grown in culture flasks. cell (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) of CCR9 is monitored by FACS analysis using the human CCR9 antibody conjugated with Fluor 647 Alexa The expression of CCR9 should not be less than 50 percent of positive cells by means of FACS in relation to the isotype control of fluorine Alexa As an approximation, a culture of 10 x 105 cells / milliliter can be divided, 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 p for a centrifugal flask culture) The cells are harvested at a density of 8 to 10 x 10 5 cells / milliliter by centrifugation at 300-100 g for 10 minutes. In general terms, the cells are grown and expanded to approximately 1. x 1010 cells. The combined cell pellet is washed once in cold phosphate-buffered serum (without calcium or magnesium), re-suspended by pipette in the cold membrane regulator at approximately 2 x 108 cells / milliliter, frozen on dry ice, and stored at -80 ° C Membrane Regulator Membrane regulator, pH-75 (1000 milliliters) Tris 75 mM, MgCI2 125 mM, EDTA 03 mM, EGTA 1 mM, sucrose 250 mM, filtrate sterile, and stored at + 4 ° C Regulator of Homoqeneizacion (50 milliliters ) Membrane regulator, 45 milliliters + 10 percent cerol Preparation of membranes The solution in cell suspension is pipetted into strong tubes, and each solution is homogenized. The homogenates are transferred to centrifuge tubes and centrifuged for 10 minutes. 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. minutes Each granule is resuspended in 3 milliliters of cold homogenization regulator with a Dounce homogenizer. The concentration of protein in the suspension is determined. homogeneous ion (BIO RAD assay, reference for bovine serum albumin) Bradford method (microassay procedure) As an approximation, 1 x 1010 cells result in a membrane yield of 10 to 20 milligrams of protein Aliquots are stored a - 80 ° C Optimized Regulators and Solutions for Testing Compounds HEPES / BSA Regulator 50 mM HEPES (pH of 74), 50 micrograms / ml of bovine serum albumin Test Regulator 25 X 50 mM HEPES, pH of 74, 50 micrograms / milliliter 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 solution of 20 times TECK 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 solutions of compound concentrated in dimethyl sulfoxide, which are diluted five times in HEPES / BASA regulator to generate solu concentrations of the 20-fold concentrated compounds, which contain a concentration of dimethyl sulfoxide of 20 percent (volume / volume) The final concentration of dimethyl sulfoxide in the tests is 1 percent (volume / volume) Membrane dilution Before used, the membranes (24 milligrams / milliliter supply, batch CCR9-1) are diluted in HEPES / BSA regulator, to give 60 micrograms / milliliter. 50 microliters of this membrane 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 microgram / milliliter of albumin of 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 micro sequence 40 Test regulator samples (20 mM HEPES, pH 75, 100 mM NaCl, 10 mM MgCl 2, 1 μM GDP, 10 micrograms / mihliter saponin, 50 micrograms / ml of bovine serum albumin) 10 micro-hours of human TECK / CCL25 agonist, 25 micrograms / milliliter (R & D Systems, # 334-TK-025) microliters of sample in 50 percent dimethyl sulfoxide 50 microchres of membranes, 60 micrograms / ml in assay buffer 50 microliters of [35S] GTP? S, 1 nM in assay buffer 40 microchors of suspension of beads, 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-hydrophilic, non-radioactive europium, Eu-GTP Materials RPMI 1640 medium (made of powder, Gibco # 074- 01800) Penicillin / streptomycin solution, liquid (Gibco # 15140-122) Fetal bovine serum (certified, obtained from Gibco [# 16000], and then heat-activated) Sodium pyruvate (Gibco # 11360-039) Puromycin (used as a selection marker, Sigma # P-8833) Complete protease inhibitor (Roche # 1697498) Human mouse anti-CCR9 antibody conjugated to Fluor 647 Alexa (Pharmingen # 557975) Isotype control lgG2a conjugated with Fluor 647 Alexa (BD Pharmingen 3557715) TECK (aa24-150-h? S6, Protema Database with BMP Tool # BTP04-005213, Solution aliquots TECK delivery (5 milligrams / milliliter, approximately 350 μM) stored at -80 ° C Bovine serum albumin (Roche Diagnostics GmbH # 775827) Eu-GTP (Perkm-Elmer Life Sciences, Wallac, Turku, Finland, product code AD0260 ), the kit contains the following components Eu-GTP (1 65 nanomoles) The hoofilized Eu-GTP was reconstituted with distilled water to provide a Eu-GTP concentration of 10 μM The aliquots of the reconstituted Eu-GTP were stored at -20CC GDP (23 micromoles) The 11 hg GDP hof is reconstituted with distilled water to provide a GDP concentration of 2 mM. The aliquots of the reconstituted GDP are stored at -20 ° C. VICTOR2 RV Multilabel Counter (Perkin-Elmer Life Sciences, Wallac, Turku, Finland) Multiple MultiScreen Vacuum (Millipore #MAVM 096OR) Cells and Cell Culture To carry out lameness is described in the present under "Cells and cell culture" in the "Scintillation Proximity Test (SPA) P Membrane Regulator and Homogenization Regulator To be carried out as described herein under" membrane regulator and homogenization regulator "in the" scintillation proximity test (SPA) "Preparation Membranes To be carried out as described herein under "membrane preparation" in the "cmtilation proximity assay (SPA)." Optimized Regulators and Solutions for Testing the Compounds To be carried out as described in present under "optimized regulators and solutions for the test of the compounds" in the "proximity test of the belt (SPA)." For Eu-GTP- The supply solution is diluted of Eu-GTP up to 10 nM in HEPES / BSA regulator before use.

GTP Wash Solution The 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. The test components are added to the wells in the following order. 40 micro samples of assay buffer are added ( 2 5X) to each well (wells B2 to G12) 5 micro-hours of TECK (74 μM) are added to the wells of columns 2 to 11, and the final concentration of TECK in the test is 037 μM 5 micro-tros are added of 0 1 percent bovine serum albumin to the wells of column 12, which serve as the baseline control. 5 micro-hours of each compound concentration (20 times of the final concentration in 20 percent dimethyl sulfoxide) are added per triplicate to columns 3 to 11 (ie, three wells per concentration) 5 microliters of 20% dimethyl sulfoxide are added to the wells of columns 2 and 12, which are the stimulated and basal controls, respectively. of final dimethyl sulfoxide in all wells are 1 percent (volume / volume) 50 microchres of membranes (3 micrograms / sample) are added to all wells, and mixed for a short time at 800 revolutions per minute on a microtiter plate shaker (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 micro-hours of 100 nM Eu-GTP are added per well to provide a final concentration of 10 nM The plate is incubate for another 30 minutes with slow agitation at 300 revolutions per minute on the orbital plate shaker. The reaction is terminated by vacuum filtration, and the filter plate is washed twice by vacuum filtration with 300 microliters of GTP wash buffer ice per well The Eu-GTP retained on the filter is measured with a VICTOR2MR V Multilabel Counter (340 nanometer excitation / 615 nanometer emission, 0.4 millisecond delay, 0.4 mi seconds window) within 30 minutes after the wash step .

