MXPA06009621A - Immunosuppressant compounds and compositions - Google Patents

Abstract

The present invention relates to immunosuppressants, processes for their production, their uses and pharmaceutical compositions containing them. The invention provides a novel class of compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with EDG receptor mediated signal transduction.

Description

COMPOSITIONS AND COMPOSITIONS IN UNOSUPPRESSORS CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of the priority of the Provisional Patent Application of E.U.A. No. 60 / 547,712, filed on February 24, 2004. The description of the priority application is incorporated herein by reference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION Field of the Invention The invention provides a new class of immunosuppressive compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with signal transduction mediated by the EDG receptor.

Background The EDG receptors belong to a family of receptors coupled by the closely related, lipid-activated G-protein. EDG-1, EDG-3, EDG-5, EDG-6 and EDG-8 (also referred to respectively as S1P1, S1P3, S1P2, S1P4 and S1P5) are identified as specific receptors for sphingosine-1-phosphate (SIP). EDG2, EDG4 and EDG7 (also called LPA1, LPA2 and LPA3, respectively) are specific receptors for lysophosphatidic acid (LPA). Among the SIP receptor isotypes, EDG-1, EDG-3 and EDG-5 are widely expressed in several tissues, while the expression of EDG-6 is confined largely to lymphoid and platelet tissues, and that of EDG-6. 8 to the central nervous system. The EDG receptors are responsible for signal transduction and are thought to play an important role in cellular processes that involve cell development, proliferation, maintenance, migration, differentiation, plasticity and apoptosis. Certain EDG receptors are associated with diseases mediated by lymphocyte interactions, for example, in transplant rejection, autoimmune diseases, inflammatory diseases, infectious diseases and cancer. An alteration in the activity of the EDG receptor contributes to the pathology and / or symptomatology of these diseases. Therefore, molecules that by themselves alter the activity of EDG receptors are useful as therapeutic agents in the treatment of these diseases.

BRIEF DESCRIPTION OF THE INVENTION This application relates to compounds of Formula I: in which: n is chosen from 0, 1 and 2; m is chosen from 1, 2 and 3; R-t is chosen from aryl of 6 to 10 carbon atoms and heteroaryl of 5 to 10 carbon atoms; wherein either aryl or heteroaryl of R ^ is optionally substituted by a radical selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms or alkyl of 1 to 10 carbon atoms; wherein any of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups of R-, can optionally be substituted by 1 to 5 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; and any alkyl group of R may optionally have a methylene replaced by a chosen atom or group of -S-, -S (O) -, -S (O) 2-, -NR4- and -O-; wherein R 4 is selected, of hydrogen and alkyl of 1 to 6 carbon atoms; R2 and are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, halogen, hydroxy, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; A is chosen from -X1C (O) OR4, -X1OP (O) (OR4) 2, -X1P (O) (OR4) 2, -X1P (O) OR4, -X1S (O) 2OR4, -X1P (O) (R4) OR4 and 1 H-tetrazol-5-yl; wherein X 1 is a bond or alkylene of 1 to 6 carbon atoms and R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; W is chosen from a bond, alkylene of 1 to 6 carbon atoms and alkenylene of 2 to 6 carbon atoms; X is selected from alkylene of 2 to 4 carbon atoms and alkenylene of 2 to 4 carbon atoms; wherein a methylene group of X can be replaced with a selected atom or group e -O-, -S-, -S (O) -, -S (O) 2-, and -NR5-; wherein R5 is hydrogen, alkyl of 1 to 6 carbon atoms and -C (O) R6; wherein R6 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; wherein any of alkylene or alkenylene of X may further be substituted by 1 to 3 radicals selected from the group consisting of halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms substituted by halogen and alkoxy of 1 to 10 carbon atoms substituted by halogen; Y is chosen from aryl of 6 to 10 carbon atoms and heteroaryl of 5 to 10 carbon atoms, wherein any aryl or heteroaryl of Y can optionally be substituted with 1 to 3 radicals chosen from halogen, hydroxy, nitro, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; Z is alkylene of 1 to 6 carbon atoms; wherein up to two methylene groups of Z can be replaced with divalent radicals selected from -NR7_, cycloalkylene of 3 to 8 carbon atoms, heterocycloalkylene of 3 to 8 carbon atoms and phenylene; wherein R7 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and (CH2) 1-2COOH; wherein Z can further be substituted by 1 to 3 radicals chosen from halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen and alkoxy of 1 to 6 carbon atoms substituted by halogen; or when -NR7-replaces at least one methylene group of Z, R7 and Y together with the nitrogen atom to which R7 is attached, forms a heteroarylene of 8 to 14 carbon atoms; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of their isomers; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of said compounds. A second aspect of the invention is a pharmaceutical composition containing a compound of Formula I or an N-oxide derivative, single isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, mixed with one or more suitable excipients. . A third aspect of the invention is a method for treating a ase in an animal in which the alteration of the signal transduction mediated by the EDG receptor can prevent, inhibit or diminish the pathology and / or symptomatology of the ase, the method which comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, single isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof. A fourth aspect of the invention is the use of a compound of Formula I in the manufacture of a medicament for treating a ase in an animal in which the alteration of signal transduction is mediated by the EDG receptor contributes to the pathology and / or symptomatology of the ase. A fifth aspect of the invention is a process for preparing compounds of Formula I and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE PREFERRED MODALITIES The invention provides compounds that are useful in the treatment and / or prevention of ases or rders mediated by lymphocyte interactions. Methods for treating such ases or rders are also provided.

Definition In this specification, unless otherwise defined: "Alkyl" as a group and as a structural element of other groups, for example alkyl substituted on halo, alkoxy, acyl, alkylthio, alkylsulfonyl and alkylsulfinyl, may be either straight or branched chain. "Alkenyl" as a group and as a structural element of other groups contains one or more carbon-carbon double bonds, and can be either straight or branched chain. Any of the double bonds can be in the cis- or trans- configuration. A preferred alkenyl group is vinyl. "Alkynyl" as a group and as a structural element of other groups and compounds contains at least one triple bond C = C and may also contain one or more C = C double bonds and may, as far as possible, be either straight chain or branched A preferred alkynyl group is propargyl. Any cycloalkyl group, alone or as a structural element of other groups may contain from 3 to 8 carbon atoms, preferably from 3 to 6 carbon atoms. "Alkylene" and "alkenylene" are divalent radicals derived from the groups "alkyl" and "alkenyl", respectively. In this application, any alkyl group of R1 can optionally be interrupted by a member of the group selected from -S-, -S (O) -, -S (O) 2-, -NR3-y and -O- (wherein R3 is hydrogen or alkyl of 1 to 6 carbon atoms). These groups include -CH2-O-CH2-, -CH2-S (O) 2-CH2-, ~ (CH2) 2NR3CH2-, -CH2-0- (CH2) 2-y and the like. "Aryl" means a fused monocyclic or bicyclic aromatic ring ring containing six to ten carbon atoms in the ring. For example, aryl of 6 to 12 carbon atoms may be phenyl, biphenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. For example, arylene as used in this application can be phenylene, biphenylene, naphthylene and the like. "Halo" or "halogen" means F, Cl, Br or 1, preferably F or Cl. Groups and alkyl compounds substituted by halo may be partially halogenated or perhalogenated, whereby in the case of multiple halogenation, the halogen substituents may be identical or different. A preferred perhalogenated alkyl group is for example trifluoromethyl. "Heteroaryl" means aryl, as defined in this application, with the proviso that one or more of the ring carbon atoms indicated are replaced by a selected heteroatom portion of N, O or S and each ring comprises from 5 to 6 atoms in the ring, unless otherwise stated. For example, heteroaryl as used in this application includes thiophenyl, pyridinyl, furanyl, isoxazolyl, benzoxazolyl or benzo [1,3] dioxolyl, preferably thiophenyl, furanyl or pyridinyl. "Heteroarylene" means heteroaryl, as defined in this application, with the proviso that the ring assembly comprises a divalent radical. As used in the present invention, a selective compound of EDG-1 (agent or modulator) has a specificity that is selective for EDG-1 on EDG-3 and on one or more of EDG-5, EDG-6 and EDG- 8 As used herein, in the selectivity for an EDG receptor (a "selective receptor") over another EDG receptor (a "non-selective receptor") means that the compound has a much higher potency by inducing mediated activities by the selective EDG receptor (eg, EDG-1) that for the SIP-specific non-selective EDG receptor. If measured in a GTP ~ S binding assay (as described in the following Example), an EDG-1 selective compound typically has an EC50 (effective concentration causing 50% of the maximum response) for a selective receptor (EDG). -1) which is at least 5, 10, 25, 50, 100, 500 or 1000 times lower than the EC50 for a non-selective receptor (e.g., one or more EDG-3, EDG-5, EDG-6 and EDG-8).

