RU2588141C2 - 2-methoxy-pyridin-4-yl derivatives - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula (I)

having activity on S1P1/EDG1 receptor, pharmaceutical compositions based thereon, as well as to use of compounds for preparing pharmaceutical composition for preventing or treating diseases or disorders associated with activated immune system.

EFFECT: novel pyridine derivatives, as well as pharmaceutical compositions based thereon, which are suitable for treating diseases associated with activated immune system.

24 cl, 4 tbl, 69 ex

Description

FIELD OF THE INVENTION

The present invention relates to agonists of the S1P1 / EDG1 receptor of formula (I), and to their use as active components in the preparation of pharmaceutical compositions. The invention also relates to related aspects, including methods for preparing compounds, pharmaceutical compositions containing a compound of formula (I), and their use as vascular function enhancing compounds and as immunomodulating agents, alone or in combination with other active compounds or types of therapy .

BACKGROUND OF THE INVENTION

The human immune system is designed to protect the body from foreign microorganisms and substances that cause infection and disease. Sophisticated regulatory mechanisms ensure that the immune response is directed to the invading substance or organism, rather than to the host. In some cases, these control mechanisms become deregulated and autoimmune reactions may develop. An uncontrolled inflammatory response results in severe damage to an organ, cell, tissue, or joint. During treatment, suppression of the entire immune system usually occurs and the body's ability to respond to infections is also significantly reduced. Typical drugs of this class include azathioprine, chlorambucil, cyclophosphamide, cyclosporine, or methotrexate. Corticosteroids, which reduce inflammation and suppress the immune response, can cause side effects when used for treatment for a long time. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain and inflammation, however, they show significant side effects. Alternative treatments include agents that activate or block the cytokine signaling pathway.

Oral active compounds with immunomodulating properties, not suppressing immune responses and having weakened side effects, will significantly improve current treatments for deregulated inflammatory diseases.

In the field of organ transplantation, in order to prevent organ rejection, the host's immune response must be suppressed. Transplant organ recipients may experience some rejection even if they are not receiving immunosuppressive drugs. Most often, rejection occurs during the first few weeks after transplantation, but cases of rejection can also occur within months or even years after transplantation. Combinations of up to three or four drugs are usually used to provide maximum protection against rejection while minimizing side effects. Standard drugs currently used to treat rejection of transplanted organs affect individual intracellular activation pathways of type T or type B leukocytes. Examples of such drugs are cyclosporine, daclizumab, basiliximab, everolimus, or FK506, which inhibit cytokine release or inhibit corresponding signaling path; azathioprine or leflunomide, which inhibit nucleotide synthesis; or 15-deoxyspergualin, an inhibitor of leukocyte differentiation.

The beneficial effect of non-specific immunosuppressive types of therapy is associated with their actions; however, the general suppression of immunity that these drugs carry out reduces the protective response of the immune system to infection or malignant neoplasms. In addition, standard immunosuppressive drugs are often used in high doses and can cause or accelerate organ damage.

Description of the invention

The present invention provides new compounds of formula (I), which are agonists of the G-protein-coupled receptor S1P1 / EDG1 and have a strong and long-lasting immunomodulatory effect, which is achieved by reducing the number of circulating and infiltrating T and B lymphocytes, without affecting the processes maturation, memory, or growth of lymphocytes. A decrease in circulating T- / B-lymphocytes due to S1P1 / EDG1 agonism, possibly in combination with the observed improvement in the functioning of the endothelial layer of cells associated with activation of S1P1 / EDG1, makes such compounds useful in the treatment of uncontrolled inflammatory diseases and in improving vascular function. Prior art document WO 2008/029371 (document D1) discloses compounds that act as S1P1 / EDG1 receptor agonists and exhibit immunomodulatory effects, as described above. Unexpectedly, it was found that the compounds of the present invention have a reduced potential to compress tissue of the respiratory tract / blood vessels in comparison with the corresponding analogues, generally stated in the document of the prior art D1. Therefore, the compounds of the present invention demonstrate superiority with respect to their safety profile, for example, a lower risk of bronchoconstriction.

Compounds generally claimed in D1 (compounds 1-4, 7 and 10) and compounds 5, 6, 8, 9 and 11, which can be considered as close analogues of examples 1-4, 7, 45, 5, 6, 35, 41 and 50, respectively, are shown in Figure 1.

Figure 1: Structures of compounds that are close analogs of the compounds of the present invention.

The data on narrowing of the rat tracheal ring, summarized in table 1, illustrates the superiority of the compounds of the present invention compared with compounds falling within the scope of the prior art D1.

For example, the compounds of examples 1 and 2 of the present invention show a significantly reduced potential for narrowing the rat tracheal ring compared to their close counterparts, compound 1 and compound 2, respectively, the above analogs fall within the scope of document D1. While Compound 1 and Compound 2 both show a significant narrowing of the rat trachea at a concentration of 30 nM, the compounds of Examples 1 and 2 show a similar effect only at a concentration 10 times higher. Similarly, the compounds of examples 3 and 4 of the present invention show a significantly reduced potential narrowing of the rat tracheal ring compared to their close analogues, compound 3 and compound 4, respectively, the above analogs fall within the scope of document D1. While Compound 3 and Compound 4 both show significant narrowing of the rat trachea at a concentration of 10 μM, the compounds of Examples 3 and 4 do not initiate any narrowing to a concentration of 30 μM. The concept of the present invention is further supported by the compounds of Examples 5 and 6. The compounds of Examples 5 and 6 clearly show a reduced potential to narrow rat tracheal rings compared to their respective counterparts, compound 5 and compound 6, respectively. Compound 6, for example, narrows rat tracheal rings already at a concentration of 10 nM, while the compound of Example 6 shows a comparable effect at only 300 nM. The compound of example 7 shows a significant narrowing at a concentration of only 1 μM, while its close analogue, generally stated in D1, compound 7, significantly narrows the tracheal rings at 100 nM. At a concentration of 100 nM, the compound of Example 50 leads to a narrowing of the trachea, comparable to that induced by 50 mM KCl. A comparable narrowing is observed with compound 11 already at 10 nM. The examples discussed so far all have a methyl-ethyl substitution scheme on the phenyl ring. The following examples demonstrate that the concept of reduced potential to narrow rat tracheal rings extends to compounds with other substitution patterns on the phenyl ring. For example, compound 9, including a chloromethyl substitution scheme on the phenyl ring, shows a significant narrowing of the trachea at concentrations of 10 and 30 nM, while the compound of Example 41 of the present invention does not show at all or shows only a slight narrowing at these concentrations. Similarly, a complete narrowing of the trachea compared to 50 mM KCl is observed at a concentration of 1 μM of compound 10, while the compound of Example 45 shows a significant narrowing of the trachea only at 10 μM. Examples of the inclusion of a chloromethoxy phenyl ring substitution scheme show the same behavior. As indicated previously, the methoxy-pyridine compounds of the present invention (e.g., the compound of Example 35) show a reduced potential to narrow rat tracheal rings compared to their nearest methyl-pyridine analogs (e.g., compound 8). The compound of example 54 means the oxadiazole isomer of example 6. As shown in table 1, these two compounds have almost the same potential to narrow the trachea of the beauty, demonstrating that the nature of oxadiazole does not affect this property of a particular compound.

Taken together, the data presented in table 1 clearly demonstrate that the 2-methoxy-pyridine derivatives of the present invention are superior to the corresponding 2-methyl-pyridine analogues, regardless of the nature of A and the substituents R ² , R ³ and R ⁴ in the formula (I) ( see below).

The compounds of the present invention can be used alone or in combination with standard drugs that inhibit T-cell activation, providing a new immunomodulating therapy with a reduced susceptibility to infections compared with standard immunosuppressive therapy. In addition, the compounds of the present invention can be used in combination with reduced doses of traditional immunosuppressant drugs, providing, on the one hand, an effective immunomodulatory effect, and, on the other hand, reducing receptor damage associated with high doses of standard immunosuppressant drugs. The observed improvement in the functioning of the endothelial cell layer associated with activation of S1P1 / EDG1 provides additional benefits of the compounds for improving vascular function.