Table A (Unfolding the Plate) eleven 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, X Lf? t R (Business ID Solutions, Guilford, Surrey, United Kingdom), for the four parameter logistic equation (Model 205) y = A + ((BA) / (1 + ((C / x) D))) where x are the concentration values , y is the percentage of stimulus above the basal link corresponding to the values of x 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 upper and lower plains), D Tilt factor (also known as Hill coefficient) The IC50 is defined as the midway point between the solvent control containing TECK, and the solvent control no 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 tests In another aspect, the present invention provides the use of the SPA assay, or the use of the Eu-GTP LINK TEST in the method for the identification of CCR9 inhibitors. The SPA and the Eu-GTP LINK TEST are used as described herein. The CCR9 inhibitors can be identified by the use of these assays include antibodies and chemical compounds, eg, 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 Gai protein sensitive to the Whooping cough toxin (PTX) A number of studies have shown the activation of different signaling pathways for most chemokines and in multiple s types of cells, 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 fluorescein imaging plate reader (FLIPR) The mobilization of intracellular calcium, in MOLT-4 cells, as measured using the FLIPR technology, shown as a useful functional assay to monitor the activation of CCR9 by TECK bj 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 microgram / milliliter streptomycin, at 37 ° C, with 5 percent C02 Human serum albumin (HSA) is obtained from ZLB Behring (Vienna, Austria) as a 20 percent solution cj 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 milliliter s 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 regulator 350 milliliters of WB + 35 milliliters of solution Probenicide supply • 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 medium + 1 05 milliliters of supply solution probenicide + 2 1 milliliter of 1M HEPES + 0.21 milliliter of Fluo-4 solution. TECK: 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 107 cells per 3 milliliters) in the dye solution for 60 minutes at 37 ° C and with 5 percent C02. Subsequently, the cells are washed twice with the regulator Probenicide, and pipetted to the 96-well assay plates (clear bottom black Styrene plates: Corning Costar # 3603) at 2 x 105 cells and to 0075 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 supply solutions are diluted in dimethyl sulfoxide, in 0 194 milliliters of WB (+ HSA) before injecting into the cell plates (0 025 milliliter / well) After a 30 minute incubation in the dark at room temperature, mobilization of intracellular Ca 2+ is monitored after injection of TECK (to give an effective concentration almost maximum of at least the EC8o), using a FLIPR instrument (Molecular Devices, Ismaning / Munich, Germany) Baseline readings are collected (at 35 second intervals) for 25 seconds before the TECK injection (0025 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 Formula d_) Calcium Calculus response = [Fmax - Fm? n] / Fm? n where Fmax represents the maximum response fluorescence, 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 XLf? tMR (ID Business Solutions, Guilford, Surrey, United Kingdom), for the four-parameter logistic equation (Model 205), to determine the IC50 values. Surprisingly, it has been found that the agents according to the present invention and the these of the formula I, where R, and R2 are defined above, and the compounds of the formula I, wherein Ri or R2, preferably Ri, in addition to the meaning defined above, is phenyl substituted by carboxyl (-COOH), for example, in free form, or in the form of a salt, optionally in the form of a solvate, they are all inhibitors of CCR9, and it has been found, according to the present invention, that they are active in the inflammatory bowel disease model of SCID mouse. The compounds of the formula OR '- N - S - R ', H || Or where R ', and R'2 are independently phenyl, for example, including unsubstituted phenyl and phenyl substituted by one or more of alkyl, such as alkyl (of 1 to 6 carbon atoms), for example, methyl, tert-butyl, haloalkyl, such as haloalkyl (from 1 to 4 carbon atoms), for example, CF3, cycloalkyl (from 3 to 12 carbon atoms), for example, cyclohexyl, adamantyl, alkoxy, such as alkoxy (from 1 to to 4 carbon atoms), for example, methoxy, for example, including unsubstituted alkoxy (from 1 to 4 carbon atoms), and alkoxy (from 1 to 4 carbon atoms) substituted by aplo (from 6 to 18 carbon atoms) ), such as benzyloxy, aploxil, such as aploxyl (from 6 to 18 carbon atoms), haloalkoxy, such as haloalkoxy (from 1 to 4 carbon atoms), for example, OCF3, -alkoxycarbonyl, such as alkoxy (from 1 to to 4 carbon atoms) -carbonyl, eg, methoxycarbonyl, carboxyl, cyano, or halogen, for example, fluorine, chlorine, bromine, for example, in free form or in the form of a salt, optionally in solvate form, wherein at least one phenyl in the meaning of R ^ or R2 is substituted by cyano or carboxyl, are also defined herein as the "IBD agents of the present invention" The IBD agents of the present invention they can be prepared as appropriate, for example, in a manner analogous to a method for the production of a compound of the present invention. In another aspect, the present invention provides a compound selected from the group consisting of. 2- (4-tert-butyl-1-benzenesulfonyl-1-amino) -5-chloro-benzoic acid, 2- (4-benzyl) -benzene-sulfonyl-amine acid) -benzo-co, 5-b-romo-2- (4-terb util-benzene-sulfonyl-amino) -benzoic acid, 5-chloro-2- (4-chloro-benzenesulfonyl-1-amino) acid -benzo? co, 2- (4-tert.-l-benzenesulfonyl-l-amino) -5-chloro-benzoic acid, -Chloro-2- (4-C-Clohexyl-l-benzenesulfonyl-1-amino) -benzoic acid, and 2- (4-adamantan-1-l-benzenesulfonyl-1-a) acid ?) -5-chloro-benzoic acid, in free form or in the form of a salt, optionally in the form of a solvate Additionally it has been found that the compounds of the formula I, wherein R and R2 are as defined above, and wherein at least one phenyl is substituted by alkoxycarbonyl, such as alkoxy (1 to 4 carbon atoms) -carbonyl, eg, methoxycarbonyl, in free form or in salt form, optionally in the form of Solvate, are powerful inhibitors of CCR9. In another aspect the present invention provides the use of a compound of formula O II R "- N - S - R" I "1 H || 2 O where. and R "2 are independently phenyl, for example, including unsubstituted phenyl and phenyl substituted by one or more of alkyl, such as alkyl (from 1 to 6 carbon atoms), for example, methyl, tert-butyl, haloalkyl, such as halo-alkyl (of 1 to 4 carbon atoms), for example, CF3, cycloalkyl (from 3 to 12 carbon atoms), for example, cyclohexyl, adamantyl, alkoxy, such as alkoxy (from 1 to 4 carbon atoms), for example, methoxyl, for example, including alkoxy (from 1 to 4 carbon atoms) carbon) unsubstituted, and alkoxy (from 1 to 4 carbon atoms) substituted by aplo (from 6 to 18 carbon atoms), such as benzyloxy, aploxyl, such as aploxyl (from 6 to 18 carbon atoms), - halo- alkoxy, such as haloalkoxy (of 1 to 4 carbon atoms), for example, OCF3, alkoxycarbonyl, such as alkoxy (of 1 to 4 carbon atoms) -carbonyl, eg, methoxycarbonyl, halogen, for example, fluorine, chlorine, bromine, for example, in free form or in the form of a salt, optionally in the form of a solvate, with the proviso that at least one phenyl in the meaning of R? Or R2 is substituted with alkoxycarbonyl, such as alkoxy (1 to 4 carbon atoms) -carbonyl, eg, methoxycarbonyl, for the preparation of a medicament for the treatment of disorders that are mediated by activity of CCR9 An IBD agent or a CCR9 agent according to the present invention may be prepared as appropriate, for example according to, for example, in a manner analogous to a conventional method, or according to, for example, in a manner analogous to, as described herein for a compound of the present invention. For example, in case the phenyl in a compound of the formula I is substituted by carboxyl instead of cyano, protection of this carboxyl group in a compound of the formula II can be an option, for example, by esterification, to obtain a corresponding alkoxycarbonyl derivative. The compound of the formula II, wherein the phenyl is substituted by alkylcarbonyloxy, can be reacted with a compound of the formula III to obtain a compound of the formula I, wherein the phenyl is substituted by alkoxycarbonyl and the The carboxylic acid ester obtained in this way can be saponified to obtain a corresponding compound of the formula I, wherein the phenyl is substituted by carboxyl. In another aspect, the present invention provides a method for the treatment of a disorder mediated by CCR9 activity, which comprises administering to a subject in need, a therapeutically effective amount of a compound of formula I ", for example, in free form or in salt form, optionally in solvate form In another aspect, the present invention provides a compound selected from the group consisting of 5-bromo-2- (4-terbutyl) methyl ester of the acid -benzene-sulfon? l-am? no) -benzo? co, and methyl ester of 2- (4-tert-butyl-l-benzenesulfonyl-1-amino) -5-chloro-benzoic acid, in free form or in the form of a salt, for example, optionally in solvate form The compounds of the formula I "in free form or in the form of a salt, are also referred to herein as the" CCR9 agents "The agents, and the IBD agents, and the CCR9 agents, of the present invention , show activity in the assays described herein, and an agent, or an agent of IBD, or a CCR9 agent of the present invention is susceptible to showing a therapeutic activity in the treatment of disorders that are mediated by the activity of CCR9 Disorders that are mediated by CCR9 activity, and that are susceptible to being successfully treated with a CCR9 inhibitor, for example, include disorders wherein CCR9 activity has a causal or contributing role, such as associated disorders with the link of 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 disorders (chronic), 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, lung inflammation (alveolitis), respiratory tract, for example asthma, such as bronchial asthma, acute respiratory distress syndrome (ARDS), inflammatory skin disorders such as hypersensitivity to contact, dermatitis atopic, fibrotic disease (eg, pulmonary fibrosis), encephalitis, inflammatory osteoarthritis, disorders associated with immune system conditions, immune, such as autoimmune disorders, for example including Graves' disease, Hashimoto's disease (chronic thyroiditis), multiple sclerosis , rheumatoid arthritis, arthritis, gout, osteoartptis, scleroderma, syndrome s of lupus, systemic lupus erythematosus, Sjoegren's syndrome, sopasis, inflammatory bowel disease, including Crohn's disease, colitis, for example ulcerative colitis, sepsis, septic shock, autoimmune hemolytic anemia (AHA), urticaria triggered by autoantibodies, pemphigoid, nephritis, glomerulonephritis, Goodpasture syndrome, ankylosing spondylitis, Reiter syndrome, polymyositis, dermatomyositis, cytokine-mediated toxicity, nterleucine-2 toxicity, alopecia areata, uveitis, lichen planus, bullous pemphigoid, myasthenia gravis, diabetes mtus type I, immuno-mediated infertility such as premature ovarian failure, glandular failure, hypothyroidism, pemphigus vulgaps, pemphigus 1-ol? aceo, paraneoplastic pemphigus, autoimmune hepatitis including that associated with the Hepatitis B (HBV), and with the hepatitis virus C (HCV), Addison's disease, autoimmune diseases of the skin, such as sopasis, dermatitis herpetiformis, epidermo sis bullosa, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, bullous chronic disease of childhood, pernicious anemia, hemohtica anemia, vitiligo , autoimmune pohglandular syndromes type I, type II, and type III, autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune Oofoptis, gestational autoimmune pemphigoid orchitis, cicatricial pemphigoid, mixed essential cipoglobulinemia, immune thrombocytopenic purpura, Goodpasture syndrome, autoimmune neutropenia, Eaton myasthenic syndrome -Lambert, rigid man syndrome, encephalomyelitis, acute disseminated encephalomyelitis, Guillam-Barre syndrome, cerebr degeneration, retinopathy, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, gluten-sensitive enteropathy, reactive arthtypsis, polymyositis / dermatomyositis, tissue disease mixed connective, s ndrome Bechet, po arteptis nodosa, allergic anguitis and granulomatosis (Churg-Strauss disease), of overlapping poliangntis (hypersensitivity) syndrome, vascuhtis, Wegener's granulomatosis, temporal arteptis, Kawasaki disease sarcoidosis, cpopatias, celiac 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 was 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, Huntmgton's disease, thalamic degeneration , dementia of Creutzfeld Jakob, dementia for HIV, schizophrenia with dementia, Korsakoff's psychosis, cognitive-related disorders, such as mild cognitive impairment, memory impairment associated with age, age-related cognitive decline, vascular cognitive impairment, attention deficit disorders, attention deficit hyperactivity disorders, and Memory disturbances 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), muscle weakness, seizures, developmental delay (difficulty of physical or mental development), mental retardation, growth failure, feeding difficulties, nfoedema, 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, i pdocic litis, cataracts, uveitis, ret diabetic opathy 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 conditions and vascular 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 and low output, acute and chronic, Right or left side, systolic or diastoic, regardless of the underlying cause, myocardial infarction (MI), prophylaxis of myocardial infarction (primary and secondary prevention), acute treatment of myocardial infarction, prevention of complications, disorders of the heart, vascular proliferative disorders, vascuhtidas, pol lartep tis nodosa, inflammatory consequences of ischemia, 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, arrhythmia s asymptomatic such as all forms of atrial and venipuncture tachyarrhythmias, atrial tachycardia, atrial flutter, atrial fibrillation, reuptake augulo-ventpcular tachycardia, pre-excitation syndrome, ventricular tachycardia, ventpcular fluter, ventpcular fibplation, bradycardic arrhythmia forms, arrhythmia, chronic obstructive pulmonary disease, hypertension, such as systolic or high diastolic 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 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 wherein the wall of the vessels is remodeled, for example including accumulation of cells, both smooth muscle cells and monocyte / macrophage inflammatory cells, in the intima of the vessel wall, hypotension, disorders associated with the liver and the kidneys, for example including kidney disorders, kidney disorders, for example acute kidney failure, acute kidney disease, liver disorders, eg cirrhosis, hepatitis, liver failure, cholestasis, acute / chronic hepatitis, sclerosing cholangitis, primary biliary cirrhosis, water / chronic interstitial glomerulonephritis, granulomatous diseases, Associated disorders with conditions of the stomach or pancreas, for example, including disorders of the stomach, for example gastric ulcer, gastrointestinal ulcer, pancreatic disorders, pancreatic fatigue, disorders associated with the respiratory tract and the lungs, for example, including lung disorders, chronic lung disease, acute respiratory failure syndrome (de adults) (ARDS), asthma, bronchitis due to asthma, bronchiectasis, diffuse interstitial lung disorders, pneumocomosis, fibrous alveolitis, pulmonary fibrosis, disorders associated with skin and connective tissue conditions, for example, including eczema, atopic dermatitis, dermatitis contact, sopasis, acne, dermatomyositis, Sjoegren's syndrome, Churg-Strauss syndrome, sunburn, skin cancer, wound healing, urticaria, toxic epidermal necróis, Disorders associated with allergic conditions, for example, including type hypersensitivity delayed, allergic conjunctivitis, drug allergies, rin itis, allergic rhinitis, 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 overdose cell proliferation, for example, including pre-malignant conditions, hyperprophylactic disorders, cancers either primary or metastatic, cervical and metastatic cancer, cancer that originates from uncontrolled cell proliferation, solid tumors, such as those described in Publication International Number WO02066019, including non-microcellular lung cancer, cervical cancer, tumor growth, lymphoma, B-cell or T-cell carcinoma, benign tumors, benign disproffective disorders, renal carcinoma, esophageal cancer, stomach cancer, renal carcinoma, cancer of bladder, breast cancer, colon cancer, lung cancer, melanoma, nasopharyngeal cancer, osteocarcinoma, ovarian cancer, uterine cancer; prostate cancer, skin cancer, leukemia, tumor neovasculapzation, angiomas, myelodysplastic disorders, lack of response to normal death-inducing signals (immortalization), increased cell mobility and invasiveness, genetic instability, poorly regulated gene expression, cancer (neuro ) endocrine (carcinoids), blood cancer, Imfocytic leukemias, 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, for example 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 disorders of the system nervous tral, 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 (for example, 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, pain related to HIV / AIDS, pain from cancer, metabolic neuropathies (eg, diabetic neuropathy, neuropathy vasculitis secondary to connective tissue disease), paraneoplastic polyneuropathy associated, for example, with lung carcinoma, or leukemia or nymphoma, or carcinoma of the prostate, colon, or stomach, trigeminal neuralgia, cranial neuralgia, and post-herpetic neuralgia, pain associated with peripheral nerve damage, central pain (ie, due to cerebral ischemia), and different chronic pains, ie, back pain, back pain (low back pain), inflammatory and / or rheumatic pain, headache ( for example, migraine with aura, migraine without aura, and other migraine disorders), headache of episodic and chronic stress type, headache of type of t depression, cluster headache, and chronic paroxysmal hemicrania, visceral pain, 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 deposit disease, lupus syndromes, systemic lupus erythematosus, sclerosis, scleroderma, multiple sclerosis, atherosclerosis, arthrosclerosis, 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 against the host, such as following a bone marrow transplant, Ischemic reperfusion injury, Birth control (by inhibiting ovulation) Although ovulation inhibition is not a disorder, birth control (by inhibiting ovulation) also pretends to be encompassed by the definition of ovulation. "disorders that are susceptible to being mediated by CCR9 activity" according to the present invention.