Detailed Description of the Invention The invention provides compounds that are useful for treating or preventing diseases or disorders that are mediated by lymphocyte interactions. In one embodiment, for compounds of Formula I, n is 0 or 1 and Z is chosen from: • N'V 5 *; * > N and * 'and x- * R7 *: R7 O * * .N' 'C® H? W ^ N > HO 'O i & * JL * • R7 R7? ? R7 ; wherein the left and right asterisks of Z indicate the point of attachment between the group - [C (R2) (R3)] n- and A of Formula I, respectively; R7 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; and J1t J2 and J3 are independently methylene or a heterogeneous atom selected from the group consisting of S, O and NR4; wherein R 4 is hydrogen or alkyl of 1 to 6 carbon atoms; as long as the number of heterogeneous atoms is 2 or less. In another embodiment, Ri is chosen from phenyl, naphthyl and thiophenyl optionally substituted by aryl of 1 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, or alkyl of 1 to 10 carbon atoms; wherein any of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R ^ can optionally be substituted by 1 to 5 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; and any alkyl group of R-α may optionally have a methylene replaced by a chosen atom or group of -S-, -S (O) -, -S (O) 2-, -NR- and -O-; wherein R 4 is hydrogen or alkyl of 1 to 6 carbon atoms. In another embodiment, Y is chosen from phenyl, pyridine, pyrimidine, thiophene, furan, thiazole and oxazole; each of which can optionally be substituted with 1 to 3 radicals chosen from halogen, hydroxy, nitro, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen. In another embodiment, R 2 and R 3 are both hydrogen and A is chosen from -C (O) OR 4 and 1 H-tetrazol-5-yl; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms. In an additional embodiment, R1 is chosen from: where the asterisk is the point of union of R-, with X; R9 is aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms or alkyl of 1 to 10 carbon atoms; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R9 can optionally be substituted by 1 to 3 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 atoms of carbon substituted by halogen and alkoxy of 1 to 10 carbon atoms substituted by halogen; and any alkyl group of R9 may optionally have a methylene replaced by a chosen atom or group of -S-, -S (O) -, -S (O) 2-, -NR4- and -O-; wherein R10 is hydrogen or alkyl of 1 to 6 carbon atoms; and R11 is selected from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen. Preferred are compounds selected from: 3- acid. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; 1- [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { [6-chloro-4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -chroman-7-ylmethyl] -amino} -propionic; acid 3-. { [3-chloro-5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -amino} -propionic; 1- [3-Chloro-5- (4-cyclohexyl-3-tri-fluoro-methyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; 1- [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxylimino) -3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; acid 3-. { [8- (4-cyclohexyl-3-tri-fluoro-methyl-benclloxyimino) -5,6,7,8-tetrahydro-quinolin-3-ylmethyl] -amino} -propionic; 1- [8- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-quinolin-3-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { 4- [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalene-2-yl] -piperazin-1-yl} -propionic; acid 3-. { [1- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -indan-5-ylmethyl] -amino} - propionic; 1 - [8- (4-cyclohexyl-3-tri-fluoro-methyl-benzyloxyimino) -5,7,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { [8- (4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; acid 3-. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3-ethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; acid 3-. { [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -chroman-6-ylmethyl] -amino} -propionic; acid 3-. { [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -chroman-7-ylmethyl] -amino} -proplonic; 1- [4- (4-cyclohexyl-3-trifluoromethylbenzyloxyimino) -chroman-7-ylmethyl] -zetidine-3-carboxylic acid; acid 3-. { [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3,4-dihydro-2H-pyrano [2,3-b] pyridin-7-ylmethyl] -amino} -propionic; 1- [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3,4-dihydro-2H-pyrano [2,3-b] pyridin-7-ylmethyl] -zetidin-3-carboxylic acid; 1- [4- (4-cyclohexyl-3-methylbenzyloxyimino) -chroman-7-ylmethyl] -zetidine-3-carboxylic acid; and acid 3-. { [4- (4-Cyclohexyl-3-methyl-benzyloxyimino) -chroman-7-ylmethyl] -amino) -propionic acid. Additional preferred compounds are shown in the examples and table 1, infra. The invention provides forms of the compound having the hydroxyl or amine groups present in a protected form; these work like drugs. Prodrugs are compounds that are converted to active drug form after administration, through one or more chemical or biochemical transformations. The forms of the compounds of the present invention that are readily converted to the claimed compound under physiological conditions are prodrugs of the claimed compounds and are within the scope of the present invention. Examples of prodrugs include forms wherein a hydroxyl group is acylated to form a relatively labile ester such as an acetate ester, and forms wherein an amine group is acylated with the glycine carboxylate group or an L-amino acid such as serine, to form a bond amide that is particularly susceptible to hydrolysis by common metabolic enzymes. The compounds of Formula I can exist in free form or in salt form, for example, adhesion salts with inorganic or organic acids. Where the hydroxyl groups are present, these groups may also be present in salt form, for example an ammonium salt or salts with metals such as lithium, sodium, potassium, calcium, zinc or magnesium or a mixture thereof. Compounds of Formula I and their salts in hydrated or solvated form are also part of the invention. When the compounds of Formula I have asymmetric centers in the molecule, several optical isomers are obtained. The present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof. Moreover, when the compounds of Formula I include geometric isomers, the present invention encompasses cis-, trans- and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms or unsaturated bonds as mentioned previously.