The nucleotide sequence and amino acid sequence of the human S1P1 / EDG1 receptor are known in the art and are published, for example, in: Hla T., and Maciag T., J. Biol Chem. 265 (1990), 9308-9313; WO 91/15583, publ. October 17, 1991; WO 99/46277, publ. September 16, 1999. The efficacy and effectiveness of the compounds of formula (I) is evaluated using GTP _Y S analysis to determine EC ₅₀ values and by measuring the number of circulating lymphocytes in rats after oral administration, respectively (see experimental part).

i) In a first embodiment, the invention relates to pyridine compounds of the formula (I),

wherein

A means

in which the asterisks indicate a bond that is attached to the pyridine group of the formula (I);

R ¹ means cyclopentyl;

R ² means methyl, and R ⁴ means ethyl or chlorine; or

R ² means methoxy, and R ⁴ means chlorine;

R ³ means —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH2OH, —OCH ₂ - (CH ₂ ) _n —NH- ( CH ₂ ) _m —COOH, —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) - (CH ₂ ) _m —COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] -ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidin-3-carboxylic acid) - 1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2 -hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH ( OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH , -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _n COOH, -OCH ₂ - (CH2) _n —N (CH ₃ ) —CO — CH ₂ OH, —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ COOH, or —OCH ₂ - (CH2) _n —N (CH ₃ ) -CO-CH ₂ CH ₂ COOH;

n independently is 1 or 2;

m independently means 1, 2 or 3; and

k means 1 or 2, as, for example, especially 2.

ii) Another embodiment of the invention relates to pyridine derivatives in accordance with embodiment i), wherein the stereo center R ^{3 of} group 2 is [(pyrrolidin-3-carboxylic acid) - 1-yl] ethoxy, 3 - [(pyrrolidin-3- carboxylic acid) -1-yl] propoxy, -O-CH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) - 1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, —OCH ₂ CH (OH) —CH ₂ NH — CH (CH ₂ OH) 2, and —OCH ₂ CH (OH) —CH ₂ NH — CO— (CH ₂ ) _n COOH is in the S configuration.

iii) Another embodiment of the invention relates to pyridine derivatives in accordance with Embodiment i), wherein the stereo center R ^{3 of} group 2 is [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(pyrrolidin-3- carboxylic acid) -1-yl] -propoxy, -O-CH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, OCH ₂ CH _{2 2} SNSON MH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl ] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, - OCH ₂ CH (OH) —CH ₂ NH — CH (CH ₂ OH) ₂ , and —OCH ₂ CH (OH) —CH ₂ NH — CO— (CH ₂ ) ₂ COOH is in the R configuration.

iv) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to iii), where A is

in which the asterisks indicate a bond that is attached to the pyridine group of the formula (I).

v) Another embodiment of the invention relates to pyridine derivatives in accordance with any one of options i) -iii), where A means

where the asterisk indicates a bond that is attached to the pyridine group of formula (I).

vi) Another embodiment of the invention relates to pyridine derivatives according to any one of i) to iii), wherein A is

vii) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to vi), where R ² is methyl and R ⁴ is ethyl or chlorine.

viii) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to vi), where R ² is methyl and R ⁴ is ethyl.

ix) Another embodiment of the invention relates to pyridine derivatives according to any one of i) to vi), wherein R ² is methoxy and R ⁴ is chlorine.

x) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to ix), where R ³ is —CH ₂ COOH, —CH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - ( CH ₂ ) _m -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidine -3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (C H ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH2OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH-CO-CH2OH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH, - OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _n COOH, -OCH ₂ - (CH ₂ ) _n - N (CH ₃ ) —CO — CH ₂ OH, —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ COOH, or —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) -CO-CH ₂ CH ₂ COOH.

xi) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to ix), where R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - ( CH ₂ ) _m -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrole idin-3-carboxylic acid) -1-yl] ethoxy, 3 - [( azetidin-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, -O-CH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃₎ -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylate Separated acid) -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1-yl] propoxy, -OCH ₂ - (CH _{2) n} -NH- CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, - OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -O-CH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH —CO — CH ₂ OH, or —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ OH.

xii) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to ix), where R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - ( CH ₂ ) _m -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidine -3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 2- hydra hydroxy-3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH -CH (CH ₂ OH) ₂ , -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -O-CH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , - OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -O-CH ₂ CH (OH) -CH ₂ NH —CO— (CH ₂ ) _n COOH, —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ COOH, or —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO -CH ₂ CH ₂ COOH.

xiii) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to ix), where R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] propoxy, -OCH ₂ CH (OH ) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1- yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -CH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH — CO— (CH ₂ ) _n COOH, —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ COOH, or —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) -CO-CH ₂ CH ₂ COOH.

xiv) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to ix), where R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl ] -ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] propoxy, or 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy.

xv) Another embodiment of the invention relates to pyridine derivatives according to any one of options i) to ix), where R ³ is —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, - OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -O-CH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, or -O-CH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ .

xvi) Another embodiment of the invention relates to pyridine derivatives according to any one of embodiments i) to xiv), where m is 1 or 2.

xvii) Another embodiment of the invention relates to pyridine derivatives according to any one of embodiments i) to xvi), where n is 1.

xviii) Another embodiment of the invention relates to pyridine derivatives according to embodiment i), where

A means

where the asterisk indicates a bond that is attached to the pyridine group of the formula (I);

R ¹ means cyclopentyl;

R ² means methyl, and R ⁴ means ethyl or chlorine; or

R ² means methoxy, and R ⁴ means chlorine; and

R ³ means —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH2OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _1-2 —NH - (CH ₂ ) _1-2 —COOH, —OCH ₂ —CH ₂ —NH— (CH ₂ ) ₃ —COOH, —OCH ₂ - (CH ₂ ) _1-2 —N (CH ₃ ) - (CH ₂ ) _1-2 -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidine- 3-carboxylic acid) -1-yl] propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _{1- 2-} NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ₂ CH ( OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH _{2) 2} -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _1-2 COOH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ COOH, or -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ CH ₂ COOH.

xix) Another embodiment of the invention relates to pyridine derivatives according to Embodiment i), wherein

R ³ means —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _1-2 -NH- (CH ₂ ) _1-2 -COOH, -OCH ₂ -CH ₂ -NH- (CH ₂ ) ₃ -COOH, -OCH ₂ - (CH ₂ ) _1-2 -N (CH ₃ ) - (CH ₂ ) _1-2 -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [( azetidine-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, - OCH ₂ CH (OH) —CH ₂ N (CH ₃ ) —CH ₂ COOH, —OCH ₂ CH (OH) —CH ₂ N (CH ₃ ) —CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ( CH ₂ OH) ₂ , —OCH ₂ - (CH ₂ ) _1-2 —NH — CH ₂ CH (OH) —CH ₂ OH, —OCH ₂ CHCH ₂ CH ₂ MH — CH ₂ CH ₂ OH, —OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH _{2) 1-2} COOH, -OCH ₂ - (CH _{2) 2} -N (CH ₃ ) -CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ COOH, or -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO- CH ₂ CH ₂ COOH.

The compounds of formula (I) may contain one or more stereogenic centers or centers of asymmetry, such as one or more asymmetric carbon atoms. The compounds of formula (I) may thus be present as a mixture of stereoisomers or, preferably, as pure stereoisomers. Mixtures of stereoisomers can be separated by a method known to a person skilled in the art.

It is understood that the plural form used in relation to compounds, salts, pharmaceutical compositions, diseases and the like, also means a single compound, salt or the like.

Any reference above or below to the compound of formula (I) should be understood as also referring to salts, especially pharmaceutically acceptable salts of the compounds of formula (I), as necessary and appropriate.

The term "pharmaceutically acceptable salts" refers to non-toxic addition salts of inorganic or organic acids and / or bases. Reference may be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The present invention also includes compounds of formula (I) labeled with isotopes, especially labeled with ² N (deuterium), where these compounds are identical to compounds of formula (I), except that one or each of several atoms is replaced by an atom that has the same atomic number, but whose atomic mass differs from the atomic mass usually found in nature. Isotopically labeled, especially labeled with ² H (deuterium) compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavy ² H isotope (deuterium) can lead to greater metabolic stability, leading, for example, to an increase in half of the half-life in vivo or a decrease in the required dosage, or may lead to a decrease in the inhibition of the cytochrome P450 enzyme, leading, for example, to an improved safety profile. In one embodiment, the compounds of formula (I) are not labeled isotopes, or they are labeled with only one or more deuterium atoms. In a variant embodiment, the compounds of formula (I) are not completely labeled isotopes. Isotope-labeled compounds of formula (I) can be prepared by analogy with the methods described below, but using a suitable isotopic variant of suitable reagents or starting materials.