Disorders that are susceptible to being mediated by CCR9, for example, preferably include autoimmune disorders, inflammatory disorders, - allergic disorders, following transplant disorders, cancer, more preferably autoimmune disorders, inflammatory disorders, disorders following transplantation, such as a disease cehaca, food allergy, rheumatoid arthritis, inflammatory bowel diseases (IBD), Crohn's disease, ulcerative colitis, sopasis, atopic dermatitis, asthma, fibrotic diseases, diseases following transplant, rejection of GVH, cancer, leukemia ( acute nfocitic leukemia), solid tumors, carcinoids, thymoma, thymic carcinoma, preferably inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, for example include ulcerative proctitis In another aspect, the present invention provides an agent of the present invention to be used as a pharmaceutical product, the use of an agent of the present invention as a pharmaceutical product, - the use of an agent of the present invention for the manufacture of a medicament, for example for the treatment of disorders mediated by the activity of CCR9, for example, an agent of the present invention for the treatment of disorders mediated by CCR9 activity, such as disorders associated with link disruption from CCR9 with CCL25. such as disorders mediated by the initiation of CCR9-mediated leukocytes in a subject. In another aspect, the present invention provides an IBD agent of the present invention for the manufacture of a medicament for the treatment of inflammatory bowel disease. For pharmaceutical use , one or more agents, or agents of IBD, of the present invention can be used, for example, in combination of two or more agents, or IBD agents, of the present invention, and preferably an agent, or IBD agent, of the present invention is used. , or an IBD agent, of the present invention, can be used as a pharmaceutical in the form of a pharmaceutical composition. In another aspect, the present invention provides a pharmaceutical composition, which comprises an agent of the present invention in association with a pharmaceutical composition. 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 and / or Emulsifying Agents, 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 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 an IBD agent of the present invention, for the treatment of inflammatory bowel disease, the use of a pharmaceutical composition comprising a CCR9 agent 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 or, the appropriate dosage, of course, will vary depending, for example, on the chemical nature and pharmacokinetic data of an agent, or IBD agent, of the present invention used, the individual host, the mode of administration, and The nature and severity of the conditions that are being treated However, in general, to have results satisfactory in higher mammals, for example in humans, an indicated daily dosage includes a range from about 00001 grams to about 1.5 grams, such as from 0001 grams to 1.5 grams, from approximately 0001 milligrams / kilogram of body weight to about 20 milligrams / kilogram of body weight, such as from 001 milligrams / kilogram of body weight to 20 milligrams / kilogram of body weight, of an agent, or an agent of IBD, or an agent of CCR9, of the present invention, for example, administered in divided doses up to four times a day An agent, or an agent of IBD, or a CCR9 agent, 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, eg low molecular weight inhibitors, of CCR9 activity. In a further aspect, the present invention provides a method for the treatment of disorders that are mediated by the activity of CCR9, for example including the disorders specified above, which treatment comprises administering to a subject in need of such treatment, a therapeutically effective amount of an agent of the present invention, by example in the form of a pharmaceutical composition In another aspect, the present invention provides an agent of the present invention for the manufacture of a medicament, the use of an agent 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 another aspect, the present invention provides an IBD agent of the present invention, for the manufacture of a medicament, the use of an agent of IBD of the present invention, for the manufacture of a medicament, for example, a pharmaceutical composition, for the treatment of inflammatory bowel disease In a further aspect, the present invention provides a method for the treatment of inflammatory bowel disease, whose treatment comprises administering to a subject in need of such treatment, a therapeutically effective amount of an IBD agent of the present invention, for example in the form of a pharmaceutical composition, an agent, or an IBD agent, or a CCR9 agent, of the present invention can be administered by any means conventional, for example enterally, for example including nasal, buccal, rectal, or oral administration; parenterally, for example including intravenous, mtra-artepal, intramuscular, intracardiac, subcutaneous, intraosseous, transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), or through inhalation, topically, administration for example including epicutaneous, intranasal, or intratracheal administration, mpepeptoneal (infusion or injection into the peptoneal cavity), epidural (pepdural) (injection or infusion into 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, solutions solids, suspensions, dispersions, solid dispersions, for example in the form of ampoules, flasks, in the form of creams, gels, pastes, inhaler powder, foams, dyes, lipsticks, drops, aerosols, or in the form of suppositories For topical use, for example, including administration to the eyes, satisfactory results can be obtained with the local administration of a concentration of 0 5 to 10 percent, such as 1 to 3 percent, of the active substance, several times a day, for example 2 to 5 times a day An agent, or an agent of IBD, or a CCR9 agent, from 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, an agent, or an IBD agent, or a CCR9 agent of the present invention in the form of a salt exhibits the same order of activity as an agent, or an IBD agent, of the present invention in free form, optionally in the form of a solvate. An agent of the present invention can be used for any method or use as described herein, and an IBD agent of the present invention can be used for the treatment of inflammatory bowel disease, and a CCR9 agent of the present invention. invention can be used for the treatment of disorders mediated by CCR9, alone or in combination with one or more, at least one second drug substance different. In another aspect, the present invention provides a combination of an agent of the present invention with at least one second drug substance, a pharmaceutical combination, which comprises an agent of the present invention in combination with at least one second drug substance, a pharmaceutical composition, which comprises an agent of the present invention in combination with at least one second drug substance, and one or more pharmaceutically acceptable excipients; an agent 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 herein; - a combination, a pharmaceutical combination, or a pharmaceutical composition, which comprises an agent of the present invention and at least one second drug substance, to be used as a pharmaceutical product; the use as a pharmaceutical product, of an agent 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 an agent 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 described 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 an agent, for example, or an IBD agent, or a CCR9 agent, of the present invention and at least one second drug substance , for example, in the form of a combination or pharmaceutical composition, - an agent 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 use in disorders mediated by CCR9 activity. In another aspect, the present invention provides a combination of an IBD agent of the present invention with at least one second drug substance, for use in the treatment of inflammatory bowel disease; - A pharmaceutical combination, which comprises an IBD agent of the present invention, in combination with at least one second drug substance, for use in the treatment of inflammatory bowel disease, A pharmaceutical composition, which comprises an agent of IBD of the present invention, in combination with at least one second drug substance, and one or more pharmaceutically acceptable excipients, for use in the treatment of inflammatory bowel disease, A method for the treatment of inflammatory bowel disease in a subject that need, which comprises co-administering, in a concomitant or sequential manner, a therapeutically effective amount of an IBD agent of the present invention, and at least one second drug substance, e.g., in the form of a combination or pharmaceutical composition, An IBD agent 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 use in the treatment of inflammatory disease of the intestine. In another aspect, the present invention provides a combination of a CCR9 agent of the present invention, with at least one second drug substance, for use in the treatment of disorders that are mediated by CCR9 activity; A pharmaceutical combination, which comprises a CCR9 agent of the present invention, in combination with at least one second drug substance, for use in disorders that are mediated by the activity of CCR9, A pharmaceutical composition, which comprises an agent of CCR9 of the present invention, in combination with at least one second drug substance, and one or more pharmaceutically acceptable excipients, for use in the treatment of disorders that are mediated by the activity of CCR9, A CCR9 agent 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 use in the treatment of disorders that are mediated by the activity of CCR9. The combinations include fixed combinations, wherein an agent, or an IBD agent, or a CCR9 agent, of the present invention, and at least one second drug substance, are in the same formulation; kits, wherein an agent, or an IBD agent, or a CCR9 agent, of the present invention and at least one second drug substance in separate formulations, are provided in the same package, for example with instructions for their administration, and free combinations, wherein an agent, or an IBD agent, or a CCR9 agent, of the present invention and at least one second drug substance, are packaged separately, but instructions are given for concomitant administration or in sequence. In another aspect, the present invention provides a pharmaceutical package, which comprises a first drug substance which is an agent of the present invention, and at least one second drug substance, in addition to instructions for its combined administration; - a pharmaceutical package, which comprises an agent of the present invention, in addition to instructions for its administration combined 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 an agent of the present invention. In another aspect, the present invention provides a pharmaceutical package, which comprises a first drug substance that is an IBD agent of the present invention, and at least one second drug substance. , in addition to instructions for its combined administration, for use in the treatment of inflammatory bowel disease, - a pharmaceutical packet, which comprises an IBD agent of the present invention, in addition to instructions for its administration combined with at least one second substance of drug, for use in the treatment of inflammatory bowel disease, - a pharmaceutical packet, which comprises at least one second drug substance, in addition to instructions for its administration in combination with an