Methods and Pharmaceutical Compositions for Treating Immunomodulatory Conditions. Compounds of Formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example properties that modulate lymphocyte recirculation, for example, as indicated by the in vitro and in vivo tests of Example 56 and therefore they are indicated for therapy. Compounds of Formula I preferably show an EC50 in the range of 1x10"11 to 1x10" 5M, preferably less than 50nM. The compounds exhibit selectivity for one or more EDG / SIP receptors preferably EDG1 / S1P-1. The EDG1 / S1P-1 selective modulators of the present invention can be identified by compound binding assay to EDG-1 / S1P-1 and one or more of the other EDG / SIP receptors (e.g., EDG-3 / SIP) -3, EDG-5 / SIP-2, EDG-6 / SIP-4, and EDG-8 / SIP-5). A selective modulator of EDG-1 / S1 P-1. normally it has an EC50 for the EDG-1 / S1P-1 receptor in the range of 1x10"11 to 1x10" 5nM, preferably less than 50 nM, more preferably less than 5 nM. It also has an EC50 for one or more of the other EDG / SIP receptors of at least 5, 10, 25, 50, 100, 500 or 1000 times greater than the EC50 for EDG-1 / S1P-1. Thus, some of the EDG-1 / S1P-1 modulator compounds will have an EC50 for EDG-1 / S1P-1 that is less than 5 nM while the EC50 for one or more of the other EDG / SIP receptors they are less than 100 nM or higher. In other assays of EDG / SIP receptor binding activity, selective agents of EDG-1 / S1P-1 can also be identified by examining with a test of the agent's ability to modify a cellular process or activity mediated by an EDG receptor / YEP. The compounds of formula 1 are, therefore, useful in the treatment and / or prevention of diseases or disorders mediated by lymphocyte interactions, for example in transplantation, such as acute or chronic rejection of cells, tissues or organs in allografts or xenografts or delayed function of grafts, graft-versus-host disease, autoimmune diseases, for example rheumatoid arthritis, systemic lupus erythematosus, hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, type I or II diabetes and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren's syndrome, uveitis, psoriasis, Grave's ophthalmopathy, alopecia areata and others, allergic diseases, for example allergic asthma, atopic dermatitis, rhinitis / allergic conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, example inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory damage to the lung, inflammatory damage to the liver, inflammatory glomerular damage, atherosclerosis, osteoarthritis, irritant contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, damage by ischemia / reperfusion, for example myocardial infarction, stroke, intestinal ischemia, renal failure or hemorrhagic shock, traumatic shock, T-cell lymphomas or T-cell leukemias, infectious diseases, for example toxic shock (for example induced superantigen), septic shock, respiratory anxiety syndrome in adults or viral infections, for example AIDS, viral hepatitis, chronic bacterial infection, or senile dementia. Examples of solid cell, tissue or organ transplants include for example pancreatic islets, germ cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, heart-lung combination, kidney, liver, intestine, pancreas, trachea or esophagus. . For the previous uses, the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the desired effect. further, the compounds of the formula I are useful in cancer chemotherapy, particularly for cancer chemotherapy of solid tumors, for example, breast cancer or as an anti-angiogenic agent. The required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the desired effect. In general, it is indicated that satisfactory results are obtained systematically at daily dosages of approximately 0.03 to 2.5 mg / kg per body weight. A dosage indicated in the larger mammals, for example humans, is in the range of about 0.5 mg to about 100 mg, conventionally administered, for example, in divided doses up to four times a day or in a delayed manner. Suitable unit dosage forms for oral administration comprise about 50 mg. of active ingredient. The compounds of Formula I can be administered by any conventional route, in particular enterally, for example, orally, for example in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, topically, for example in the form of lotions, gels, ointments or creams or in nasal or suppository form. Pharmaceutical compositions comprising a compound of Formula I in free form or in pharmaceutically acceptable salt form in association with at least one acceptable pharmaceutical carrier or diluent can be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. The compounds of Formula I can be administered in free form or in pharmaceutically acceptable salt form, for example, as previously indicated. The salts can be prepared in conventional manner and exhibit the same order of activity as the free compounds.