Examples of pyridine compounds in accordance with formula (I) are selected from:

3- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -propionic acid,

1- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethyl) -azetidine-3-carboxylic acid,

(S) -1- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -3- (2-hydroxy-ethylamino) -propan-2-ol,

2 - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6 -methyl-phenoxy} -2-hydroxy-propylamino) propane-1,3-diol,

{4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} -acetic acid,

4- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} oil acid,

(2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} - ethylamino) -acetic acid,

1- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethyl) -pyrrolidine-3-carboxylic acid,

((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl -phenoxy} -2-hydroxy-propylamino) -acetic acid,

3 - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6 -methyl-phenoxy} -2-hydroxy-propylamino) propionic acid,

[((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6- methyl-phenoxy} -2-hydroxy-propyl) methyl-amino] -acetic acid,

1 - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6 -methyl-phenoxy} -2-hydroxy-propyl) -azetidine-3-carboxylic acid,

2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} -N - (2-hydroxy-ethyl) -acetamide,

semi-amide N - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl- 6-methyl-phenoxy} -2-hydroxy-propyl) -malonic acid,

semi-amide N - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl- 6-methyl-phenoxy} -2-hydroxy-propyl) succinic acid,

[(2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} ethyl) methyl methyl] acetic acid,

3 - [(2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} ethyl) methyl] amino] propionic acid,

(3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} - propylamino) acetic acid

3- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propylamino) -propionic acid,

[(3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} -propyl) methyl-amino] -acetic acid,

3 - [(3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -propyl) methyl-amino] propionic acid,

1- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propyl) -azetidine-3-carboxylic acid,

2- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -ethanol,

2- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } propylamino) ethanol,

2- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -propane-1,3-diol,

2- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propylamino) -propane-1,3-diol,

3- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -propan-1,2-diol,

3- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propylamino) -propan-1,2-diol,

N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propyl) -2-hydroxy-acetamide,

N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propyl) -2-hydroxy-N-methyl-acetamide,

N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} propyl) malonic acid,

N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} propyl) succinic acid,

N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -propyl) -N-methyl-malonic acid,

N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -propyl) -N-methyl-succinic acid,

4- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy} -based acids

4- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy} -N - (2-hydroxy-ethyl) -butyramide,

3- (2- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy } -ethylamino) -propionic acid,

N- (3- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy } -propyl) -2-hydroxy-acetamide,

4 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) butanoic acid, and

4- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) butanoic acid.

Additional examples of pyridine compounds in accordance with formula (I) are selected from:

2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) acetic acid,

2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methyl-phenoxy) -M- (2 -hydroxyethyl) acetamide,

3 - ((2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) amino ) propanoic acid,

1- (2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

2 - ((2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) amino ) ethanol

4- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N- (2-hydroxyethyl ) butanamide,

(S) -3 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) propanoic acid,

(R) -3 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) propanoic acid,

3 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) -3-oxopropanoic acid,

4 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) -4-oxobutanoic acid,

2 - ((2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) amino ) acetic acid

1- (2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) azetidine- 3-carboxylic acid

2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) acetic acid,

4- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) butanoic acid,

2 - ((2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) acetic acid

2 - ((2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) ( methyl) amino) acetic acid,

3 - ((2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid,

1- (2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

2 - ((3- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) acetic acid

2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) acetic acid,

4- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) butanoic acid,

3 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid,

1- (2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

(S) -1- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) -3- ((2-hydroxyethyl) amino) propan-2-ol,

(S) -2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) propane-1,3-diol, and

(S) -4 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) -4-oxobutanoic acid.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical compositions for enteral (such as, for example, especially oral) or parenteral (including topical or inhalation) administration, which are suitable for reducing the number of circulating lymphocytes and for the prevention and / or treatment of diseases or disorders associated with an activated immune system.

Pharmaceutical compositions can be prepared in a manner familiar to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st edition (2005), part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by introducing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenic dosage form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid substances - n carriers and, if necessary, conventional pharmaceutical excipients.

Pharmaceutical compositions containing a compound of formula (I) are useful for preventing and / or treating diseases or disorders associated with an activated immune system.

Such diseases or disorders associated with the activated immune system and to be prevented / treated by the compounds of formula (I), for example, are selected from the group consisting of rejection of transplanted organs, tissue or cells; graft versus host reactions caused by transplantation; autoimmune syndromes, including rheumatoid arthritis; systemic lupus erythematosus; antiphospholipid syndrome; thyroiditis Hashimoto; lymphocytic thyroiditis; multiple sclerosis; severe myasthenia gravis; type I diabetes; uveitis; episcleritis; scleritis; Kawasaki disease, uveoretinitis; back (lumbar) uveitis; uveitis associated with Behcet's disease; uveomeningial syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases, including rheumatic fever and post-infectious glomerulonephritis; inflammation and hyperproliferative skin diseases; psoriasis; psoriatic arthritis; atopic dermatitis; myopathy myositis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrheic dermatitis; lichen planus; pemphigus; bullous pemphigoid; congenital bullous epidermolysis; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; scleroderma; alopecia areata; keratoconjunctivitis; spring conjunctivitis; keratitis; herpetic keratitis; epithelial dystrophy of the cornea of the eyes; cornea leukomas; ophthalmic pemphigus; Morena's ulcers; ulcerative keratitis; scleritis; Graves Ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; hay fever; reversible obstructive airways disease; bronchial asthma; allergic asthma; hereditary bronchial asthma; acquired bronchial asthma; asthma caused by dust; chronic or advanced asthma; late asthma and hypersensitivity of the respiratory tract; bronchiolitis; bronchitis; endometriosis; orchitis stomach ulcers; ischemic bowel disease; inflammatory bowel disease; necrotizing enterocolitis; pathological changes in the intestine associated with thermal burns; celiac disease; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; damage to blood vessels caused by ischemic diseases and thrombosis; atherosclerosis; heart obesity; myocarditis; myocardial infarction; aortitis; cachexia due to a viral disease; vascular thrombosis; migraine; rhinitis; eczema interstitial nephritis; lgA-induced nephropathy; Goodpasture syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; tubulointerstitial nephritis; interstitial cystitis; dermatomyositis; Guillain-Barré syndrome; Meniere's disease; polyneuritis; multiple polyneuritis; myelitis; mononeuritis; radiculopathy; hyperthyroidism; bazedovoy disease; thyrotoxicosis; true red blood cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; fibroids of the lungs; idiopathic interstitial pneumonia; dermatomyositis; ordinary leukoderma; ordinary ichthyosis; photoallergic sensitivity; cutaneous T-cell lymphoma; nodose polyarteritis; Huntington's chorea; Sydenham's chorea; myocardosis myocarditis; scleroderma; Wegener granulomas; Sjogren's syndrome; adiposis; eosinophilic fasciitis; damage to the gums, periodontal, alveolar bone, dental cement; alopecia (male type) or senile; muscular dystrophy; pyoderma; Cesari's syndrome; pituitary gland; chronic adrenal insufficiency; Addison's disease; organ damage during ischemia / secondary perfusion after storage; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal failure; chronic renal failure; lung cancer malignant neoplasms of lymphoid origin; acute or chronic lymphocytic leukemia; lymphomas pulmonary emphysema; cataracts; siderosis; retinitis pigmentosa; senile macular degeneration; vitreous scarring; alkaline burn of the cornea of the eyes; dermatitis erythema; vesiculate dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis peripheral artery disease; carcinogenesis; solid tumors; carcinoma metastases; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial resection of the liver; acute liver necrosis; cirrhosis; alcoholic cirrhosis; liver failure; fulminant liver failure; late liver failure; and acute against a background of chronic liver failure.

Preferred diseases or disorders to be treated and / or prevented by the compounds of formula (I) are selected from the group consisting of rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft versus host reactions caused by stem cell transplantation; autoimmune syndromes, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, psoriatic arthritis, thyroiditis, such as Hashimoto's thyroiditis, uveoretinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma type I diabetes; post-infectious autoimmune diseases, including rheumatic fever and post-infectious glomerulonephritis; solid cancer and tumor metastases.

More preferred diseases or disorders to be treated and / or prevented by the compounds of formula (I) are selected from the group consisting of rejection of transplanted organs selected from the kidney, liver, heart and lung; graft versus host reactions caused by stem cell transplantation; autoimmune syndromes selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, and Hashimoto's thyroiditis; and atopic dermatitis. Particularly preferred diseases or disorders to be treated and / or prevented by the compounds of formula (I) are selected from multiple sclerosis and psoriasis.

The present invention also relates to a method for preventing or treating a disease or disorder mentioned in this application, comprising administering to a subject a pharmaceutically active amount of a compound of formula (I).