IBD agent of the present invention, for use in the treatment of inflammatory bowel disease In or In this aspect, the present invention provides a pharmaceutical package, which comprises a first drug substance that is a CCR9 agent of the present invention, and at least one second drug substance, in addition to instructions for its combined administration, for use in the treatment of inflammatory disease of intestine, a pharmaceutical packet, which comprises a CCR9 agent of the present invention, in addition to instructions for its administration in combination with at least one second drug substance, for use in the treatment of inflammatory bowel disease, a pharmaceutical packet, which comprises at least one second drug substance, in addition to instructions for its administration in combination with a CCR9 agent of the present invention, for use in the treatment of inflammatory bowel disease. Treatment with combinations according to the present invention can provide improvements comparing with the individual treatment In another aspect, the present invention provides a pharmaceutical combination, which comprises an amount of an agent of the present invention, and an amount of a second drug substance, wherein the amounts are appropriate to produce a therapeutic effect without energetically, - a method for improving the therapeutic utility of an agent of the present invention, which comprises the co-administration, for example in a concomitant or sequential manner, of a therapeutically effective amount of an agent of the present invention, and a second drug substance, - a method to improve the therapeutic utility of a second drug substance, which comprises the co-administration, for example, in a concomitant or sequential manner, of a therapeutically effective amount of an agent of the present invention, and a second drug substance. In another aspect, the present invention provides a pharmaceutical combination, which comprises an amount of an IBD agent of the present invention, and an amount of a second drug substance, wherein the amounts are appropriate to produce a synergistic therapeutic effect, for use in the treatment of disease Inflammatory bowel a method for improving the therapeutic utility of an IBD agent of the present invention, which comprises the co-administration, for example in a concomitant or sequential manner, of a therapeutically effective amount of an IBD agent of the present invention, and a second drug substance, for use in the treatment of inflammatory bowel disease, a method for improving the therapeutic utility of a second drug substance, which comprises co-administration, for example, in a concomitant or sequential manner. , of a therapeutically effective amount of an IBD agent of the present invention, and a second drug substance, for use in the treatment of inflammatory bowel disease In another aspect, the present invention provides. a pharmaceutical combination, which comprises an amount of a CCR9 agent of the present invention, and an amount of a second drug substance, wherein the amounts are appropriate to produce a synergistic therapeutic effect, to be used in the treatment of disorders that are mediated by the activity of CCR9, a method for improving the therapeutic utility of a CCR9 agent of the present invention, which comprises the co-administration, eg, concomitantly or in sequence, of a therapeutically effective amount of a CCR9 agent of the present invention, and a second drug substance, for use in the treatment of disorders that are mediated by the activity of CCR9, - a method for improving the therapeutic utility of a second drug substance, which comprises the co-administration, for example, in a concomitant or sequential manner, of a therapeutically effective amount of an agent e CCR9 of the present invention, and a second drug substance, for use in the treatment of disorders that are mediated by CCR9 activity. A combination of the present invention, and a second drug substance, as a combination component, can be administered by any conventional route, for example as set forth above for a compound, agent, IBD agent, or agent of CCR9, 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, including 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 means of mixing, granulating, coating, dissolving, or loftening processes. unit dosage may contain, for example, from about 0 1 milligrams to about 1,500 milligrams, such as from 1 milligram to about 1,000 milligrams. The pharmaceutical compositions comprising a combination of the present invention, and pharmaceutical compositions comprising a second drug such 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 substance" "drug" means a chemotherapeutic drug, especially any Chemotherapeutic agent, different from an agent of the present invention. For example, a second drug substance, as used in the present, includes other CCR9 inhibitors other than an agent of the present invention, for example, including antibodies and low molecular weight compounds, anti-inflammatory drugs and / or immunomodulators, anti-allergic drugs, anti-cancer drugs, anesthetic drugs, anti-diarrheal drugs 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 that 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 drugs and / or immunomodulators that are susceptible to being used in combination with an agent, or an IBD agent, for example, or with a CCR9 agent, of the present invention include, for example - mediators, eg inhibitors, of the activity of mTOR, 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? -alkyl-rapam? c? na, such as 40- O- (2-h? Drox?) - et? L-rapamycin (everolimus), 32-deoxo-rapam? C? Na derivatives and 32-hydroxy-rapamycin derivatives, such as 32-deoxo-rapam? C? na, 16-O-substituted derivatives of rapamycin, 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-methyl? -propanoate] -rapam? Cina (also known as CCI779), rapamycin derivatives which are substituted at position 40 by heterocyclic, for example 40-ep? - (tetrazole?) -rapamycin ( also known as ABT578), the so-called rapalogos, for 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 bio mus (for example, biolimus A9), mediators, for example inhibitors, of calcineupna, for example ciclospopna A, FK 506, ascomycins having 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 immunosuppressive derivative thereof, mediators, for example inhibitors, of the activity of cinna sa tyrosma bcr-abl, mediators, for example inhibitors of the receptor tyrosine kinase activity c-kit, - mediators, for example inhibitors, of the activity of the platelet-derived growth factor receptor tyrosome kinase, for example Gleevec (imatmib), mediators, eg inhibitors, of MAP p38 activity, mediators, eg inhibitors, of tyrosine kinase activity receptor endothelial growth factor to vascular, 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 inhibitors, of the kinase activity JAK3, for example N-benzyl-3,4-d? h? drox? -benc? l? den-c? ano-acetamide ac? an- (3 , 4-d? H? Drox?) - [N-benc? Lc? Namam? Da (Tirfostma AG 490), prodigiosma 25-C (PNU156804), [4- (4'-h? Drox? -fen? L ) -am? no-6,7-d? methox? -qu? nazol? na] (WHI-P131), [4- (3'-bromo-4'-h? drox? -fen? l) -am ? no-6,7-d? methox? -qu? nazol? na] (WH lP 154), [4- (3 ', 5' -di 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 the activity of the S1P receptor, for example FTY720 optionally phospho-pholated or an analogue thereof, for example 2-amino-2- [4- (3-benzlox? -t? ofen? l) -2-chloro-phen ?] -et? -1,3-propanedodol optionally phospho- pholated, or 1 - acid. { 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, IL-12 receptor, IL-17 receptor, IL-23 receptor, or their gandos, other immunomodulatory compounds, for example a molecule recombinant binding that has at least a portion of the extracellular domain of CTLA4 or a mutant thereof, for example at least an extracellular portion of CTLA4 or a mutant thereof, bound to a protein sequence other than CTLA4, for example CTLA4lg (for example, designated as ATCC 68629), or a mutant thereof, for example 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, of MIF activity, - 5-am? no-salt? c? lato (5-ASA) agents, such as sulfasalazine, Azulfidine®, Asacol®, Dipentum®, Pentasa®, Rowasa®, Canasa®, Colazal®, for example the drugs containing mesalamine, for example mesalazine in combination with hepapna, - mediators, for example inhibitors, of the activity of TNF-alpha, for example including antibodies that bind TNF-alpha, for example infliximab (Remicade®), thalidomide, lenadomide, 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, eg agonists, of the G-protein-coupled receptor GPBAR1 , mediators, for example inhibitors, of the activity of ceramide kinase, - "multi-functional anti-inflammatory" drugs (MFAIDs), for example inhibitors of cytostatic phosphohpase A2 (cPLA2), such as inhibitors of membrane bound A2 phospho-linked with glycosaminoghcanes, antibiotics, such as penicillins, cephalosporms, epromycins, tetracyclic sulfonamides, such as sulfadiazm, sulfisoxazole, sulfones, such as dapsone, pleuromutihnas, 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, saquinavir, stavudine, valaciclovir, valganciclovir, zidovudine Anti-inflammatory drugs that are susceptible to being useful in combination with an agent, or an agent of IBD, for example, a CCR9 agent, of the present invention include, for example, non-steroidal anti-flamatous agents (NSAIDs), such as derivatives of propionic acid (ammoprofen, benoxaprofen, bucloxic acid). , caprofen, fenbufeno, fenprofeno, fluprofeno, flurbiprofeno, ibuprofeno, indoprofeno, quetoprofeno, miroprofeno, naproxe no, oxaprozma, pirprofen, pranoprofen, suprofeno, thiaprofenic acid, and thioxaprofen) derivatives of acetic acid (indomethacin, acemetacin, alclofenac, clidanaco, diclofenac, fenclofenac, fencloric acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetina, zidometacina, and zomepiraco), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenyl carboxylic acid derivatives (dif lunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam , and tenoxicam), salt icilates (acetyl-salic acid hco, sulfasalazma), and pyrazolones (apazone, bezpipeplone, feprazone, mofebutazone, oxifenbutazone, phenyl-butazone), c-clo-oxygenase-2 (COX-2) inhibitors, such as celecoxib, type IV phosphodiesterase inhibitors (PDE-IV), chemokine receptor antagonists, especially CCR1, CCR2, and CCR3, cholesterol-lowering agents, such as HMG-CoA reductase inhibitors (lovastatin, simvastatma, pravastatin, fluvastatma, atorvastatma, and other statins), sequestrants (colestiramma and colestipol), nicotmic acid, derivatives of fenofibpco acid (gemfibrozil, clofibrate, fenofibrate, and benzafibrate), and probucol, anticohnergic agents, such as antimuscapnin antagonists (ipratropium bromide), other compounds, such as teofihna, sulfasalazma, and amino-sa cilates, for example 5-amino-salt-c? l? co acid, and pro-drugs thereof, anti-rheumatic The anti-allergic drugs that are susceptible to being useful in combination with an agent, for example, or a CCR9 agent, of the present invention include, for example, antihistamines (histamine-H1 antagonists), for example bromo-femramine, chlorpheniramine, dexclorfemramine, tp pro dina, clemastma, diphenhydramine, diphenylpyraban, tppelenamine, hydroxyzma, metdilazine, promethazma, tpmeprazine, azatadine cyproheptadine, antazohna, feniramma, piplamin, astemizole, terfenadine, loratadine cetipzine, fexofenadine, descarboethoxy loratadine, and anti-asthmatics nonsteroidal , such as agon-stas-ß2 (terbutaline, metaproterenol, fenoterol, isoetapna, albuterol, bitolterol, salmeterol, and pirbuterol), teofihna, n-sodium chromium, atropine, ipratropium bromide, leukotpene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), inhibitors