The compounds of Formula I can be administered in free form or in pharmaceutically acceptable salt form, for example, as indicated above. Said salts can be prepared in a conventional manner and exhibit the same order of activity as the free compounds. In accordance with the foregoing the present invention further provides: 1.1 A method for preventing or treating disorders or diseases mediated by lymphocytes, for example, as previously indicated, in a subject in need of treatment, which comprises administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; 1.2 A method for preventing or treating acute or chronic rejection of transplantation or inflammatory or autoimmune diseases mediated by T cells, for example, as previously indicated, in a subject in need of such treatment, which comprises administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; 1.3 A method for inhibiting or controlling deregulated angiogenesis, for example, sphingosine-1-phosphate (S1P) mediated angiogenesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof. 1. A method for preventing or treating diseases mediated by a process of neo-angiogenesis or associated with a regulated angiogenesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically salt acceptable of it. 2. A compound of Formula I, in free form or in a pharmaceutically acceptable salt form for use as a drug, for example in any of the methods indicated in 1.1 to 1.4 previously. 3. A pharmaceutical composition, for example for use in any of the methods as in 1.1 to 1.4 previously comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefor. . 4. A compound of Formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in any of the method as in 1.1 to 1.4 previously. The compounds of formula I can be administered as an active ingredient alone or in conjunction with, for example, as an adjuvant for other drugs, for example immunosuppressive or immunomodulatory agents or other anti-inflammatory agents, for example for the treatment or prevention of acute or chronic rejection. - or xenograft or inflammatory or autoimmune diseases, or a chemotherapeutic agent, for example an anti-proliferative agent of malignant cells. For example, the compounds of the formula I can be used in combination with a calcineurin inhibitor, for example cyclosporin A or FK 506; an mTOR inhibitor, for example rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, CC1779, ABT578 or AP23573; an ascomycin having immunosuppressive properties, for example, ABT-281, ASM981, etc .; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribin; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualin or a homolog, analog or immunosuppressive derivative thereof; immunosuppressive monoclonal antibodies, for example, monoclonal antibodies against leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40. CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, for example, a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, eg, at least one extracellular portion of CTLA4 or a mutant thereof linked to a sequence protein that is not CTLA4, eg, CTLA4lg (eg, designated ATCC 68629) or a mutant thereof, eg, LEA29Y; adhesion molecule inhibitors, for example, LFA-1 antagonists, ICAM-1 or -3 antagonist, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent. The term "chemotherapeutic agent" means any chemotherapeutic agent and includes, but is not limited to, i. an aromatase inhibitor, ii. an anti-estrogen, an anti-androgen (especially in the case of cancer of the prostate) or a gonadorelin agonist, iii. a topoisomerase 1 inhibitor or a topoisomerase II 'inhibitor, iv. an active agent in microtubium, an alkylating agent, an antineoplastic antimetabolite or platinum compound, v. a compound directed / decreasing the activity of a protein or lipid kinase or of a protein or lipid phosphatase, an additional anti-angiogenic compound or a compound that induces cell differentiation processes, vi. an antagonist of bradykinin 1 receptor or angiotensin vii. a cyclooxygenase inhibitor, a bisphosphonate inhibitor, a histone deacetylase inhibitor, a heparanase inhibitor (which prevents the degradation of heparan sulfate), for example, PI-88, a biological response modifier, preferably a lymphokine or interferons , for example, interferon gamma, an inhibitor of ubiquitination or an inhibitor that blocks the antl-apoptotic pathways, viii. an inhibitor of Ras oncogenic isoforms, for example, H-Ras, K-Ras or N-Ras or a farnesyl transferase inhibitor, for example, L-744,832 or DK8G557, ix. a telomerase inhibitor, for example, telomestatin, x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, for example, bengamide or a derivative thereof, or a proteosome inhibitor, for example PS-341, and / or xi. an mTOR inhibitor. The term "aromatase inhibitor" as used herein relates to a compound that inhibits the production of estrogen, ie the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testoiactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. A combination of the invention comprises a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, for example, breast tumors. The term "anti-estrogen" as used herein is related to a compound that antagonizes the estrogen effect at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. A combination of the invention comprises a chemotherapeutic agent that is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, for example, breast tumors. The term "anti-androgen" as used herein is related to any substance that is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide. The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in W099 / 17804). The term "topoisomerase II inhibitor" as used herein includes, but is not limited to anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. The term "microtubule active agent" relates to agents that stabilize and destabilize microtubules that include, but are not limited to, taxanes, for example, paclitaxel and docetaxel, vinca alkaloids, for example, vinblastine, especially vinblastine sulfate, especially vincristine. vincristine sulfate, and vinorelbine, discodermolides and epothilones and derivatives thereof, for example, epothilone B or a derivative thereof. The term "alkylating agent" as used herein includes, but is not limited to, busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel ™). The term "antineoplastic antimetabolite" includes, but is not limited to. -fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine, thioguanine, methotrexate and edatrexate. The term "platinum compound" as used herein includes, but is not limited to carboplatin, cis-platinum and oxaliplatin. The term "targeted compounds / which decreases the activity of a protein or lipid kinase or additionally anti-angiogenic compounds" as used herein includes, but is not limited to inhibitors of tyrosine kinase proteins and / or serine and / or threonine kinase or lipid kinase inhibitors, for example, compounds directed to, which decrease or inhibit the activity of the tyrosine kinase receptor family of the epidermal growth factor (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers), the tyrosine kinase receptor family of vascular endothelial growth factor (VEGFR), platelet-derived growth factor receptor (PDGFR) receptors, the factors of fibroblast growth factor (FGFR), insulin-like growth factor receptor 1 (IGF-1R), the tyrosine kinase receptor family Trk, the tyrosine kinase receptor family Axl, and the receptor kinase of Ty tyrosine Ret, tyrosine kinase receptor Kit / SCFR, members of the c-Abl family and their gene fusion products (eg BCR-Abl), members of protein kinase C (PKC) and the Raf family of serine kinases / threon ina, members of the MEK family, SRC, JAK, FAK, PDK or Pl (3) kinase, or the family of related kinases Pl (3) kinase, and / or members of the cyclin dependent kinase family (CDK) and anti-angiogenic compounds that have some other mechanism for their activity, for example not related to inhibition of proteins or lipids. Compounds that target, decrease or inhibit the activity of VEGFR are especially compounds, proteins or antibodies that inhibit the receptor tyrosine kinase VEGF, inhibit a VEGF receptor or bind to VEGF, and in particular are those compounds, proteins or antibodies monoclonal antibodies and specifically described in WO 98/35958, for example 1- (4-cyanoanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof, for example succinate, in WO 00/27820, for example an amide derivative of N-aryl (thio) anthranilic acid for example, 2 - [(4-pyridyl) methyl] amino-N- [3-methoxy-5- (trifluoromethyl) phenyl] benzamide or 2 - [(1 - Oxido-4-pyridyl) methyl] amino-N- [3-trifluoromethylphenyl] benzamide, or in WO 00/09495, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; those described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Nati Acad. Sci. E.U., vol. 93, pp. 14765-14770, Dec. 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology, Vol. 27, no. 1, pp. 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin ™, described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; Endostatin ™, described by M. S. O'Reilly et al, Cell 88, 1997, 277-285; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies, for example RhuMab. By antibodies it is meant that intact monoclonal antibodies, polyclonal antibodies, muitespecific antibodies formed of at least 2 intact antibodies and fragments of antibodies so large that they exhibit the desired biological activity. Compounds which target, diminish or inhibit the activity of the epidermal growth receptor family are especially compounds, proteins or antibodies that inhibit the members of the tyrosine kinase family of the EGF receptor, for example, the EGF receptor, ErbB2, ErbB3 and ErbB4 either bind to EGF or to EGF-related ligands or have a dual inhibitory effect on the ErbB and VEGF receptor kinase and in particular are those compounds, proteins or generic monoclonal antibodies and specifically described in WO 97/02266, by example the compound of ex. 39 or EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, E.U. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (for example, the compound known as CP 358774), WO 96/33980 (for example, the compound ZD 1839) and WO 95/03283 (for example compound ZM 105180) or PCT / EP02 / 08780; for example trastuzumab (Herpetin®), cetuximab, Iressa, OSI-774, C1-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11 , E6.3 or E7.6.3. The compounds directed to, which decrease or inhibit the activity of PDGFR are especially compounds that inhibit the PDGF receptor, for example an N-phenyl-2-pyrimidine-amine derivative, for example, imatinib. The compounds directed to, which decrease or inhibit the activity of the members of the c-Abl family and their gene fusion products are, for example, an N-phenyl-2-pyrimidine-amine derivative, for example imatinib; PD180970; AG957; or NSC 680410. Compounds targeted to, which decrease or inhibit the activity of family members protein kinase C, Raf, MEK, SRC, JAK, FAK and PDK, or Pl (3) kinase or family members related to Pl (3) kinase, and / or members of the family of cyclin dependent kinases (CDK) are especially those derived from staurosporine discovered in EP 0 296 110, for example midoesturin; examples of additional compounds include, for example, UCN-01, safingol, BAY 43-9006, Briostatin 1, Perifosine; Ilmofosin; RO 318220 and RO 320432; GO 6976; Isis 3521; or LY333531 / LY379196. Additional anti-angiogenic compounds are for example, thalidomide (TALOMID) and TNP-470. The compounds directed to, which decrease or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1, phosphatase 2A, PTEN or CDC25 inhibitors, for example okacaic acid or derivatives thereof. The compounds that induce cell differentiation processes are, for example, retinoic acid, α-, α- or d-tocopherol or α-, β- or d-tocotrienol.