In addition, the compounds of formula (I) are also useful, in combination with one or more immunomodulatory agents, for the prevention and / or treatment of the diseases and disorders mentioned in this application. According to a preferred embodiment of the invention, the above agents are selected from the group consisting of immunosuppressants, corticosteroids, NSAIDs (non-steroidal anti-inflammatory drugs), cytotoxic drugs, adhesion molecule inhibitors, cytokines, cytokine inhibitors, cytokine receptor antagonists and recombinant receptors.

The present invention also relates to the use of a compound of formula (I) for the preparation of a pharmaceutical composition, optionally for use in combination with one or more immunomodulatory agents, for the prevention or treatment of the diseases and disorders mentioned in this application.

Compounds of formula (I) can be prepared by the methods described below, by the methods described in the examples, or by similar methods. The optimal reaction conditions may vary depending on the particular reagents or solvents used, however, such conditions can be determined by a person skilled in the art using conventional optimization techniques.

The compounds of formula (I) of the present invention can be obtained in accordance with the General reaction sequence outlined below. Only a few synthetic possibilities are described leading to the compounds of formula (I).

Compounds of formula (I), which are 5-pyridin-4-yl [1, 2, 4] oxadiazole derivatives, are prepared by the reaction of a compound of structure 1 in a solvent such as toluene, pyridine, DMF, THF, dioxane, DME and etc. at c.t. or elevated temperatures, in the presence or absence of excipients, such as acids (e.g. TFA, acetic acid, HCl, etc.), bases (e.g. NaH, NaOAc, Na ₂ CO ₃ , K ₂ CO ₃ , NEt ₃ etc.), tetraalkylammonium salts, or water-stripping agents (e.g. oxalyl chloride, carboxylic anhydride, POCl ₃ , PCl ₅ , P ₄ O ₁₀ , molecular sieves, Burgess reagent, etc.) (lit .: for example AR Gangloff, J. Litvak, E.J. Shelton, D. Sperandio, VR Wang, KD Rice, Tetrahedron Lett. 42 (2001), 1441-1443; T. Suzuki, K. Iwaoka, N. Imanishi, Y. Nagakura , K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem. Pharm. Bull. 47 (1999), 120-122; RF Poulain, AL Tartar, BP Deprez, Tetrahedron Lett. 42 (2001), 1495 -149 8; RM Srivastava, FJS Oliveira, DS Machado, RM Souto-Maior, Synthetic Commun. 29 (1999), 1437-1450; EO John, JM Shreeve, Inorganic Chemistry 27 (1988), 3100-3104; B. Kaboudin, K Navaee, Heterocycles 60 (2003), 2287-2292).

Compounds of structure 1 can be prepared by reacting a compound of structure 2 with a compound of structure 3 in a solvent such as DMF, THF, DCM, etc. in the presence of one or more combination agents, such as TBTU, DCC, EDC, HBTU, CDI, etc. and in the presence or absence of a base such as NEt ₃ , DIPEA, NaH, K ₂ CO ₃ , etc. (lit .: e.g., A. Hamze, J.-F. Hernandez, P. Fulcrand, J. Martinez, J. Org. Chem. 68 (2003), 7316-7321; and the literature cited above).

The compounds of formula (I), which are a derivative of 3-pyridin-4-yl- [1, 2, 4] oxadiazole, are obtained in a similar manner (lit .: for example, C.T. Brain, J.M. Paul, Y. Loong, PJ Oakley, Tetrahedron Lett. 40 (1999), 3275-3278) by reacting a compound of structure 4 with a compound of structure 5 and subsequent cyclization of the corresponding intermediate compound, a hydroxyamidine ester.

Compounds of structure 3 and 4 can be prepared by reacting compounds of structure 6 and 7, respectively, with hydroxylamine or one of its salts in a solvent such as MeOH, EtOH, pyridine, etc. in the presence or absence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , potassium tert-butylate, NEt ₃ , etc. (lit .: e.g., E. Meyer, A. C. Joussef, N. Gallardo, Synthesis 2003, 899-905, WO 2004/035538 (Merck & Co., Inc., USA)).

Depending on the nature of the functionalities present in residue R ³ in structures 3, 5 and 6, these functionalities may require temporary protection. Suitable protecting groups are known to those skilled in the art and include, for example, a benzyl or trialkylsilyl group for protecting the alcohol, a ketal for protecting the diol, etc. These protecting groups can be used in accordance with standard procedures (see, e.g., T.W. Greene, PGM. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley New York, 1991; PJ Kocienski, Protecting Groups, Thieme Stuttgart, 1994). Alternatively, the desired residues R ³ and R ⁴ , in particular R ³ , can also be introduced at later stages, which follow the combination of the pyridine compound of structure 2 or 4 with the phenyl derivatives of structure 3 or 5 by using a suitable precursor of the compound of structure 3 and 5 The desired R ³ residues may be introduced by a series of one or more alkylation, acylation and / or substitution reactions known to one skilled in the art. Phenyl compounds of structures 3, 5 and 6 or their precursors are either commercially available or prepared according to methods known to one skilled in the art.

Compounds of formula (I), which are 2-pyridin-4-yl- [1,3,4] oxadiazole, are prepared similarly by reacting a compound of structure 2 with hydrazine (using a coupling reagent such as TBTU, DCC, EDC, HBTU, RuBOP, CDI, etc.), with the formation of a compound of structure 8, which is then combined with a compound of structure 5 to obtain a compound of structure 9. The compound of structure 9 can also be obtained by carrying out the reactions in the reverse order, that is, primarily by combination of a compound of structure 5 with hydrazine followed by reaction respective intermediate - hydrazide with a compound of structure 2. Dehydration of a compound of structure 9 to give the desired 2-pyridin-4-yl- [1, 3, 4] oxadiazole derivative is performed by treating a compound of Structure 9 with a reagent such as POCl _3, CCl _4, or CBr ₄ in combination with PPh ₃ , P ₂ O ₅ , Burgess reagent, etc. in a solvent such as toluene, MeCN, dioxane, THF, CHCl ₃ , etc. at temperatures between 20 and 120 ° C in the presence or absence of microwave irradiation, (lit .: for example, M.A. Garcia, S. Martin-Santamaria, M. Cacho, F. Moreno de la Llave, M. Julian, A. Martinez, B. De Pascual-Teresa, A. Ramos, J. Med. Chem. 48 (2005), 4068-4075; CT Brain, JM Paul, Y. Loong, PJ Oakley, Tetrahedron Lett. 40 (1999), 3275 -3278).

Methods that enable the conversion of a compound of structure 2 or 5 to a compound of structure 7 or 6, respectively, or vice versa, are known to one skilled in the art.

Compounds of structure 2 can be prepared by reacting 2,6-dichloro-isonicotinic acid or its suitable ester derivative with methanol in the presence or absence of a base such as NaOH, NaOMe, potassium tert-butylate, etc. in a solvent such as methanol, THF, dioxane, etc. to obtain a compound of structure 10 (R = H or, preferably, Me, Et, tert-butyl, etc.) (lit .: for example, N. Wild, U. Groth, Eur. J. Org. Chem. 2003, 4445-4449). The compound of structure 10 can then be reacted with a cyclopentyl-Zn reagent under Negishi conditions (lit .: e.g., N. Matsushita, E. Negishi, J. Org. Chem. 47 (1982), 4161-4165), with a suitable cyclopentyl Grignard reagent, for example, in the presence of Fe (acac) ₃ , in a solvent such as THF, dioxane, DMF, NMP, etc., or combinations thereof, at a temperature in the range of -78 to 25 ° C under Fürstner conditions ( lit .: for example, A. Furstner, A. Leitner, M. Mendez, N. Krause, J. Am. Chem. Soc. 124 (2002), 13856-13863; A. Fürstner, A. Leitner, Angew. Chem. 114 (2002), 632-635) or with a cyclopentyl derivative or a derivative of 1-cyclopentenylboron (lit .: Imer, F. Kerins, DF O'Shea, J. Org. Chem. 67 (2002), 4968-4971) under the conditions of a combination of Suzuki (lit .: e.g. N. Doucet, Eur. J. Org. Chem. 2008, 2013-2030). If derivatives of 1-cyclopentenylboron are used to introduce the carbon skeleton of R ¹ , a subsequent hydrogenation step is required to form the target cyclopentyl group. In conclusion, when pyridine-4-carboxylic acid ester is used in the steps described above, hydrolysis of the ester under basic or acidic reaction conditions provides the desired compound of structure 2.