of leukotpene biosynthesis (zileuton, BAY-1005), bronchodilators, anti-asthmatics (mast cell stabilizers) Cancer drugs that are susceptible to being useful as a combination component with a compound of the present invention, for example, include i A spheroid, for example prednisone n An inhibitor of the adenosine kinase, which directs, reduces, or inhibits the metabolism of nucleobase, nucleoside, nucleotide, and nucleic acid, such as 5-iodo-tuberc? d? na, which it is also known as 7H-pyrrolo- [2,3-d] -p? r? m? d? n-4-am? na, 5-iodo-7-b-Dr? bofurans? it nor an adjuvant , which improves the binding of 5-FU-TS, as well as a compound that directs, reduces, or inhibits alkaline phosphatase, as ucovopna, 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 protein kinase 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 tpcipbina, which is also known as 1, 4,5,6, 8-penta-aza-acenaft? Len-3-amine, 1,5-d? H? Dro-5-met? L-1-β-D-pbofuranosyl vi An alkylating agent, which causes DNA alkylation, and results in breaks in DNA molecules, as well as crosslinking of the twin chains, thereby interfering with DNA replication and RNA transcription, such as nitrogen mustards, for example. chlorambucil, chlormetma, cyclophosphamide, ifosfamide, melphalan estramustma (Emcit®), nitrosoureas, such as carmustine fotemustma, lomustma, streptozocma (streptozotocin, STZ, Zanosar®), BCNU, Gliadel, dacarbazma, mechlorethamine, for example in the form of a hydrochloride , procarbazine, for example in the form of a hydrochloride, thiotepa, temozolomide (TEMODAR®), mitomycin, alt retamma, busulfan, estramustine, uramustma Cyclophosphamide can be administered, for example, in the form as it is traded, for example the registered trademark CICLOSTIN®, and the ifosfamide as HOLOXAN® VII An inhibitor of angiogenesis, which directs, reduces, or inhibits the production of new blood vessels, for example, which directs the ammo-peptidase of methano-na-2 (MetAP-2), the inflammatory protein of macrophages-1 (MIP-1alpha), CCL5, TGF-beta, poxygenase, cyclo-oxygenase, and topoisomerase, or that directs indirectly 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- [2 5] -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, 2 - [[3- (3,4 -d? methox? -phen?) -1 -oxo-2-propen? l] -am? no], ursolic acid, suramma, bengamide or a derivative thereof, thalidomide, TNP-470. vin An anti-androgen, which blocks the action of androgen 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 is disclosed in U.S. Pat. No. 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. estrogen, that is, the conversion of androstenedione and testosterone substrates to estrone and estradiol, respectively, for example including atamestane, exemestane, formestane, amino-glutethimide, rogletimide, pindo-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 Trade as EVISTA® Fulvestrant can be formulated as disclosed in US Pat. No. 4,655,916, and is marketed as FASLODEX® x An anti-hypercalcemia agent, which is used to treat hypercalcemia, such as hydrate of gallium nitrate (III), and pamidronate-disodium xi An antimetabohto, which inhibits or interrupts the synthesis of DNA that results in cell death, such as folic acid, for example methotrexate, pemetrexed, ralitrexed, pupnas, for example 6-mercapto-purine, cladpine, clofarabine, fludarabine, thioguanine (thioguanine), 6-t? Oguan? Na, pentostatin (deoxy-coformicin), cytarabine, flexupdma, fluoro-uracil, 5-fluoro-uracil (5- FU ), floxupdme (5-FUdR), capecitabine, gemcitabine, gemcitabma hydrochloride, hydroxy urea (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 way it is traded, such as XELODA® and GEMZAR® xu An inducer of apoptosis, which induces the normal series of events in a cell leading to its death, for example selectively induces the X-linked mammalian inhibitor of the apoptosis protein XIAP, or, for example, which decreases BCL-xL, such as ethanol, 2 - [[3- (2,3-d? chlorophenoxy?) - prop?] -am? no]; gambógico acid, embe na, which is also known as 2,5-c? clohexad? ene-1, 4-d? ona, 2,5-d? h? drox? -3-undec? lo- (9CI), arsenic trioxide xni An aurora kinase inhibitor, which directs, reduces, or inhibits the later stages of the cell cycle from the G2 / M checkpoint 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-phen?) -4-c? ano-1H-p? razol-5-? l] -N, Nd? met? l- (9CI). xiv An inhibitor of Bruton tyrosine kinase (BTK), which directs, reduces, or inhibits the development of human B-cells and mupno, such as terreic acid. xv. An inhibitor of calcineupna, which directs, reduces, or inhibits the T-cell activation pathway, such as cipermetpna, which is also known as 3- (2,2-d? Chloro-ethene) -2.2 -d? methylene (3-phenoxy? -fen? l) -met? l-ester of cyclopropane-carboxylic acid, deltametpna, which is also known as 3- (2,2-d? bromo-ethane) ?) -2,2-d? met? l- (S) -c? an- (3-phenox? -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? an- (3-phenox? -phen?) -met? l-benzene-acetic acid ester , and Tirfostma 8, but excluding ciclospopna or FK506 xvi A CaM II kinase inhibitor, which directs, reduces, or inhibits CaM kinases, which are a family of structurally related enzymes including 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-phen? l) -1-p? Peraz? N? L) -prop? L] -fen? L-ester of 5-? Soqu? Nol? N-sulfon? Co acid (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 tyrosine phosphatase CD45, which directs, reduces, or inhibits the pTyr residues that regulate dephospholation on the kinases of tyrosine protein from the Src family, which help in the treatment of a variety of inflammatory and immune disorders, such as phosphonic acid, [[2- (4-bromo-phenoxy?) - 5-n? tro-phen?] - h? drox? -met? lo] xvn A CDC25 phosphatase inhibitor, which directs, reduces, or inhibits dephosphocylated cyclin dependent kinases overexpressed in tumors, such as 2,3-b? s - [(2- h? drox? -et? l) -t? o] -1, 4-naphtalenod? ona xix A CHK kinase inhibitor, which directs, reduces, or inhibits the overexpression of the antiapoptotic protein Bcl-2, such as debromo-imenialdisine It directs a kinase inhibitor CHK which is CHK1 and / or CHK2 xx A control agent to regulate the genistema, olomucin, and / or typhostim, such as daidzein, which it is also known as 7-hydroxy? -3- (4-h? drox? -fen? l) -4H-1-benzop? ran-4-one, iso-olomucine, and Tyrphostin 1 xxi A cyclo-oxygenase inhibitor, for example, including Cox-2 inhibitors, which direct, reduce, or inhibit the enzyme Cox-2 (c? clo-ox? genasa-2) , such as 1 - (4-chloro-benzoyl) -5-methox-2-met? lN- (2-phen? l-et? l) -1 H-? ndol-3-acetam? da, 2-aryl-amino-phenyl-acetic acid substituted by 5-alkyl, and its derivatives, for example celecoxib (CELEBREX®), rofecoxib (VIOXX®), etopcoxib, valdecoxib, or a 5-alk acid -2-ar? L-am? No-fen? L-acet? Co, for example 5-met? L-2- (2'-chloro-6'-fluoro-an? L? No) -fen? l-acetic acid, lumiracoxib, and celecoxib xxn A cRAF kinase inhibitor, which directs, reduces, or inhibits the increase of E-selectin and vascular adhesion molecule-1, induced by TNF, such as 3- (3,5-d-bromo-4-hydroxyl-benzyl) -5-iodo-1,3-d? -hydro-2-one, and 3- (d? met? l-am? no) -N- [3 - [(4-h? drox? -benzo? l) -am? no] -4-met? l-phen? l] -benzam? da The RAF kinases have an important role as extracellular signal regulatory kinases in the difference cell proliferation, and apoptosis A target of the cRAF kinase inhibitor includes, but is not limited to, RAF-1 xxi 11 A cyclin-dependent kinase inhibitor, which directs, reduces, or inhibits the cyclin-dependent kinase that it has a role in regulating the mammalian cell cycle, such as N9-? soprop? l-olomucin, olomucin, purvalanol B, which is also known as benzoic acid, 2-chloro-4 - [[2 - [[ (1 R) -1 - (hydroxymethyl) -2-met? L-prop? L] -am? No] -9- (1-met? L-et? L) -9H-pur? N-6 -? l] -am? no] - (9CI), roascovitma, indirubin, which is also known as 3- (1, 3-d? h? dro-3-oxo-2H-? ndol-2-? l? den) -1,3-d? h? dro-2H -? ndol-2-one (9CI), quenpaullone, which is also known as 9-bromo-7,12-d? h? dro-? ndolo- [3,2-d] [1] -benzazep? n- 6 (5H) -one (9CI), purvalanol A, which is also known as 2 - [[6 - [(3-chloro-phen? L) -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 regulated by a series of events in sequence that include the activation and subsequent inactivation of the cyclin-dependent kinases (Cdks), and cyclins. Cyclin-dependent kinases are a group of septen / threonine kinases that form active heterodimepcos complexes through their binding to their regulatory subunits, the cyclins 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 a, 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-1 - ( 2-phenol-et? L) -prop? L] -am? No] -2-oxo-1 - (phenol-met? L) -et? L] -morf or n-carboxamide xxv An intercalator of DNA, which binds to DNA, and inhibits the synthesis of DNA, RNA, and protein, such as plicamycin, dactinomycin xxvi A DNA chain breaker, which causes DNA chain separation, and results in 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 ligase, which inhibits the transfer of ubiquitme chains to the 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 xxviii A endocrine hormone, which, by acting mainly on the pituitary gland, causes the suppression of hormones in males, the net effect being a reduction of testosterone to the levels of castration, in females, both estrogen of ovaries are inhibited the synthesis of androgen, such as leuprolide, megestrol, megestrol acetate xxix Compounds that direct, reduce, or inhibit the activity of the tyrosome 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 that bind to EGF or with 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 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 Number WO 9503283, for example a compound known as ZM105180, for example including the double-acting tyrosine kinase inhibitor (ErbB1 and ErbB2) lapatmib (GSK572016), for example lapatinib ditosylate, panituzumab, trastuzumab (HERCEPTIN®), cetuximab, iressa, OSI-774 CI-1033, EKB-569, GW-2016, E1 1, E24, E25, E62, E64, E2 11, E63 or E763, derivatives of 7H-pyrrolidone [2,3-d] -p? R? M? D? Na, which, for example, are disclosed in International Publication Number WO03013541, erlotmib, gefitmib Erlotmib can be administered in the way it is traded, for example TARCEVA®, and gefitinib as IRESSA®, and human monoclonal antibodies against the epidermal growth factor receptor, including ABX-EGFR xxx A tyrosine kinase inhibitor EGFR, PDGFR, such as the EGFR kinase inhibitors, including tyrphostin 23, tirfostma 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?) -met? Len] -3-p? R? D? N-aceton? Tr? Lo, (aZ), an example of an EGFR tyrosine kinase inhibitor , PDGFR, for example, includes tirfostma 46 The cmasa inhibitor of tyrosma PDGFR includes tyrphostin 46 Targets of an EGFR kinase inhibitor include guanylyl cyclase (GC-C) HER2, EGFR, PTK, and tubulma xxxi A farnesyl transferase inhibitor, 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?] -am? no] -3-met? l-pent? l] -ox?] - 1-oxo-3-phen? l-prop? l] -am? no] -4- (meth? ls u Ifoni I) - 1-methyl-ethyl ester of butanoic acid, (2S), manumicin A, L-744,832, or DK8G557, tipifarnib (R115777), SCH66336 (lonafarnib), BMS-214662 XXXII 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? l] -N- (3-phen? l-prop? l) - (2E) -2-propenam? da One target of a Flk kinase inhibitor -1 includes, but is not limited to, KDR XXXIII A glycogen-3 synthase kinase inhibitor (GSK3), which directs, reduces, or inhibits glgase synthase kinase Gen-3 (GSK3), such as? nd? rrub? na-3'-mono-ox? ma The glycan-3 synthase kinase (GSK-3, protein tau I kinase), a protein kinase highly conserved and ubiquitously expressed septa / threonine, 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 the synthesis of protein, cell proliferation, cell differentiation, assembly / disassembly of microtubules, and apoptosis xxxiv A histone deacetylase inhibitor (HDAC), which inhibits histone deacetylase, and which possesses anti-prophylactic 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, hydroxyamic acid of suberoil anhydrate (SAHA) , p-r? d? n-3? -methyl ester of the acid [4- (2-am? no-phen? l-carbamo? l) -benc? l] -carbam? co, and its derivatives, butyric acid, piroxamide, tpcostatin A, oxamflatma, apicidin, depsipeptide, depudecin, trapoxma, HC toxin, which is also known as c? clo- [L-alan? lD-alan? l- (aS, 2S) - a-am? no-ß-oxo-ox? ran-octane? lPp rol i lo] (9CI), sodium phenyl-butyrate, suberoyl-bis-hydroxamic acid, Tpcostatma A, BMS-27275, piroxamide, 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 the client proteins of HSP90 by means of the ubiquitose proteasome pathway Compounds that direct, reduce, or inhibit the intrinsic activity of HSP90 ATPase are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, eg, 17- al? l-am? no-17-demethoxy-geldanamycin (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-am? no) Potential indirect targets of an HSP90 inhibitor include FLT3, BCR-ABL, CHK1, CYP3A5 * 3 and / or NQ01 * 2 Nilotinib is an example of a tyrosome kinase inhibitor BCR-ABL xxxvi An inhibitor of k-lappa 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) XXXVII An inhibitor of insulin receptor tyrosine kinase, which modulates the activities of the kinase of phosphatidyl-mositol 3, protein associated with microtubules, and S6 kinases, such as hydroxyl-2-naphthalene? -methyl-phosphonic acid LY294002 XXXVIII An N-terminal kinase kinase inhibitor 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 phosphorylation and act ivation 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 A microtubule binding agent, the which acts by interrupting the microtubule network that is essential for the mitotic cell function and interface, such as vinca alkaloids, for example vmblastin, sulfate ae vmblastin, vincpstin, vincpstma sulfate, vindesine, vinorelbine, taxanes, such as taxanes, example docetaxel, paclitaxel, discodermohdas, colchicine, epothilones and their derivatives, for example epothilone B or a derivative thereof Paclitaxel is marketed as TAXOL®, docetaxel as TAXOTERE®, vmblastin sulfate as VINBLASTIN RP®, and sulphate of vincpstma such as FARMISTIN® Also included are the generic forms of paclitaxel, as well as different dosage forms of paclitaxel. Generic forms of pac taxel include, but are not limited to, betaxolol hydrochloride. Different forms of paclitaxel dosage include, but are not limit to, paclitaxel in albumin nanoparticles sold by ABRAXANE®, ONXOL®, CYTOTAX® Discodermolide can be obtained, for example, as disclosed in US Pat. No. US5010099 Also included are epothilone derivatives , which are disclosed in the Patent Numbers US6194181, WO98 / 0121, W09825929, WO9808849, WOT943653, W09822461 and WO0031247. especially Epohtona 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? -benzene-sulfonamide The mitogen-activated protein kinases (MAPs) are a group of protein sepna / threonine kinases that are activated in response to a variety of extracellular stimuli, and mediate signal transduction from the cell surface to the core Regulate various physiological and pathological cellular phenomena, including inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion, and metastasis xh 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 xln An MEK inhibitor, 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 A goal of MEK includes, but is not limited to, ERK An indirect target of an MEK inhibitor includes, but is not limited to, cyclin D1 xlin A matrix metalloproteinase (MMP) inhibitor, which directs, reduces, or inhibits an enzyme class of protease that selectively catalyzes the hydrolysis of polypeptide bonds, including the enzymes MMP-2 and MMP-9 that are involved in the promotion of the loss of structure of tissue around the tumors, and that facilitate tumor growth, angiogenesis, and metastasis, such as actinonin, which is also known as N-4-h? drox? -N1 - [(lS) -1 - [[(2S) -2- (h? drox? -met? l) -1-p? rrol? d? n? l] -carbon? l] -2-met? l-prop? l] -2-pent? l-butan-d? amine, (2R) - (9CI), epigallocatechin gallate, peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, for example the hydroxamate peptidomimetic inhibitor, batimastat, and its orally bioavailable analogue mapmastate, ppnomastate, metastate, neovastate, tanomastat, TAA211, BMS-279251, BAY 12-9566, MMI270B or AAJ996 A target of an MMP inhibitor includes, but is not limited to, polypeptide deformylase xv An inhibitor of tyrosine kinase NGFR, which directs , reduces, or inhibits phosphorylation of trk-dependent tyrosine p140c trk nerve growth factor, such as tyrphostin 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-phen? l) -5- (4-p? r? d? n? l) -1 H-? m? dazol-2-? l] -phenol A 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] -benzamide A member of the MAPK family is a sepna / threonine kinase active The phosphorylation of the tyrosine and threonine residues This phospho- line kinase is 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. p56 tyrosine kinase inhibitor, which directs, reduces, or inhibits tyrosine kinase p56, which is an enzyme that is a tyrosine kinase of the src family specific to critical nuclides for cell development and activation. T, 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 target of a tyrosma kinase inhibitor p56 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 TCR-mediated activation of TCR cells xlvn A tyrosine kinase inhibitor PDGFR, which directs, reduces, or inhibits the activity of receptor tyrosine kinases C-kit (part of the PGDFR family), as directed, reduces, or inhibits, the activity of the c-Kit receptor tyrosome kinase family, especially that inhibits the c-Kit receptor. Examples of the objectives 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-am? No-4- (1 H-? Ndol-5-? L) - 1, 3-butad? Eno-1, 1, 3-tr? -carbonitplo, a derivative of N-phen? L-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 the dimeopic 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 xlvni A kinase inhibitor of phosphatid? d-l-ε? tol-3, which directs, reduces, or inhibits PI3 kinase, such as wortmanin, which is also known as 11- (acetyl lox?) - l , 6b, 7, 8, 9a, 10,11, 11 b-octah? Dro-1 - (methox? -met? L) -9a, 11 bd? Met? L-3H-furo- [4,3,2 -de] -? nd ene- [4,5-h] -2-benzop? ran-3,6,9-tr? ona, (1 S, 6bR, 9aS, 11 R, 11 bR) - (9CI) , 8-phenol-2- (morpholin-4-? L) -chromen-4-one, quercetma, quercetma dihydrate It has been shown that PI3 kinase activity 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 has been implicated in processes related to cell growth and transformation An example of a phospholipid-mositol-3 kinase inhibitor target includes, but not limited to, PI3K xl ix A phosphatase inhibitor, which directs, reduces, or inhibits phosphatase, such as cantapidic acid, cantapdma, and L-leucinamide, N- [4- (2-carbox? -ethen l) -benzo? l] -gl? c? l-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 DNA synthesis by forming cross-chain cross-linking and intra-chains of DNA molecules, such as carboplatin, cisplatin, oxaliplatin, cisplatmo, satraplatma, and platinum agents, such as ZD0473, BBR3464 Carboplatma can be administered, for example, in the form as it is traded, for example CARBOPLAT®, and oxa-platin as ELOXATIN® A phosphatase inhibitor of protein, including an inhibitor of PP1 and PP2, and a tyrosine phosphatase inhibitor, which directs, reduces, or inhibits protein phosphatase Examples of a PP1 and PP2A inhibitor include cantapdic acid and / or cantapdma Examples of a tyrosma phosphatase inhibitor include, but are not limited to, LP-bromo-tetramisole oxalate, 4-hydroxyl-5- (hydrox? -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 protein phosphatases Ser / Thr Type I phosphatases, which include PP1, can be inhibited by two heat-stable proteins known as inhibitors. dor-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), dependent on Ca2 + (PP2B), and Mg2 + -dependent (PP2C) The term "tyrosine phosphatase inhibitor", as used herein, refers to compounds that direct, reduce, or inhibit tyrosine phosphatase Protease tyrosine phosphatases (PTPs) are relatively recent additions to the Phosphatase family Remove phosphate groups from protein tyrosome residues of proteins PTPs exhibit various structural characteristics, and have important roles in the regulation of cell proliferation, differentiation, cell adhesion and mobility, and cytoskeletal function. of the targets of a tyrosine phosphatase inhibitor include, but are not limited to, alkaline phosphatase (ALP), heparanase, PTPase, and / or prostatic acid phosphatase In A PKC inhibitor and a PKC delta kinase inhibitor The term " a "PKC inhibitor", as used herein, 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 signal transduction associated with 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-? ] -4- (1H-? Ndol-3-? L) -1-Hp? Rrolo-2,5-d? Ona; bisindolyl-maleimide IX; sphingosine, which is known as 2-am? no-4-octadecene-1, 3-d? ol, (2S, 3R, 4E) - (9CI); staurospopne, which is known as 9,13-epoxy-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, staurospopne derivatives, such as are disclosed in European Patent Number EP0296110, for example midostaupna; 2,3,10,11, 12,13-hexahydro-10-methox? -9-met? L-11 - (methyl-amino) -, (9S, 10R, 11 R.13R) - (9CI), tyrphostin 51, and hipepcma, which is also known as 1, 3,4,6,8,13-hexah? Drox? -10,11 -dimetil-fenantro - [1, 10,9,8-opqra] -per? Leno-7,14-d? Ona, this isomeric isomer (6CI, 7CI, 8CI, 9CI), UCN-01, safmgol BAI 43-9006, bpostatma 1 , pepfosma, ilmofosina, RO 318220 and RO 320432, GO 6976, Isis 3521, LI333531 / LI379196 The term "a PKC delta cmase inhibitor", as used herein, refers to a compound that directs, reduces, or inhibits delta isozymes of PKC. Isozima delta is a conventional PKC isozyme and is dependent on Ca2 + An example of a PKC delta kinase inhibitor includes, but is not limited to, Rottlepna, which is also known as 1- [6 - [(3-acetyl-2,4,6-tr? H? ? -5-met? L-phen?) -met? L] -5,7-d? H? Drox? -2,2-d? Met? L-2H-1-benzop? Ran-8-? l] -3-phenol-2-propen-1 -one, (2E) - (9Cl) Im An inhibitor of the synthesis of polyamine, which directs, reduces, or inhibits spermidine po amines, such as DMFO, which is also known as (-) - 2-d? fluoro-met? l-orn? t? na, N1.N12-diethyl- 4HCI spermine The spermidine and spermine polyamines are of vital importance for cell proliferation, although its precise mechanism of action is unclear. Tumor cells have an altered polyamine homeostasis reflected by increased activity of biosynthetic enzymes and elevated polyamine stores. I iv A proteasome inhibitor, which directs, reduces, or inhibits the proteasome, such as aclacinomycin A, gliotoxin, PS-341, MLN 341, bortezomib, velcade Examples of the objectives of a Proteasome inhibitors 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, a tyrosine protein kinase inhibitor; such as N- [4- (2-carbox? -ethe? l) -benzo? l] -gl? c? l-L-a-glutam? l-L-leuc? nam? da, (E) Ivi. A tyrosine protein kinase inhibitor, including an inhibitor of the tyrosine kinase of the SRC family; an inhibitor of Syk tyrosine kinase; and a tyrosine kinase inhibitor JAK-2 and / or JAK-3 The term "a protein tyrosine kinase inhibitor", as used herein, refers to a compound that directs, reduces, or inhibits the kinases of tyrosma protein Tyrosine protein kinases (PTKs) have a key role in the regulation of proliferation, differentiation, metabolism, migration, and cell survival. They are classified as receiving PTKs and non-receptor PTKs. The receiving PTKs contain a single polypeptide chain 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 