The term "cyclooxygenase inhibitors" as used herein includes, but is not limited to, for example celecoxib (Celebrex®), rofecoxib (Vioxx®), etoricoxib, vaidecoxib or a 5-alkyl-2-arylaminophenylacetic acid, for example 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenylacetic acid. The term "histone deacetylase inhibitor" as used herein includes, but is not limited to MS-27-275, SAHA, piroxamide, FR-901228 or valproic acid. The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic, and zolidronic acid. The term "matrix metalloproteinase inhibitor" as used herein includes, but is not limited to peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, for example hydroxamate the peptidomimetic inhibitor batimastat and its orally bioavailable analog marimastat prinomastat , BMS-279251, BAY 12-9566, TAA211 or AAJ996. The term "mTOR inhibitor" as used herein includes, but is not limited to rapamycin (sirolimus) or a derivative thereof, for example 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxo rapamycin, 16-pent-2-ynyloxy-32 (S) -dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S) -dihydro-40-O- (2-hydroxyethyl) -rapamycin and, more preferably, 40- 0- (2-hydroxy-etiI) -rapamycin. Additional examples of rapamycin derivatives include, for example, CC1779 or 40- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoate] -rapamycin or a pharmaceutically acceptable salt thereof, as described in USP 5,362,718, ABT578 or 40 - (tetrazolyl) -rapamycin, particularly 40-epi- (tetrazolyl) -rapamycin, for example as described in WO 99/15530 or rapporteurs as described for example in WO 98/02441 and WO01 / 14387, for example AP23573. Where the compounds of the formula I are administered in conjunction with another immunosuppressive / immunomodulatory, anti-inflammatory or chemotherapeutic therapy, the dosages of the immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic compound co-administered will of course vary depending on the type of co-drug employed, for example if it is a steroid or a calcineurin inhibitor, of the specific drug employed, of the condition to be treated etc. According to the foregoing the present invention provides in yet another aspect: A method as defined above comprising co-administering, for example concomitantly or in sequence, a therapeutically effective non-toxic amount of a compound of Formula I and at least a second drug substance, for example an immunosuppressive, immunomodulatory, anti-inflammatory or chemotherapeutic drug, as previously indicated. 6. A pharmaceutical combination, for example a kit, comprising a) a first agent that is a compound of formula I as described herein, in free form or in pharmaceutically acceptable salt form, and b) at least one - agent, for example an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, for example as previously described. The team can understand instructions for its administration. The terms "co-administration" or "combined administration" or the like as used herein implies that it encompasses the administration of the selected therapeutic agents to a single patient and is intended to include treatment regimens in which the agent is necessarily Administered by the same administration route or at the same time. The term "pharmaceutical combination" as used herein means a product that results from mixing or combining more than one active ingredient and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient, for example a compound of Formula I and a co-agent, are not administered together to a patient as separate entities either simultaneously, concurrently or sequentially without specific time limits, wherein the administration provides therapeutically effective levels of the 2 components in the patient's body. The latter also applies to cocktail therapy, for example the administration of 3 or more active ingredients.

Methods for Preparing Compounds of the Invention The present invention also includes processes for preparing the immunomodulatory compounds of the invention. In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where desired in the final product, to avoid their unwanted participation in the reactions. Conventional protection groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991. The compounds of Formula I, in which A is 2-carboxy-ethyl, can be prepared by the process of the following reaction scheme: wherein A, W, X, Y, Z, R- ^ R2, R3, and n are as defined in Formula I above. The compounds of Formula I can be prepared by reacting a compound of formula 2 with a compound of formula 3 in the presence of a suitable solvent (for example, methanol, and the like) and a suitable acid (for example, acetic acid, and similar). The reaction proceeds at a temperature of about 0 to about 60 ° C and may take up to about 48 hours to complete.

Additional Processes for Preparing Compounds of the Invention: A compound of the invention can be prepared as a pharmaceutically acceptable addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates. The free acid or free base forms of the compounds of the invention can be prepared in corresponding form of addition base salt or addition acid salt, respectively. For example, a compound of the invention in the form of the addition acid salt can be converted to the corresponding free base by treatment with a suitable base (for example, a solution of ammonium hydroxide, sodium hydroxide, and the like). A compound of the invention in a base salt form of the addition can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).

The compounds of the invention in non-oxidized form can be prepared from N-oxides of compounds of the invention by treatment with a reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride , tribromide, or the like) a suitable inert organic solvent (for example acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 ° C. Drugs derived from the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (eg, for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, page 1985). For example, suitable prodrugs can be prepared by reaction of a non-derivatized compound of the invention with a suitable carbamylating agent (eg, 1,1-acyloxyalkylcarbanoclohydrate, carbonate for nitrophenyl, or the like). The protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable in the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry" 3rd edition, John Wiley and Sons, Inc., 1999. The compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (for example, hydrates). The hydrates of the compounds of the present invention can be conveniently prepared by crystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol. The compounds of the invention can be prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While the resolution of the enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (eg, crystalline diastereomeric salts). The diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by taking advantage of these inequalities. The diastereomers can be separated by chromatography or preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that do not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from the racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc. ., 1981. In summary, the compounds of Formula I can be made by a process, which involves: (a) reacting a compound of formula 3; and (b) optionally converting a compound of the invention to a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the invention to a non-salt form; (d) optionally converting a non-oxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the invention to its non-oxidized form; (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers; (g) optionally converting a non-derivatized compound of the invention to a pharmaceutically acceptable pro-drug derivative; and (h) optionally converting a pro-drug derivative of a compound of the invention to its non-derivatized form. While the production and starting materials are not particularly described, the compounds known can be prepared in a manner analogous to methods known in the art or as described in the Examples herein above. One of skill in the art will appreciate that the above transformations are only representative of methods for the preparation of the compounds of the present invention, and that other well-known methods can be used in a similar manner.

EXAMPLES The following examples provide detailed descriptions of the preparation of representative compounds and are presented in different ways, but not to limit the present invention.

Example 1 3- (f5- (4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethip-amino) -propionic acid To a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde (0.1 mmol) in MeOH (1 mL) was added ß-alanine (0.2 mmol) and Et3N (0.16 mmol). The mixture was heated to 50 ° C with stirring for 1 hour. After cooling to room temperature, NaBH 3 CN (0.3 mmol) was added in one portion and the resulting mixture was stirred for 30 minutes. Then O- (4-cyclohexyl-3-trifluoromethyl-benzyl) -hydroxylamine (0.12 mmol) was added to the above reaction mixture and the prH of the solution was adjusted to 5-6 by adding AcOH. Purification by LCMS of preparation results in 3- acid. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} propionic; 1 H NMR (600 MHz, CD 3 OD) d 8.00 (d, 1 H), 7.65 (s, 1 H), 7.59 (d, 1 H), 7.52 (d, 1 H), 7.35-7.26 (m, 2 H), 5.22 (s, 2H), 4.21 (s, 2H), 3.30 (t, 2H), 2.94 (m, 1H), 2.78 (m, 6H), 1.90-1.70 (m, 7H), 1.60-1.45 (m, 2H), 1.45 -1.30 (m, 3H); MS (ES): 503.2 (M + 1) +.

EXAMPLE 2 Acid 1-r5- (4-Cyclohexyl-3-trifluoride eti I -be ncyloxyimine) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl-3-carboxylic acid 1 H NMR (600 MHz, CD 3 OD) d 7.99 (d, 1 H), 7.64 (s, 1 H), 7.59 (d, 1 H), 7.53 (d, 1 H), 7.30-7.20 (m, 2 H), 5.33 (s, 2H), 4.36 (s, 2H), 4.35-4.25 (m, 4H), 3.75-3.65 (m, 1H), 2.95-2.85 (m, 1H), 2.78 (t, 4H), 1.90-1.70 (m, 7H), 1.60-1.35 (m, 5H). MS (ES): 515.2 (M + 1) +.

Example 3 Acid 3-. { (6-Chloro-4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -chroman-7-ylmethylamino}. -propionic 1 H NMR (600 MHz, CD 3 OD) d 7.94 (s, 1 H), 7.66 (s, 1 H), 7.61 (d, 1 H), 7.55 (d, 1 H), 7.16 (s, 1 H), 5.25 (s, 2 H) , 4.34 (s, 2H), 4.23 (t, 2H), 3.38 (t, 2H), 2.95 (t, 2H), 2.90-2.85 (m, 1H), 2.79 (t, 2H), 1.90-1.85 (m , 2H), 1.80-1.75 (m, 3H), 1.60-1.30 (m, 5H). MS (ES): 539.2 (M + 1) +.