Whenever the compounds of formula (I) are obtained in the form of mixtures of enantiomers, enantiomers can be separated using methods known to those skilled in the art: for example, by forming and separating diastereomeric salts or by HPLC on a chiral stationary phase, such as a column Regis Whelk-O1 (R, R) (10 μm), Daicel ChiralCel OD-H column (5-10 μm), or Daicel ChiralPak IA (10 μm) or AD-H column (5 μm). Typical conditions for chiral HPLC are an isocratic mixture of eluent A (EUN, in the presence or absence of an amine, such as NEt ₃ , diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 ml / min.

experimental part

The following examples illustrate the invention, but do not in any way limit its scope.

All temperatures are in ° C. Compounds were characterized by ¹ H-NMR (300 MHz) or ¹³ C-NMR (75 MHz) (Varian Oxford; chemical shifts are given in ppm relative to the signals of the solvent used; multiplicity: s = singlet, d = doublet, t = triplet , p = pentuplet, hex = hexet, hept = heptet, m = multiplet, br = wide, interaction constants are given in Hz); LC-MS (Finnigan Navigator with a binary pump HP 1100 and DAD, column: 4.6 × 50 mm, Zorbax SB-AQ, 5 μm, 120 Å, gradient: 5-95% MeCN in water, 1 min, with 0.04% TFA, flow: 4.5 ml / min, t _{R is} given in min; retention times or LC-MS indicated by * refer to LC analysis under the following conditions: Waters Xbridge C18, 2.5 μm, 4.6 × 30 mm, gradient: 5-95% MeCN in water, 1 min, with 0.04% TFA, flow: 4.5 ml / min; retention times or LC-MS marked ∗∗ refer to LC analysis under the following conditions: column: Zorbax Extended C18, 1.8 μm, 4.6 × 20 mm, gradient: 5-95% MeCN in water, 1 min, with 0.04% TFA, flow: 4.5 ml / min); TLC (TLC plates from Merck, Silica gel 60 F ₂₅₄ ); or melting point. Compounds are purified using prep. HPLC (column: X-terra RP18, 50 × 19 mm, 5 μm, gradient: 10-95% MeCN in water containing 0.5% formic acid) or by HPLC (Labomatic MD-80-100 pump, UVIS- linear detector 201, column: 350 × 18 mm, Labogel-RP-18-5s-100, gradient: 10% MeOH in water - 100% MeOH).

Abbreviations (used here):

aq. water BSA bovine serum albumin Burgess reagent methoxycarbonylsulfamoyl triethylammonium hydroxide KX column chromatography Cdi carbonyl diimidazole DCC N, N′-dicyclohexyl carbodiimide DXM dichloromethane Dipa hüning base, diethylisopropylamine Dme 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1′-bis (diphenylphosphino) ferrocene EA ethyl acetate Edc N- (3-Dimethylaminopropyl) -N′-ethyl-carbodiimide Et ethyl EtOH ethanol Fbs fetal bovine serum Fe (acac) ₃ iron (III) acetylacetone complex FRET resonance fluorescence energy transfer h clock) HBTU hexafluorophosphate O- (benzotriazol-1-yl) -N, N, N ′, N′- tetramethyluronium Heps 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid Hobt 1-hydroxy-benzotriazole HPLC high performance liquid chromatography BB high vacuum LC-MS liquid chromatography - mass spectrometry Lit. literature Me methyl Mecn cetonitrile Meon methanol min minute (s) JHSD medium pressure liquid chromatography NaOAc sodium acetate Neaa minor amino acids NEt ₃ triethylamine Nmp 1-methyl-2-pyrrolidone org organic PEG polyethylene glycol PPh ₃ triphenylphosphine RuVOR hexafluorophosphate benzotriazol-1-yl-hydroxy-trispyrrolidinophosphonium teacher preparative ct room temperature sat. saturated S1p sphingosine 1-phosphate TVME tert-butyl methyl ether TBTU 2- (1H-benzotriazol-1-yl) -1,2,3,3- tetrafluoroborate tetramethyluronium t- tertiary Tfu trifluoroacetic acid THF tetra hydrophura n TLC thin layer chromatography t _R Hold Time

Preparation of Intermediates

2-cyclopentyl-6-methoxy-isonicotinic acid

a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 ml). The stirred mixture becomes warm (34 ° C) and then, before it is cooled to rt, it is heated to 70 ° C for 4 hours. The mixture is neutralized by adding 32% aq. HCl (100 ml) and 25% aq. HCl (700 ml). The mixture was stirred at rt. during the night. The white precipitate that forms is collected, washed with methanol and dried. The filtrate was evaporated and the residue was suspended in water (200 ml). The resulting mixture was heated to a temperature of 60 ° C. The solid is collected, washed with water and dried. The combined batches give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: t _R = 0.80 min, [M + 1] ⁺ = 187.93.

b) To a suspension of 2-chloro-6-methoxy-isonicotinic acid (244 g, 1.30 mol) in methanol (2.5 L) was added H ₂ SO ₄ (20 ml). The mixture, before it was cooled to 0 ° C, was stirred under reflux for 24 hours. The solid was collected, washed with methanol (200 ml) and water (500 ml) and dried in BB to give methyl ester 2 -chloro-6-methoxy-isonicotinic acid (165 g) as a white solid; LC-MS: t _R = 0.94 min, [M + 1] ⁺ = 201.89.

c) Under argon, Pd (dppf) (2.00 g, 2.4 mmol) was added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (32.0 g, 0.159 mol) in THF (100 ml). A 0.5 M solution of cyclopentylzinc bromide in THF (330 ml) was added through a dropping funnel. After complete addition, the mixture, before it is cooled to rt, is heated to a temperature of 85 ° C for 3 hours. The reaction mixture is concentrated, diluted with 1 N. aq. HCl (275 ml) and extracted with TBME (275 ml). Organic extract is washed with 1 N. aq. HCl (275 ml), filtered through celite and washed with water (275 ml). Org the extract was concentrated and dried to give crude 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (34.8 g) as a brown oil. This substance is dissolved in ethanol (180 ml), water (45 ml) and 32% aq. NaOH solution (45 ml). The mixture, before being cooled to rt, was stirred at 90 ° C for 30 minutes. Ethanol was evaporated and the remaining solution was diluted with water (150 ml) and extracted with DCM (200 ml). Vodn. the phase is acidified by adding 32% aq. HCl (45 ml), and then extracted twice with DCM (2 × 100 ml). Org extracts are combined and concentrated. The crude product is purified by crystallization from hot acetonitrile (174 ml). The crystalline substance is collected and dried at 50 ° C in BB. A second batch of crystalline material can be obtained from the mother liquor. The two batches are combined to give 2-cyclopentyl-6-methoxy-isonicotinic acid (24.1 g) as a pale gray crystalline powder; LC-MS: t _R = 0.93 min, [M + 1] ⁺ = 222.02; ¹ H NMR (CDCl ₃ ): δ 1.68-1.77 (m, 2 N), 1.81-1.90 (m, 4 N), 2.03-2.12 (m, 2 N), 3.15-3.25 (m, 1 N), 3.99 (s, 3 N), 7.18 (d, J = 1.0 Hz, 1 N), 7.35 (d, J = 0.8 Hz, 1 N).

2-Cyclopentyl-Y-hydroxy-6-methoxy-isonicotinamidine

a) A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (3.19 g, 13.6 mmol) in 7 N NH ₃ in methanol (50 ml) was stirred at 60 ° C for 18 hours. The solvent was removed in vacuo and the residue dried in BB to give crude 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g) as a pale yellow solid; LC-MS ∗∗: t _R = 0.57 min, [M + 1] ⁺ = 221.38.

b) Pyridine (8.86 g, 91.3 mmol) was added to a solution of 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g, 15.2 mmol) in DCM (100 ml). The mixture, before trifluoroacetic acid anhydride (9.58 g, 45.6 mmol) is added in portions, is cooled to 0 ° C. The mixture was stirred at 0 ° C for 1 h and then diluted with DCM (100 ml) and washed with sat. aq. NaHCO ₃ solution (100 ml) and brine (100 ml). Separated org. the phase is dried over MgSO ₄ , filtered and concentrated. The crude product was purified by chromatography on silica gel, eluting with a 9: 1 heptane: EA mixture to give 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g) as a pale yellow oil; LC-MS ∗∗: t _R = 0.80 min, [M + 1] ⁺ = not detected; ¹ H NMR (D ₆ -DMSO): δ 1.61-1.82 (m, 6 N), 1.94-2.03 (m, 2 N), 3.16 (quint. J = 7.8 Hz, 1 N), 3.89 (s, 3 N ), 7.15 (s, 1 H), 7.28 (s, 1 H).

c) To a solution of 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g, 10.3 mmol) in methanol (100 ml) is added hydroxylamine hydrochloride (2.15 g, 31.0 mmol) and NaHCO ₃ (3.04 g, 36.2 mmol). The mixture, before being filtered and the filtrate was concentrated, was stirred at 60 ° C for 18 hours. The residue was dissolved in EA (300 ml) and washed with water (30 ml). Wash liquids are back extracted with EA (4 × 100 ml) and DCM (4 × 100 ml). The combined organic extracts were dried over MgSo ₄ , filtered, concentrated and dried in BB to give the title compound (2.74 g) as a white solid; LC-MS ∗∗: t _R = 0.47 min, [M + 1] ⁺ = 236.24; ¹ H NMR (D ₆ -DMSO): δ 1.61-1.82 (m, 6 N), 1.92-2.01 (m, 2 N), 3.04-3.13 (m, 1 N), 3.84 (s, 3 N), 5.90 (s, 2 H), 6.86 (s, 1 H), 7.13 (s, 1 H), 9.91 (s, 1 H).