tyrosma 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-selectma. The examples of a Tyrosine kinase inhibitor include, but are not limited to, tirfostma AG 126, tirfostma Ag 1288, tirfostma Ag 1295, geldanamycin, and genistema Non-receptor tyrosome kinases include members of the families Src, Tec, JAK, Fes, Abl, FAK, Csk, and Syk are located in the cytoplasm, as well as in the nucleus. They exhibit different regulation, substrate phosphorylation, and kinase function. The poor regulation of these kinases has also been linked to several human diseases. The term "a Tyrosine kinase inhibitor of the SRC family ", as used herein, refers to a compound that directs, reduces, or inhibits SRC. Examples of a tyrosine kinase inhibitor of the SRC family include, but are not limit to, PP1, which is also known as 1- (1,1-d? met? l-et? l) -3- (1-naphthalene? l) -1H-p? razolo- [3,4-d ] -p? r? m? d? n-4-am? na (9CI), and PP2, which is also known as 3- (4-chloro-phen? l) -1- (1,1-d? met? l-et? l) -1H-p? razolo- [3,4-d] -p? r? m? d? n-4-am? na, (9CI) E I term "a Syk tyrosine kinase inhibitor", as used herein, refers to a compound that directs, reduces, or inhibits Syk. Examples of the targets for a Syk tyrosine kinase inhibitor 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 - [(1E) -2- (3,5- d? h? drox? -fen? l) -eten? l] -1, 2-benzene? ol (9CI) The term "an inhibitor of tyrosine cmase Janus (JAK-2 and / or JAK-3)", as used herein, it refers to a compound that directs, reduces, or inhibits Janus tyrosine kinase It has been shown that Janus tyrosome kinase inhibitors are anti-leukemic agents with anti-thrombosis, anti-allergy, and immunosuppressive properties The 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 tyrosine kinase inhibitor JAK-2 and / or JAK-3, includes, but does not are limited to, CDK2 Examples of the tyrosome kinase inhibitors JAK-2 and / or JAK-3 include, but are not limited to, Tirfostma AG490, and 2-naft? lv? n? l-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 dependent receptors of retmoides, such as isotretinoma, tretinoma, alitretmoina, bexarotene Ivni An inhibitor of RNA II polymerase elongation, which directs, reduces, or inhibits the nuclear and cytosine kinase ca p70S6 stimulated by insulin in CHO cells, directs, reduces, or inhibits transcription of RNA II polymerase, which may depend on casein II kinase, and directs, reduces, or inhibits the breakdown of the germinal vesicle in bovine oocytes, such as 5,6-d? chloro-1 -bet-Dr? bofurans? -benz? dazol Ivix A septa / threonine kinase inhibitor, which inhibits septa / threonine kinases, such as 2-am? no-pur? na example of a target of a septa / threonine kinase inhibitor includes, but is not limited to, the dsRNA-dependent protein kinase (PKR) Examples of the indirect targets of a septa / threonine kinase inhibitor include, but are not limited to, are limited to, MCP-1, NF-kappaB, elF2alpha COX2, RANTES, IL8.CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, eptropoietma, and / or CYP1 A1 Ix An inhibitor of sterol biosynthesis, which inhibits the biosynthesis of sterols, such as cholesterol, such as terbinadine The 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 analogs, 9-n-tro-camptotecna, and the macro-molecular camptothecin conjugate PNU-166148 (compound A1 of International Publication Number WO9917804), -h? drox? -camptotec? na, for example the acetate salt, idarubicin, for example the hydrochloride, ipnotecan, for example the hydrochloride, etoposide, teniposide, topotecan, topotecan hydrochloride, doxorubicin, epirubicin, epirubic hydrochloride ina, mitoxantrone, mitoxantrone, for example the hydrochloride, daunorrubicma, daunorubicin hydrochloride, valrubicin, dasatmib (BMS-354825) The ipnotecan can be administer, for example, in the way it is traded, for example under the registered trademark CAMPTOSAR® The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTIN® The term "inhibitor" of topoisomerase M ", as used herein, includes, but is not limited to, anthracyclines, such as doxorubicin, including the posomal formulation, eg CAELYX®, daunorubicin, including the hposomal formulation, eg DUANOSOME®, epirubicin, idarubicin, and nemorubicin, anthraquimans mitoxantrone and losoxantrone, and podophyllotoxins etoposide and teniposide Etoposide is marketed as ETOPOPHOS®, teniposide as VM 26-BRISTOL®, doxorubicin as ADRIBLASTIN® or ADRIAMYCIN®, epirubicin as FARMORUBICIN® , idarubicin as ZAVEDOS®, and mitoxantrone as NOVANTRON® Ixu VEGFR tyrosine kinase inhibitor, which directs, reduces, and / or inhibits known angiogenic growths and the cytokines involved in the modulation of normal and pathological angiogenesis The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine pools [VEGFR-1 (Fit - 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 nfangiogenic processes An example of a kinase inhibitor of tyrosine VEGFR includes 3- (4-d? met? l-am? no-benc? l? den? l) -2-? ndol? none Compounds that direct, reduce, or inhibit VEGFR activity are especially compounds, proteins, or antibodies that inhibit VEGF receptor tyrosine kinase, that 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?) -ftalazine, or a pharmaceutically acceptable salt thereof, for example succinate, or in Patent Numbers WO0009495, WO0027820, WO0059509, W09811223, WO0027819 and EP0769947, for example, those 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 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, anthranyl 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 formed of at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity An example of a VEGF-R2 inhibitor, for example, includes axitmib IXIII A gonadore agonist, such as abarelix, gosere na, goserelin acetate Ixiv A compound that induces cell differentiation processes, such as rheumatoid acid, alpha-, gamma-, or delta-tocopherol, or alpha-, gamma-, or delta-tocotpenol Ixv A bisphosphonate, for example including etpdonic, clodronic, tiludronic acid, pamidronic, alendronic, ibandronic, psedronic, and zoledronic Ixvi A heparanase inhibitor, which prevents the degradation of heparan sulfate, for example PI-88 I xvi i A biological response modifier, preferably ahnfocin or interferons, for example interferon -alpha IXVIII A telomerase inhibitor, for example telomestatin. Ixix Mediators, such as catechol or methyltransferase inhibitors for example entacapone Ixx. ispinesib, permetrexed (Alimta®), sunitinib (SU11248), diethylstilbestrol (DES), BMS224818 (LEA29Y) Ixxi Somatostatin or a somatostatma analog, such as octeotpda (Sandostatm® or Sandostatin LAR®) Ixxn Hormone receptor antagonists growth, such as pegvisomant, filgrastim, or pegfilgrastim, or interferon-alpha Ixxin Monoclonal antibodies, for example useful for the treatment of leukemia (AML), such as alemtuzumab (Campath®), ptuximab / Rituxan®), gemtuzumab, (ozogamicin, Mylotarg®), epratuzumab Ixxiv altretamma, amsacpna, asparagmase ( Elspar®), denileukin diftitox, masoprocol pegaspargasa Ixxv A phosphodiesterase inhibitor, for example anagre da (Agrylin®, Xagpd®) Ixxvi A cancer vaccine, such as MDX-1379 Cancer treatment with an agent, 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 anesthetic drugs that are n susceptible to being useful as a combination component with an agent, or an agent of IBD, for example, a CCR9 agent, of the present invention include, for example, ethanol, bupivacaine, chloroprocama, levobupivacama, lidocama, mepivacaine, procama , ropivacama, tetracama, desflurane, isoflurane, quetamma, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcama, mepepdine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocam, dibucaine, linden chloride, xylocaine, and phenazopipdm. Anti-diarrheal drugs that are likely to be useful as a combination component with an agent, or with an agent of IBD, for example, or a CCR9 agent, of the present invention, for example, include diphenoxylate, loperamide, codeine If the agents, including the IBD agents and the CCR9 agents, of the present invention, are administered in combination with other drugs, the dosages of the second co-administered drug will, of course, vary depending on the type of co-drug employed, the specific drug employed, the condition being treated, as in the case of a compound of the present invention . In general, dosages similar to those provided by the second drug provider may be appropriate. The chemical names of the compounds of the present invention, as indicated herein, are copies of ISIS, version 22 (AutoNom 2000 Yam). The chemical names of the second drug substances, or of other substances, can be derived from the Internet, for example, by means of a search program, such as the SCI FINDER. In the following Examples, all temperatures are in degrees Celsius. . The following abbreviations are used EtOAc Ethyl acetate RT Ambient temperature Example 1 4 -tertbutyl-N- (4-chloro-2-cyano-phenyl) -benzenesulfonamide (compound 1 of Table 1) A solution of 0 15 grams of 2-am? no-5-chloro-benzonitoplo and 023 grams of 4-tert-butyl-benzenesulfonyl chloride are dissolved in 2 milliliters of NMP (N-methyl-2-pyrrolidone), and cooled in an ice bath at 5 ° C 25 milliliters of a solution of potassium terbutylate (1N in tetrahydrofuran) are added, and the mixture obtained is stirred for 30 minutes, quenched with water, and the solvent obtained is evaporated from the mixture obtained. The residue of the evaporation is dissolved in EtOAc, washed with a saturated solution of NaHCO 3, and dried The solvent is evaporated, and the residue of the evaporation is chromatographed on a reversed phase column. The 4-terbut is obtained. lN- (4-chloro-2-c? ano-phen? l) -benzenesulfonamide 1H-NMR (DMSO) 1 27 (s, 9 H), 706 (d, J = 85 Hz, 1H), 757- 770 (m, 5 H), 799 (d, J = 2 Hz, 1H), 106 (broad s, 1H, NH) Example 2 Met 2- (4-tert-butyl-benzenesulfonyl-amino) -5-chloro-benzoic acid ester (compound 26 of Table 1) To a solution of 254 grams of the methyl ester of 2-ammonium- 5-chloro-benzo co in 30 milliliters of pipdin, added to it 3 18 grams of 4-tert.-l-benzenesulfonyl chloride The mixture is stirred for 72 hours at room temperature, the solvent is evaporated off from the obtained mixture, and the residue of the evaporation is taken up in EtOAc and The organic layer obtained is dried, and the solvent is evaporated in vacuo. The evaporation residue obtained is subjected to chromatography. The methyl ester of the acid 2- (4-tert-butyl) -benzenesulfon is obtained. ?) -5-chloro-benzo? co in the form of a white solid Example 3 2- (4-tert-butyl-benzenesulfonyl-amino) -5-chloro-benzoic acid (compound 27 of Table 1) 358 grams of the methyl ester of 2- (4-tert.-l-benzenesulfonyl-1-amino) -5-chloro-benzoic acid, are dissolved in 80 milliliters of a mixture of 1 liter of water and tetrahydrofuran. add 1 19 grams of LiOH x H20, and the obtained mixture is stirred for 18 hours at room temperature. The organic solvent is evaporated in vacuo, and the obtained aqueous phase is washed with CH2Cl2, it is brought to a pH of 4 by adding 6N HCl ion, and extracted with EtOAc The organic layer obtained is dried, and the solvent is evaporated. The acid is obtained 2- (4-tert.-l-benzenesulfonyl-1-amino) -5-chloro- benzo? co 'H-NMR (DMSO) d 1 23 (s, 9H), 753 (d, J = 9 Hz, 1H), 758 (broad d, J = 7 Hz, 2H), 761 (dd, J = 26 and 9 Hz, 1H), 774 (broad d, J = 7 Hz, 2H), 783 (d, J = 26 Hz, 1H), 11 1 (broad, 1 NH) In a manner analogous to the methods described in Examples 1 to 3, but using the appropriate starting materials (intermediates), the compounds of the Formula are obtained. O -N- S- FL O where R-t and R2 are as stipulated in the following Table 1, which have a melting point p. f (° C) as defined in the following Table 1: TABLE 1 "CP" in TABLE 1 means "Compound number"