Example 4 Acid 3-. { 4. [5- (4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ip-piperazin-1-yl} -propionic 1 H NMR (400 MHz, CD 3 OD) d 7.82 (d, 1 H), 7.63 (s, 1 H), 7.56 (d, 1 H), 7.50 (d, 1 H), 6.84 (d, 1 H), 6.75 (s, 1 H) , 5.15 (s, 2H), 3.75-3.35 (m, 8H), 3.47 (t, 2H), 2.95-2.80 (m, 1H), 2.89 (t, 2H), 2.75-2.60 (m, 4H), 1.90 -1.70 (m, 7H), 1.60-1.30 (m, 5H). MS (ES): 558.3 (M + 1) +.

Example 5 Acid 1-F8- (4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydroquinolin-3-ylmethyl-azetidine-3-carboxylic acid 1 H NMR (600 MHz, CD 3 OD) d 8.42 (s, 1 H), 7.70 (s, 1 H), 7.58 (s, 1 H), 7.52 (d, 1 H), 7.45 (d, 1 H), 5.23 (s, 2 H ), 4.40 (s, 2H), 4.30-4.20 (m, 4H), 3.65-3.55 (m, 1H), 2.90-2.75 (m, 5H), 1.85-1.75 (m, 4H), 1.75-1.65 (m , 3H), 1.50-1.20 (m, 5H). MS (ES): 516.2 (M + 1) +.

Example 6: 3-8- (4-Cyclohexyl-3-tri-fluoro-methyl-benzyloxyimino) -5,6,7,8-tetrahydro-quinolin-3-ylmet-p-amino acid} -propionic 1 H NMR (600 MHz, CD 3 OD) d 8.55 (s, 1 H), 7.96 (s, 1 H), 7.60 (s, 1 H), 7.55 (d, 1 H), 7.45 (d, 1 H), 5.28 (s, 2 H) , 4.25 (s, 2H), 3.25 (t, 2H), 2.90-2.75 (m, 5H), 2.70 (t, 2H), 1.90-1.80 (m, 2H), 1.80-1.70 (m, 2H) , 1.70-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.40-1.20 (m, 3H). MS (ES): 504.3 (M + 1) +. By repeating the procedure described in the previous examples, using the appropriate starting materials, the following compounds of Formula I were obtained as identified in Table 1.

TABLE 1 Example 22 Compounds of Formula I Exhibit Biological Activity A. In vitro: Scintillation proximity assay (SPA) to measure GTP [? -35S] which binds to membranes prepared from CHO cells expressing human EDG / S1P receptors. Binding assay of EDG-1 (S1P1) GTP [? -35S]: membrane protein suspensions were prepared from CHO cell clones stably expressing an N-terminal c-myc label of human EDG-1. Solutions of test compounds ranging from 10mM to 0.01nM in DMSO / 50mM HCl were prepared and then diluted to a pH regulating assay (20mM HEPES, pH 7.4, 100mM NaCl, 10mM MgCl2, 0.1% fat-free BSA). The assay pH buffer containing 10mM GDP was mixed with SPA beads coated with wheat germ agglutinin (1 mg / well) followed by the addition of a human EDG-1 membrane protein suspension (10 μg / well) and the test compound. The components of the bead / membrane / compound assay were then mixed for 10-15 minutes in beaker at room temperature. GTP [? -35S] (200 pM) and a bead / membrane / compound assay mixture were added to individual wells of a 96 cavity Optiplate ™ plate (final volume 225 μl / well), sealed and incubated at room temperature environment for 110 to 120 minutes under constant agitation. After centrifugation (200 rpm, 10 minutes) the luminescence was measured with a TopCount ™ instrument. The EC50 values were obtained by adjusting the GTP binding curves [? -35S] (baseline data) with the dose response curve-fitting tool of ORIGIN V.6.1. The basal binding (without compound) and the highest stimulation of the GTP binding [? -35S] obtained by an agonist were used as the adjustment scale. Seven different concentrations were used to generate a concentration response curve (using two or three data points per concentration). Binding assays of EDG-3, -5, -6 and -8 GTP [? -35S] were performed in a manner comparable to the binding assay of EDG-1 GTP [? -35S] using CHO membranes, or in the case of EDG-8 membranes RH7777, of cells stably expressing labeled or unlabeled receptors of c-myc c-terminals. Membrane-expressing EDG receptor concentrations vary from 13-19 μg per well. The compounds of the invention were tested in accordance with the above test and were found to exhibit selectivity for the EDG-1 receptor. For example, acid 3-. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic has an EC50 of 0.78 nM in the above assay and is at least 1000 times selective for EDG-1 compared to one or more of the other receptors, including EDG-3, EDG-5, EDG-6 and EDG-8 .

B. In vitro: FLIPR calcium flux assay. The compounds of the invention are tested for agonist activity of EDG-1, EDG-3, EDG-5 and EDG-6 with a FLIPR calcium flux assay. Briefly, CHO cells expressing an EDG receptor are maintained in an F-12K medium (ATCC), which contains % FBS, with 500ug / ml of G418. Before the assay, cells are plated on 384 bright black background plates at a density of 10,000 cells / well / 25μl in the medium of F-12K containing 1% FBS. On the second day, the cells were washed three times (25 μl / each time) with washing pH regulator. Approximately 25 μl of pigment is added to each well and incubated for 1 hour at 37 ° C and 5% C02. The cells are then washed four times with a washing pH regulator (25 μl / each time). The flow of calcium is assayed after adding 25 μl of the SEQ2871 solution to each cell cavity. The same assay is performed with cells expressing each of the different EDG receptors. The crushing in the FLIPR calcium flow assay is recorded over a 3 minute interval, and quantified as a maximum peak percentage percentage response relative to the activation of EDG-1.

C. In vivo: Classification Analysis for measurement of blood lymphocyte reduction and assessment of cardiac effect Measurement of circulating lymphocytes: The compounds are dissolved in DMSO and diluted to obtain a final concentration of 4% DMSO (v / v, concentration final) and then further diluted in a constant volume of 25% TweendO / H2O, v / v. 25% TweendO / H2O (200 μL), 4% DMSO and FTY720 (10 μg) are included as negative and positive controls, respectively. The mice are administered (C57bl / 6 male, 6-10 weeks of age) 250-300 μl of the compound solution orally by gastric tube or in short isoflurane anesthesia. Blood is collected from the retro-orbital sinus 6 and 24 hours after administration of the drug in short isoflurane anesthesia. Total blood samples are subjected to blood tests. Peripheral lymphocyte counts are determined using an automated analyzer. Sub-populations of peripheral blood lymphocytes are stained by fluorochrome-conjugated specific antibodies and analyzed using a fluorescence activated cell sorter (Facscalibur). Two mice are used to test the decrease in lymphocyte activity of each classified compound. The result is an ED50, which is defined as the effective dose required to deploy 50% of the decrease in blood lymphocytes. The compounds of the invention were tested according to the above test and were preferably found to exhibit an ED50 of less than one mg / kg, more preferably an ED50 of less than 0.5 mg / kg. For example: compound 2 exhibits an ED50 of 0. 2 mg / kg. Evaluation of the Cardiac Effect: The effect of the compounds on cardiac function is monitored using the AnonyMOUSE ECG classification system. Electrocardiograms are recorded in conscious mice (C57bl / 6 male, 6-10 weeks of age) before and after administering the compound. The ECG signals are then processed and analyzed using the e-MOUSE software. 90 μg of the diluted compound is injected in an IP manner in 200 μl of water, 15% of DMSO. Four mice are used to test the cardiac effect of each compound.