2-cyclopentyl-6-methoxy-isonicotinic acid hydrazide

a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), benzyl ester of hydrazinecarboxylic acid (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 ml), TBTU (3.19 g, 9.94 mmol) was added. The mixture, before it is diluted with EA (250 ml), washed twice with sat. aq. a solution of ManSO ₃ (150 ml) and then with brine (100 ml), dried over MgSO ₄ , filtered and concentrated, stirred at rt within 2 hours. The crude product is purified by chromatography on silica gel, eluting with a heptane: EA 4: 1 mixture to obtain N ′ - (2-cyclopentyl-6-methoxy-pyridin-4-carbonyl) -hydrazinecarboxylic acid benzyl ester (2.74 g) in the form of a pale yellow oil; LC-MS ∗∗: t _R = 0.74 min, [M + 1] ⁺ = 369.69; ¹ H NMR (D ₆ -DMSO): δ 1.62-1.83 (m, 6 N), 1.95-2.05 (m, 2 N), 3.10-3.21 (m, 1 N), 3.88 (s, 3 N), 5.13 (s, 2 N), 6.97 (s, 1 N), 7.23 (s, 1 N), 7.28-7.40 (m, 5 N), 9.45 (s, 1 N), 10.52 (s, 1 N).

b) Pd / C (500 mg, 10% Pd) is added to a solution of N ′ - (2-cyclopentyl-6-methoxy-pyridin-4-carbonyl) -hydrazinecarboxylic acid benzyl ester (2.74 g, 7.42 mmol) in THF ( 50 ml) and methanol (50 ml). The mixture was stirred at rt. . pressure 1 bar H ₂ for 25 hours The catalyst was removed by filtration and the filtrate was concentrated and dried in HV to give the title compound (1.58 g) as an off-white solid; LC-MS ∗∗: t _R = 0.51 min, [M + 1] ⁺ = 236.20; ¹ H NMR (D ₆ -DMSO): δ 1.60-1.82 (m, 6 N), 1.94-2.03 (m, 2 N), 3.08-3.19 (m, 1 N), 3.86 (s, 3 N), 4.56 (s br, 2 N), 6.93 (d, J = 1.0 Hz, 1 N), 7.20 (d, J = 1.0 Hz, 1 N), 9.94 (s, 1 N).

3-Ethyl-4-hydroxy-5-methyl-benzonitrile

The title compound was prepared from 3-ethyl-4-hydroxy-5-methyl-benzaldehyde following the procedures described in the literature (A. K. Chakraborti, G. Kaur, Tetrahedron 55 (1999) 13265-13268); LC-MS: t ^R = 0.90 min; ¹ H NMR (CDCl ₃ ): δ 1.24 (t, J = 7.6 Hz, 3 N), 2.26 (s, 3 N), 2.63 (q, J = 7.6 Hz, 2 N), 5.19 (s, 1 N) 7.30 (s, 2 N).

3-chloro-4-hydroxy-5-methyl-benzonitrile

The title compound was prepared from commercially available 2-chloro-6-methyl-phenol by analogy with the procedures described in the literature (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: t _R = 0.85 min. ¹ H NMR (CDCl ₃ ): 6 2.33 (s, 3 H), 6.10 (s, 1 H), 7.38 (s, 1 H), 7.53 (d, J = 1.8 Hz, 1 N).

3-Ethyl-4, N-dihydroxy-5-methyl-benzamidine

The title compound was prepared from 3-ethyl-4-hydroxy-5-methyl-benzonitrile or from commercially available 2-ethyl-6-methyl-phenol following the procedures described in the literature (G. Trapani, A. Latrofa, M Franco, C. Altomare, E. Sanna, M. Usala, G. Biggio, G. Liso, J. Med. Chem. 41 (1998) 1846-1854; AK Chakraborti, G. Kaur, Tetrahedron 55 (1999) 13265 -13268; E. Meyer, AC Joussef, H. Gallardo, Synthesis 2003, 899-905); LC-MS: t _R = 0.55 min; ¹ H NMR (D ₆ -DMSO): 6 9.25 (s br, 1H), 7.21 (s, 2H), 5.56 (s, 2H), 2.55 (q, J = 7.6 Hz, 2H), 2.15 (s, 3H ), 1.10 (t, J = 7.6 Hz, 3H).

3-Chloro-4, N-dihydroxy-5-methyl-benzamidine

The title compound was prepared from commercially available 2-chloro-6-methyl-phenol by analogy with the procedures described in the literature (e.g., B. Roth et al. J. Med. Chem. 31 (1988) 122-129; and literature cited for 3-ethyl-4, N-dihydroxy-5-methyl-benzamidine); 3-chloro-4-hydroxy-5-methyl-benzaldehyde: LC-MS: t _R = 0.49 min, [M + 1] ⁺ = 201.00; ¹ H NMR δ 2.24 (s, 2 H), 2.35 (s, 4 H), 5.98 (s br, 1 H), 7.59 (d, J = 1.8 Hz, 1 N), 7.73 (d, J = 1.8 Hz , 1 H); 9.80 (s, 1 H); 3-chloro-4, N-dihydroxy-5-methyl-benzamidine: ¹ H NMR (D ₆ -DMSO): δ 2.21 (s, 3 N), 5.72 (s br, 2 N), 7.40 (s, 1 N ), 7.48 (s, 1 H), 9.29 (s br, 1 H), 9.48 (s br, 1 H).

3-Chloro-4, N-dihydroxy-5-methoxy-benzamidine

The title compound was prepared from commercially available 3-chloro-4-hydroxy-5-methoxy-benzaldehyde by analogy with the literature for 3-ethyl-4, N-dihydroxy-5-methyl-benzamidine; LC-MS: t _R = 0.49 min, [M + 1] ⁺ = 216.96; ¹ H NMR (D ₆ -DMSO): δ 3.84 (s, 3 N), 5.79 (s, 2 N), 7.22 (d, J = 1.5 Hz, 1 N), 7.27 (d, J = 1.8 Hz, 1 H), 9.52 (s, 1 H), 9.58 (s br, 1 H).

3-Chloro-4- (2,2-diethoxyethoxy) -N-hydroxy-5-methylbenzimidamide

a) To a mixture of 3-chloro-4-hydroxy-5-methyl-benzonitrile (4.16 g, 24.8 mmol) and Cs ₂ SO ₃ (16.2 g, 49.6 mmol) in DMF (60 ml), bromoacetaldehyde diethyl acetal (5.90 g, 29.9 mmol). The mixture was stirred at 80 ° C for 18 hours. The brown suspension was dissolved in water (200 ml) and extracted four times with EA (4 × 100 ml). United org. the extracts are dried over MgSO ₄ , filtered and concentrated. The crude product was purified by silica gel gel chromatography, eluting with an EA gradient in heptane to give 3-chloro-4- (2,2-diethoxyethoxy) -5-methylbenzonitrile (3.60 g) as a white solid; LC-MS: t _R = 0.92 min, [M + 1] ⁺ = not detected; ¹ H NMR (CDCl 3): 6 7.54 (d, J = 1.6 Hz, 1 H), 7.41 (d, J = 0.8 Hz, 1 H), 4.88 (t, J = 5.2 Hz, 1 N), 4.06 (d , J = 5.2 Hz, 2 N), 3.72-3.83 (m, 2 N), 3.58-3.71 (m, 2 N), 2.38 (s, 3 N), 1.26 (t, J = 7.1 Hz, 6 N) .

b) To a solution of 3-chloro-4- (2,2-diethoxyethoxy) -5-methylbenzonitrile (4.54 g, 16.0 mmol) in methanol (50 ml), hydroxylamine hydrochloride (3.34 g, 48.0 mmol) and NaHCO ₃ (2.69 g, 32.0 mmol). The mixture, before it was diluted with EA (120 ml) and washed with water (100 ml), was stirred at 75 ° C for 2 hours. The washing liquid was extracted twice with EA (2 × 75 ml). United org. the extracts are dried over MgSO ₄ , filtered and concentrated to give the title compound (4.43 g) as a beige wax, which slowly solidifies upon standing; LC-MS: t ^R = 0.55 min, [M + 1] ⁺ = 317.28.