Claims (16)

1 A compound of formula O

II R? - H-S-2 IO wherein Ri and R 2 are independently phenyl, for example, including unsubstituted phenyl and phenyl substituted by one or more de-alkyl (of 1 to 6 carbon atoms), - haloalkyl ( from 1 to 4 carbon atoms), - cycloalkyl (from 3 to 12 carbon atoms), - alkoxy (from 1 to 4 carbon atoms), - haloalkoxy (from 1 to 4 carbon atoms), - cyano, or - halogen, with the proviso that at least one of Rt and R2 is phenyl substituted with cyano, and with the proviso that the compound of N- (2-c? ano-phen? l) -4-tr is excluded. Fluoro-methanol-benzenesulfonamide A compound according to claim 1, which is selected from the group consisting of 4-tert.-N- (4-chloro-2-c? ano-phen? l) -benzenesulfonamide, 4-tert.-N- (5-chloro-2-c? ano-phen?) -benzenesulfonamide, N- (4-chloro-2-c? ano- fen? l) -4-tr? fluoro-met? l-benzene

sulfonamide, N- (5-chloro-2-c? ano-phen?) -4-tr? uoro-met? l -benzenesulfonamide, 4-terbut? lN- (2-c? ano-phen? l) ) -benzene-sulfonamide, 2- (4-tert-butyl-l-benzenesulfonyl-1-amino) -5-chloro-benzoic acid, N- (4-chloro-2-c-ano-phen) l) -4-metho-benzenesulfonamide, 2,4-d? chloro-N- (4-c? ano-2-tr? uoro-methox? -phen?) -benzenesulfonamide, 2- (4-benzyl) -benzo-sulfonyl-amine) -benzoic acid,

2,4-d? Chloro-N- (5-chloro-2-c? Ano-phen? L) -benzenesulfonamide, N- (4-chloro-2-c? Ano-phen? L) -2, 4-d? Methox? -benzenesulfonamide, N- (4-chloro-2-c? Ano-phen?) -2-methox? -4-met? L-benzenesulfonamide, 5-chloro-2 acid - (4-chloro-benzene-sulfo n-l-amine) -benzoic acid, 4-tert-butyl- (3-c-ano-phenol) -benzenesulfonamide, N- (5- chloro-2-c? ano-phen? l) -4-met? l-benzenesulfonamide,

N- (4-cyano-2-tr? Fluoro-methox? -phen?) -3,5-b? -tr? Fluoro-methyl-benzenesulfonamide, N- (3-chloro-4-) c? ano-phen?) -3,5-b? s-tr? fluoro-met? l-benzenesulfonamide, 2,4-d? chloro-N- (3-chloro-4-c? ano- fen? l) -benzene-

sulfonamide, N- (3-cyano-phenol) -4-tr? fluoro-methox? -benzenesulfonamide, 2,4-d? chloro-N- (4-c? ano-2-met? l-phenol) -benzenesulfonamide, 5-bromo-2- (4-tert-butyl-1-benzenesulfonyl-1-amino) -benzoic acid methyl ester, 5-b-romoic acid methyl ester 2- (4-terb util-benzene-sulfoml-amino) -benzoic acid, methyl ester of 2- (4-tert-butyl-l-benzenesulfonyl-amine) -5-chlorobenzoic acid, acid 2 - (4-tert.-l-benzenesulfonyl-amine) -5-chloro-benzoic acid, 5-chloro-2- (4-c? Clohexyl) -benzenesulfonyl-amine ) -benzoic acid, 2- (4-adamantan-1-? l-benzenesulfonyl-l-amino) -5-chloro-benzoic acid, 4-tert-butyl-N- (2-c? ano-5-met) L-phenol) -benzenesulfonamide, and N- (4-cyano-2-met? l-phen? l) -3,5-b? s-tr? fluoro-met? l -benzenesulfonamide 3 A compound according to any of claims 1 or 2, in the form of a salt 4 A compound according to any of claims 1 to 3, or the compound of N- (2-c? an) -fen? l) -4-

10

tpfluoro-methyl-benzenesulfonamide, to be used as a pharmaceutical product A pharmaceutical composition, which comprises a compound of any of claims 1 to 4, in association with at least one pharmaceutically acceptable excipient, The use of a compound of according to any one of claims 1 to 4, for the manufacture of a medicament for the treatment of disorders that are mediated by the activity of CCR9. The use of a compound according to any of claims 1 to 5, for the manufacture of a medication for the treatment of disorders that are mediated by the activity of CCR9 8 The use of a compound of formula O

II R '- N - S - R' r 1 H || 2 or wherein R'I and R'2 are independently unsubstituted phenyl or phenyl substituted by one or more of alkyl (of 1 to 6 carbon atoms), - haloalkyl (of 1 to 4 carbon atoms), - cycloalkyl (from 3 to 12 carbon atoms), - alkoxy (from 1 to 4 carbon atoms), - aplo (from 6 to 12 carbon atoms) - alkoxyl (from 1 to

4 carbon atoms), - haloalkoxy (1 to 4 carbon atoms), - carboxyl, - cyano, or - halogen, wherein at least one phenyl in the meaning of R, and R2 is carboxyl or cyano, in free form or in the form of a salt, for the manufacture of a medicament for the treatment of inflammatory bowel disease. The use of a compound of the formula O R '. - N- S- R 'r IH 11 or where R ", and R" 2 are independently phenyl, for example, including unsubstituted phenyl and phenyl substituted by one or more alkyl (of 1 to 6 carbon atoms), haloalkyl (of 1 to 4 carbon atoms), cycloalkyl (of 3 to 12 carbon atoms), alkoxy (of 1 to 4 carbon atoms), aplo (of 6 to 12 carbon atoms) alkoxy (of 1 to 4 carbon atoms), - haloalkoxy (of 1 to 4 carbon atoms), - alkoxy (of 1 to 4 carbon atoms) - carbonyl, o - halogen,

in free form or in the form of a salt, with the proviso that at least one phenyl in the meaning of R, or R 2 is substituted with alkoxy (of 1 to 4 carbon atoms) -carbonyl, for the preparation of a medication for the treatment of disorders that are mediated by 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 5, and further comprising a second drug substance 11 A pharmaceutical combination, which comprises a compound according to claim 8, optionally in the form of a pharmaceutical composition, and a second drug substance, for the treatment of inflammatory bowel disease. A pharmaceutical combination, which comprises a compound according to claim 9, optionally in the form of a pharmaceutical composition, and a second drug substance, for the treatment of disorders that are mediated by the activity of CCR9 A method for the treatment of disorders that are mediated by the activity of CCR9, whose treatment comprises administering to a subject in need of such treatment, a therapeutic amount effective composition of a compound according to any one of claims 1 to 4, or a composition

n:

Pharmaceutical according to claim 5, or a compound as defined in claim 9, optionally in combination with a second drug substance 14 A method for the treatment of inflammatory bowel disease, which treatment comprises administering to a subject in need thereof A therapeutically effective amount of a compound according to claim 8, optionally in combination with a second drug substance. A compound selected from the group consisting of 2- (4-tert-butyl) -benzenesulfon? l-amin) -5-chloro-benzoic acid, 2- (4-benzyl) -benzene-sulfonyl-amine) -benzoic acid, 5-b-romo-2- (4-) acid terb ut? l-benzenesulfonyl-amine) -benzoic acid, 5-chloro-2- (4-chloro-benzenesulfonyl-amine) -benzoic acid, acid 2- (4-tert.-l-benzenesulfonyl-amine) -5-chloro-benzoic acid, 5-chloro-2- (4-c-clohexyl-l-benzenesulfonyl-amine) -benzoic acid and 2- (4-adamantan-1-? l-benzenesulfonyl-1-amino) -5-chloro-benzoic acid, in free form or in the form of a salt.

16 A compound selected from the group consisting of 5-bromo-2- (4-tert-butyl-1-benzenesulfonyl-1-amino) -benzoic acid methyl ester, and methyl acid ester 2- (4-tert.-l-benzenesulfonyl-amine) -5-chloro-benzoic acid, in free form or in the form of a salt