D: In vivo: Anti-anqiocene activity Porous chambers containing (i) sphingosine-1-phosphate (5 μM / chamber) or (ii) human VEGF (1 μg / chamber) in 0.5 ml agar 0.8% w / v ( containing heparin, 20 .U / ml) are implanted subcutaneously in the side of the mice. S1P or VEGF induce the growth of vascularized tissue around the chamber. This response is dose dependent and can be quantified by measuring the weight and blood content of the tissue. Mice are treated once daily orally or intravenously with a compound of Formula I starting 4-6 hours before the implantation of the cameras and continuing for 4 days. Animals are sacrificed to measure vascularized tissues 24 hours after the last dose. The weight and blood content of the vascularized tissues around the chamber are determined. Animals treated with a compound of formula 1 show decrease in weight and / or blood content of vascularized tissues compared to animals treated with the vehicle alone. The compounds of Formula I are anti-angiogenic when administered at doses of from about 0.3 to about 3 mg / kg.

E: In vitro: Antitumor activity A mouse breast cancer cell line originally isolated from a mammary carcinoma is used, for example JygMC (A). The cell number is adjusted to 5xl05 to be plated on a fresh medium before the procedure. The cells are incubated with a fresh medium containing 2.5mM thymidine without FCS for 12 hours and then washed twice with PBS, followed by the addition of a fresh medium with 10% FCS and further incubated for another 12 hours. After this the cells are incubated with a fresh medium containing 2.5mM thymidine without FCS for 12 hours. To release the cells from the block, the cells are washed twice with PBS and plated in a fresh medium with 10% FCS. After synchronization, the cells are incubated with or without various concentrations of a compound of formula 1 for 3, 6, 9, 12, 18 or 24 hours. The cells are harvested after treatment with 0.2% EDTA, fixed with a 70% ethanol solution cooled with ice, hydrolyzed with 250 μg / ml RNase (type 1-A: Sigma Chem. Co.) at 37 ° C. for 30 minutes and stained with propidium iodide at 10 mg / ml for 20 minutes. After the incubation period, the number of cells is determined by counting the cells in a Coulter counter and by SRB colorimetric assay. Under these conditions the compounds of formula 1 inhibit the proliferation of tumor cells at concentrations ranging from 10"12 to 10" 6M. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light of them will be suggested to persons skilled in the art and will be included within the spirit and understanding of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference for all purposes.

Claims (12)