3-Chloro-4- (2,2-dimethoxyethoxy) -N-hydroxy-5-methoxybenzimidamide

The title compound was prepared by analogy with 3-chloro-4- (2,2-diethoxyethoxy) -N-hydroxy-5-methylbenzimidamide; LC-MS: t _R = 0.53 min, [M + 1] ⁺ = 305.18.

4-benzyloxy-3-ethyl-5-methyl-benzoic acid

a) To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (34.9 g, 0.213 mol, obtained from 2-ethyl-6-methyl-phenol according to the literature given for 3-ethyl-4, N- dihydroxy-5-methyl-benzamidine) in MeCN (350 ml), K ₂ CO ₃ (58.7 g, 0.425 mol) and benzyl bromide (36.4 g, 0.213 mol) are added. The mixture, before it is cooled to rt, is diluted with water and extracted twice with EA, stirred at 60 ° C for 2 hours. Org. the extracts were washed with water and concentrated to give crude 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (45 g) as an orange oil. ¹ H NMR (CDCl ₃ ): δ 1.29 (t, J = 7.5 Hz, 3 N), 2.40 (s, 3 N), 2.77 (q, J = 7.8 Hz, 2 N), 4.90 (s, 2 N) , 7.31-7.52 (m, 5 N), 7.62 (d, J = 1.5 Hz, 1 N), 7.66 (d, J = 1.8 Hz, 1 N), 9.94 (s, 1 N).

b) To a mixture of 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (132 g, 0.519 mol) and 2-methyl-2-butene (364 g, 5.19 mol) in tert-butanol (1500 ml), add a solution NaH ₂ PO ₄ dihydrate (249 g, 2.08 mol) in water (1500 ml). To this mixture was added NaClO ₂ (187.8 g, 2.08 mol) in portions. The temperature of the reaction mixture was maintained below 30 ° C, and gas evolution was observed. After complete addition, before it is diluted with TBME (1500 ml), the orange two-phase mixture is mixed well for 3 hours. Org. the layer is separated and washed with 20% aq. NaHS solution (1500 ml) and water (500 ml). Org the phase is then extracted three times with 0.5 N. aq. NaOH (1000 ml), aq. phase acidified with 25% aq. HCl (500 ml) and extracted twice with TBME (1000 ml). These org. the extracts were combined and evaporated to dryness to give the title compound; ¹ H NMR (D ₆ -DMSO): δ 1.17 (t, J = 7.5 Hz, 3 N), 2.31 (s, 3 N), 2.67 (q, J = 7.5 Hz, 2 N), 4.86 (s, 2 H), 7.34-7.53 (m, 5 N), 7.68 (s, 2 N), 12.70 (s, 1 N).

Example 1

3 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid

a) A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (21.0 g, 102 mmol), 3-ethyl-4, N-dihydroxy-5-methyl-benzamidine (20.0 g, 103 mmol) and HOBt (1.24 g, 9 mmol) in THF (200 ml), before a solution of DCC (20.0 g, 97 mmol) in THF (100 ml) was added dropwise, cooled to 5 ° C. After complete addition, the mixture is stirred at rt for 18 hours, then at 75 ° C for 48 hours. The solvent was evaporated and the remaining residue was dissolved in TBME (200 ml). The precipitate that formed was removed, filtered off and washed with additional TBME (200 ml). The filtrate was washed with approximately 4% aq. NaHCO ₃ solution (100 ml) and water (100 ml), and concentrated. The crude product was recrystallized from hot acetonitrile (200 ml) to give 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl -6-methyl-phenol (28.6 g) as a white solid; ¹ H NMR (CDCl ₃ ): δ 1.33 (t, J = 7.5 Hz, 3 N), 1.70-1.80 (m, 2 N), 1.84-1.96 (m, 4 N), 2.05-2.16 (m, 2 N ), 2.36 (s, 3 N), 2.74 (q, J = 7.3 Hz, 2 N), 3.25 (quint., J = 7.5 Hz, 1 N), 4.02 (s, 3 N), 5.01 (s), 7.31 (s, 1 H), 7.51 (s, 1 H), 7.85 (s, 2 H).

b) To a solution of 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenol (1.26 g, 3.32 mmol) in DMF (20 ml) was added SEGCO3 (6.49 g, 19.9 mmol). The mixture, before 2-bromoethanol (2.07 g, 16.6 mmol) was added, was stirred at rt. within 10 minutes The mixture was stirred at 60 ° C for 5 days. The mixture is cooled to rt, diluted with sat. aq. NaHCO ₃ solution (50 ml) and extracted twice with EA (2 × 200 ml). Org the extracts are combined and concentrated. The crude product is purified by KX on silica gel, eluting with a heptane: EA 4: 1 mixture to obtain 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2, 4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethanol (639 mg) as a pale yellow oil; 1 H NMR (CDCl ₃ ): 5: 7.90 (s, 1 H), 7.88 (s, 1 H), 7.51 (s, 1 H), 7.31 (s, 1 H), 4.02 (s, 3 H), 3.97 -4.01 (m, 4 N), 3.21-3.29 (m, 1 N), 2.79 (q, J = 7.6 Hz, 2 N), 2.42 (s, 3 N), 2.15 (t, J = 5.5 Hz, 1 H), 2.06-2.14 (m, 2 N), 1.83-1.95 (m, 4 N), 1.68-1.80 (m, 2 N), 1.33 (t, J = 7.6 Hz, 3 H).

c) To a solution of 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethanol (638 mg, 1.51 mmol) in THF add DIPEA (389 mg, 3.01 mmol). The mixture, before methanesulfonyl chloride (207 mg, 1.81 mmol) was added, was cooled to 0 ° C. The mixture, before it is diluted with EA (100 ml) and washed with sat. aq. Manso ₃ solution (50 ml) and brine (50 ml), stirred at rt within 30 minutes Org the extract was dried over MgSO ₄ , filtered and concentrated to give 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl- 6-methylphenoxy) ethyl methanesulfonate (733 mg) as a yellow oil; LC-MS: t _R = 1.19 min, [M + H] ⁺ = 502.05.

d) Solution of 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (245 mg, 0.488 mmol), ethyl 3-aminopropanoate (286 mg, 2.44 mmol, obtained from the corresponding HCl salt by substituting HCl using ion exchange with carbonate) and Et ₃ N (247 mg, 2.44 mmol) in ethanol (6 ml) was stirred at 60 ° C for 72 hours. The mixture was diluted with sat. aq. NaHCO ₃ solution and extracted twice with DCM. United org. the extracts are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified on prep plates. TLC using DCM: MeOH 9: 1 to give ethyl 3 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methyl-phenoxy) ethyl) amino) propanoate (88 mg) as a pale yellow oil; LC-MS: t _R = 0.99 min, [M + H] ⁺ = 523.13.

e) Ethyl 3 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methyl solution phenoxy) ethyl) amino) propanoate (88 mg, 0.168 mmol) in MeOH (0.5 ml), THF (0.5 ml) and 2 N. aq. LiOH (0.2 ml) was stirred at rt. for 2 hours. The mixture is concentrated, diluted with 2 N. aq. HCl (10 ml) and extracted four times with DCM (4 × 20 ml). United org. the extracts are dried over MgSO ₄ , filtered and concentrated. The crude product is purified using prep. HPLC to give the title compound (63 mg) as an off-white solid; LC-MS: t _R = 0.93 min, [M + H] ⁺ = 495.12; ¹ H NMR (CDCl ₃ ): δ 8.37 (s br, 2 H), 7.78 (s, 1 H), 7.72 (s, 1 H), 7.43 (s, 1 H), 7.20 (s, 1 H), 4.07-4.18 (m, 2 N), 3.99 (s, 3 N), 3.34-3.42 (m, 2 N), 3.16-3.34 (m, 3 N), 2.62-2.76 (m, 4 N), 2.33 ( s, 3 N), 2.09 (m, 2 N), 1.81-1.94 (m, 4 N), 1.68-1.79 (m, 2 N), 1.27 (t, J = 7.5 Hz, 3 N).