1. CLAIMS A compound of the formula I: wherein: n is chosen from 0, 1 and 2; m is chosen from 1, 2 and 3; R is chosen from aryl of 6 to 10 carbon atoms and heteroaryl of 5 to 10 carbon atoms; wherein any of aryl or heteroaryl of R1 is optionally substituted by a radical selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms or alkyl of 1 to 10 carbon atoms; wherein any of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups of R 1 can be optionally substituted by 1 to 5 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; and any alkyl group of R ,, may optionally have a methylene replaced by a chosen atom or group of -S-, -S (O) -, -S (O) 2-, -NR4- and -O-; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R2 and are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, halogen, hydroxy, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; A is chosen from -X1C (O) OR4, -X1OP (O) (OR4) 2, -X1P (O) (OR4) 2) -X? P (O) OR4, -X1S (O) 2OR4l -X1P (O ) (R4) OR4 and 1 H-tetrazol-5-yl; wherein X - is a bond or alkylene of 1 to 6 carbon atoms and R is selected from hydrogen and alkyl of 1 to 6 carbon atoms; W is chosen from a bond, alkylene of 1 to 6 carbon atoms and alkenylene of 2 to 6 carbon atoms; X is selected from alkylene of 2 to 4 carbon atoms and alkenylene of 2 to 4 carbon atoms; wherein a methylene group of X can be replaced with a selected atom or group e -O-, -S-, -S (O) -, -S (O) 2-, and -NR5-; wherein R5 is hydrogen, alkyl of 1 to 6 carbon atoms and -C (O) R6; wherein R6 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; wherein any of alkylene or alkenylene of X may further be substituted by 1 to 3 radicals selected from the group consisting of halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms substituted by halogen and alkoxy of 1 to 10 carbon atoms substituted by halogen; Y is chosen from aryl of 6 to 10 carbon atoms and heteroaryl of 5 to 10 carbon atoms, wherein any aryl or heteroaryl of Y can optionally be substituted with 1 to 3 radicals chosen from halogen, hydroxy, nitro, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; Z is alkylene of 1 to 6 carbon atoms; wherein up to two methylene groups of Z can be replaced with divalent radicals selected from -NR7-, cycloalkylene of 3 to 8 carbon atoms, heterocycloalkylene of 3 to 8 carbon atoms and phenylene; wherein R7 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and (CH2) 1-2COOH; wherein Z can further be substituted by 1 to 3 radicals chosen from halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen and alkoxy of 1 to 6 carbon atoms substituted by halogen; or when -NR7-replaces at least one methylene group of Z, R7 and Y together with the nitrogen atom to which R7 is attached, forms a heteroarylene of 8 to 14 carbon atoms; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of their isomers; and the pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof.
2. 2. The compound according to claim 1, wherein n is 0 or 1 and Z is selected from: "N? 'N * N RT * r •• R? RT Ry •' NN ^ '^ Il • • NN '' VV l * 'N'V R7FF R, O ^ H ^ * - *' R7 OHH wherein the left and right asterisks of Z indicate the point of attachment between the group - [C (R2) (R3)] n- and A of Formula I, respectively; R7 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; and J ,, J2 and J3 are independently methylene or a heterogeneous atom selected from the group consisting of S, O and NR; wherein R is hydrogen or alkyl of 1 to 6 carbon atoms; as long as the number of heterogeneous atoms is 2 or less.
3. The compound according to claim 1, wherein Ri is selected from phenyl, naphthyl and thiophenyl optionally substituted by aryl of 1 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms carbon-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, or alkyl of 1 to 10 carbon atoms; wherein any of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R 1 can optionally be substituted by 1 to 5 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 atoms of carbon substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; and any alkyl group of R optionally may have a methylene replaced by a chosen atom or group of -S-, -S (O) -, -S (O) 2-, -NR4- and -O-; wherein R 4 is hydrogen or alkyl of 1 to 6 carbon atoms.
4. 4. The compound according to claim 1, wherein And it is chosen from phenyl, pyridine, pyrimidine, thiophene, furan, thiazole and oxazole; each of which can optionally be substituted with 1 to 3 radicals chosen from halogen, hydroxy, nitro, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen.
5. 5. The compound according to claim 1, wherein R2 and R3 are both hydrogen and A is chosen from -C (O) OR and 1H-tetrazole-5i or lo; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms.
6. 6. The compound according to claim 1, wherein Ri is selected from: wherein the asterisk is the junction point of R1 with X; Rg is aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms or alkyl of 1 to 10 carbon atoms; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R9 can optionally be substituted by 1 to 3 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 atoms of carbon substituted by halogen and alkoxy of 1 to 10 carbon atoms substituted by halogen; and any alkyl group of R9 may optionally have a methylene replaced by a chosen atom or group of ~ S-, -S (O) -, -S (O) 2-, -NR4- and -O-; wherein R10 is hydrogen or alkyl of 1 to 6 carbon atoms; and R-n is selected from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen.
7. 7. The compound according to claim 1, selected from: 3- acid. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetra-idro-naphthalen-2-ylmethyl] -amino} -propionic; 1- [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { [6-chloro-4- (4-cyclohexyl-3-trifluoromethi-benzyloxyimino) -chroman-7-ylmethyl] -amino} - propionic; acid 3-. { [3-chloro-5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -amino} -propionic; 1- [3-Chloro-5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; 1- [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3-methoxy-5,6,7,8-tetrahydro-n-afta I in -2-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; acid 3-. { [8- (4-Cyclohexyl-3-tri-fluoro-methyl-benzyloxyimino) -5,6,7,8-tetrahydro-quinolin-3-ylmethyl] -amino} -propionic; 1- [8- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-quinolin-3-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { 4- [5- (4-cyclohexyl-3-trifluoromethyl-benzyloxy-amino) -5,6,7,8-tetrahydro-naphthalen-2-yl] -piperazin-1-yl} -propionic; acid 3-. { [1- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -indan-5-ylmethyl] -amino} -propionic; 1- [8- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -zetidin-3-carboxylic acid; acid 3-. { [8- (4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; acid 3-. { [5- (4-cyclohexyl-3-trifluoromethyl-benzylxyimino) -3-ethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl] -amino} -propionic; acid 3-. { [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -chroman-6-ylmethyl] -amino} -propionic; acid 3-. { [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -chroman-7-ylmethyl] -amino} -propionic; 1- [4- (4-cyclohexyl-3-trifluoromethylbenzyloxyimino) -chroman-7-ylmethyl] -zetidine-3-carboxylic acid; acid 3-. { [4- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -3,4-dihydro-2H-pyrano [2,3-b] pyridin-7-ylmethyl] -amino} ~ propionic; 1- [4- (4-Cyclohexyl-3-tr-fluoro-methyl-benzyloxyamino) -3,4-dihydro-2H-p-pyrano [2,3-b] pyridin-7-ylmethyl] -azetic acid d-n-3-carboxylic acid; 1- [4- (4-cyclohexyl-3-methylbenzyloxyimino) -chroman-7-ylmethyl] -zetidin-3-carboxylic acid; and acid 3-. { [4- (4-cyclohexyl-3-methyl-benzyloxyimino) -chroman-7-ylmethyl] -amino) -propionic acid.
8. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.
9. 9. A method for treating a disease in an animal wherein the alteration of the signal transduction mediated by the EDG / S1P receptor can prevent, inhibit or mitigate the pathology and / or symptomatology of the disease, the method comprises administering to the animal a Therapeutically effective amount of a compound of claim 1.
10. 10. A method for preventing or treating disorders or diseases mediated by lymphocytes, for treating acute or chronic transplant rejection or inflammatory or autoimmune diseases, for inhibiting or controlling poorly regulated angiogenesis, or for treating diseases mediated by a process of neo-angiogenesis or associated with poorly regulated angiogenesis, in a subject, comprising administering to the subject with the need thereof, an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof .
11. The use of a compound according to claim 1, in the manufacture of a medicament for treating a disease in an animal, in which the alteration of the signal transduction mediated by the EDG / S1P receptor contributes to the pathology and / or symptomatology of the disease.
12. 12. A process for preparing a compound of Formula I: wherein: n is chosen from 0, 1 and 2; m is chosen from 1, 2 and 3; R ?, is selected from aryl of 6 to 10 carbon atoms and heteroaryl of 5 to 10 carbon atoms; wherein either aryl or heteroaryl of R is optionally substituted by a radical selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 6 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms or alkyl of 1 to 10 carbon atoms; wherein any of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups of R 1 can be optionally substituted by 1 to 5 radicals chosen from halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; and any alkyl group of R-i, may optionally have a methylene replaced by a chosen atom or group of -S-, -S (O) -, -S (O) 2-, -NR4- and -O-; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R2 and are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, halogen, hydroxy, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms. carbon substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; A is chosen from -X1C (O) OR4, -X1OP (O) (OR4) 2, -X1P (O) (OR4) 2, -X1P (O) OR4, -X1S (O) 2OR4, -X! P (O) (R4) OR4 and 1 H-tetrazol-5-yl; wherein X-i is a bond or alkylene of 1 to 6 carbon atoms and R is selected from hydrogen and alkyl of 1 to 6 carbon atoms; W is chosen from a bond, alkylene of 1 to 6 carbon atoms and alkenylene of 2 to 6 carbon atoms; X is selected from alkylene of 2 to 4 carbon atoms and alkenylene of 2 to 4 carbon atoms; wherein a methylene group of X can be replaced with a selected atom or group e -O-, -S-, -S (O) -, -S (O) 2-, and -NR5-; wherein R5 is hydrogen, alkyl of 1 to 6 carbon atoms and -C (O) R6; wherein R6 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; wherein any of alkylene or alkenylene of X may further be substituted by 1 to 3 radicals selected from the group consisting of halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms substituted by halogen and alkoxy of 1 to 10 carbon atoms substituted by halogen; Y is chosen from aryl of 6 to 10 carbon atoms and heteroaryl of 5 to 10 carbon atoms, wherein any aryl or heteroaryl of Y can optionally be substituted with 1 to 3 radicals chosen from halogen, hydroxy, nitro, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with halogen and alkoxy of 1 to 10 carbon atoms substituted with halogen; Z is alkylene of 1 to 6 carbon atoms; wherein up to two methylene groups of Z can be replaced with divalent radicals selected from -NR7-, cycloalkylene of 3 to 8 carbon atoms, heterocycloalkylene of 3 to 8 carbon atoms and phenylene; wherein R7 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and (CH2) 1-2COOH; wherein Z can additionally be substituted by 1 to 3 radicals chosen from halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen and alkoxy of 1 to 6 carbon atoms substituted by halogen; or when -NR7-replaces at least one methylene group of Z, R7 and Y together with the nitrogen atom to which R7 is attached, forms a heteroarylene of 8 to 14 carbon atoms; said process comprises: (a) reacting a compound of formula 2; with a compound of formula 3: W-R-, H2N-O (3) wherein A, W, X, Y, Z, Ri, R2) R3 and n are as defined for Formula I above; and (b) optionally converting a compound of the invention to a pharmaceutically acceptable salt.; (c) optionally converting a salt form of a compound of the invention to a non-salt form; (d) optionally converting a non-oxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the invention to its non-oxidized form; (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers; (g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable derivative pro-drug; and (h) optionally converting a pro-drug derivative of a compound of the invention to its non-derivatized form.