Example 2

1- (2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

The title compound (123 mg) was obtained as an off-white foam by analogy with Example 1 starting from 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4- oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (500 mg, 0.997 mmol) and azetidine-3-carboxylic acid methyl ester (302 mg, 1.99 mmol); LC-MS: t _R = 0.88 min, [M + H] ⁺ = 507.23; ¹ H NMR (CDCl ₃ ): δ 8.20 (s, 1 H), 7.92 (d, J = 1.8 Hz, 1 H), 7.89 (d, J = 1.6 Hz, 1 H), 7.55 (s, 1 H) , 4.37-4.48 (m, 4 N), 4.08-4.13 (m, 2 N), 4.01 (s, 3 N), 3.69-3.74 (m, 2 N), 3.49-3.59 (m, 1 N), 3.26 -3.31 (m, 1 N), 2.79 (q, J = 7.7 Hz, 2 N), 2.42 (s, 3 N), 2.08-2.17 (m, 2 N), 1.86-1.98 (m, 4 N), 1.74-1.82 (m, 2 N), 1.34 (t, J = 7.5 Hz, 3 N).

Example 3

(S) -1- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -3- ((2-hydroxyethyl) amino) propan-2-ol

a) To a solution of 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenol (2.32 g, 4.91 mmol) in 2-propanol (60 ml) and 3 N. aq. NaOH (6 ml) add (R) -epichlorohydrin (4.55 g, 49.1 mmol). The mixture, before it is diluted with EA (100 ml) and washed twice with 1 N. aq. NaOH (2 × 15 ml) and then brine (25 ml) were stirred at 45 ° C for 6 hours. Org the extract was dried over MgSO ₄ , filtered and concentrated. The crude product is purified by HPLC on silica gel eluting with a 1: 1 heptane: EA mixture to give (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3-ethyl-5-methyl- 4- (oxiran-2-ylmethoxy) phenyl) -1,2,4-oxadiazole (2.04 g) as a colorless wax; LC-MS: t _R = 1.52 min, [M + H] ⁺ = 436.11; ¹ H NMR (CDCl ₃ ): 6 7.88-7.90 (m, 1 H), 7.85-7.88 (m, 1 H), 7.51 (d, J = 1.1 Hz, 1 H), 7.31 (d, J = 1.2 Hz , 1 N), 4.14 (dd, J ₁ = 11.1 Hz, J ₂ = 3.1 Hz, 1 N), 4.02 (s, 3 N), 3.83 (dd, J ₁ = 11.1 Hz, J ₂ = 6.0 Hz, 1 H), 3.40-3.44 (m, 1 N), 3.19-3.29 (m, 1 N), 2.94 (dd, J ₁ = 4.9 Hz, J ₂ = 4.3 Hz, 1 N), 2.75-2.83 (m, 3 H), 2.41 (s, 3 N), 2.06-2.16 (m, 2 N), 1.84-1.94 (m, 4 N), 1.70-1.79 (m, 2 N), 1.33 (t, J = 7.5 Hz, 3 H).

b) A solution of (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3-ethyl-5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2, 4-oxadiazole (245 mg, 0.563 mmol) and ethanolamine (4.46 g, 4.39 mmol) in ethanol (8 ml) were stirred at 60 ° C for 18 hours. The solvent was evaporated and the crude product was purified using prep. HPLC to give the title compound (154 mg) as a white solid; LC-MS: t ^R = 0.73 min, [M + H] ⁺ = 497.25; ¹ H NMR (CD ₃ OD): δ 7.85 (s, 1 H), 7.83 (s, 1 H), 7.51 (s, 1 H), 7.26 (s, 1 H), 4.13-4.20 (m, 1 N ), 4.00 (s, 3 Н), 3.84-3.90 (m, 2 Н), 3.67-3.78 (m, 2 Н), 3.23-3.30 (m, 1 Н), 2.96 (dd, J ₁ = 12.2 Hz, J ₂ = 3.7 Hz, 1 N), 2.76-2.89 (m, 5 N), 2.41 (s, 3 N), 2.05-2.17 (m, 2 N), 1.85-1.98 (m, 4 N), 1.71- 1.83 (m, 2 N), 1.31 (t, J = 7.6 Hz, 3 N).

Example 4

(S) -2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) propane-1,3-diol

The title compound (93 mg) was obtained as a pale yellow solid in accordance with the procedure described for Example 3 and starting from (8) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3-ethyl-5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2,4-oxadiazole (100 mg, 0.230 mmol) and serinol (42 mg, 0.459 mmol); LC-MS *: t _R = 0.92 min, [M + H] ⁺ = 527.27; ¹ H NMR (CDCl ₃ ): δ 8.51 (s, 1 H), 7.82 (s, 1 H), 7.80 (s, 1 H), 7.46 (s, 1 H), 7.25 (s, 1 H), 4.44 -4.52 (m, 1 Н), 3.69-4.07 (m, 13 Н), 4.00 (s, 3 Н), 3.48-3.55 (m, 1 Н), 3.28-3.37 (m, 2 Н), 3.18-3.27 (m, 1 N), 2.71 (q, J = 7.5 Hz, 2 N), 2.35 (s, 3 N), 2.05-2.14 (m, 2 N), 1.82-1.94 (m, 4 N), 1.68- 1.80 (m, 2 N), 1.29 (t, J = 7.5 Hz, 3 N) (formic acid salt); ¹ H NMR (CD ₃ OD): 5 8.51 (s, 1 H), 7.89 (s, 1 H), 7.87 (s, 1 H), 7.55 (s, 1 H), 7.30 (s, 1 H), 4.29-4.37 (m, 1 N), 4.01 (s, 3 N), 3.83-4.00 (m, 4 N), 3.72-3.83 (m, 2 N), 3.47-3.55 (m, 1 N), 3.22- 3.30 (m, 3 N), 2.82 (q, J = 7.3 Hz, 2 N), 2.43 (s, 3 N), 2.06-2.17 (m, 2 N), 1.85-1.98 (m, 4 N), 1.70 -1.84 (m, 2 N), 1.33 (t, J = 7.6 Hz, 3 N) (formic acid salt).

Example 5

2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) acetic acid

To a solution of 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenol (203 mg, 0.535 mmol) in DMF (5 ml) at 0 ° C add NaH (43 mg, 1.07 mmol, 60% in mineral oil). The mixture was stirred at 0 ° C and ethyl bromoacetate (98 mg, 0.588 mmol) was added. Stirring is continued at 0 ° C for 30 minutes, then at rt. within 72 hours. The reaction was quenched by adding water (2 ml) and the mixture was concentrated. The residue was dissolved in THF (10 ml), methanol (10 ml) and 2 N. aq. LiOH (10 ml). The mixture, before it is cooled to rt, acidified by adding 2 N. aq. HCl and extracted three times with EA (3 × 20 ml), stirred at 60 ° C for 2 hours. Combined org. the extracts are concentrated and the crude product is purified using prep. HPLC to give the title compound (146 mg) as a white solid; LC-MS: t _R = 1.14 min, [M + H] ⁺ = 438.07; ¹ H NMR (CDCl ₃ ): δ 7.90 (s, 1 H), 7.88 (s, 1 H), 7.79 (s br, 1 H), 7.50 (s, 1 H), 7.29 (s, 1 H), 4.57 (s, 2 N), 4.01 (s, 3 N), 3.20-3.29 (m, 1 N), 2.79 (q, J = 7.5 Hz, 2 N), 2.42 (s, 3 N), 2.04-2.16 (m, 2 N), 1.82-1.95 (m, 4 N), 1.68-1.80 (m, 2 N), 1.34 (t, J = 7.5 Hz, 3 N).

Example 6

4- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) butanoic acid

The title compound (146 mg) was obtained as a white solid, following the procedure described in Example 5 and starting from 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2 , 4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenol (200 mg, 0.528 mmol) and ethyl 4-iodobutyrate (256 mg, 1.06 mmol); LC-MS: t _R = 1.19 min, [M + H] ⁺ = 465.82; ¹ H NMR (CDCl ₃ ): δ 7.87 (s, 1 H), 7.86 (s, 1 H), 7.51 (s, 1 H), 7.30 (s, 1 H), 4.02 (s, 3 H), 3.90 (t, J = 6.1 Hz, 2 N), 3.19-3.30 (m, 1 N), 2.70-2.78 (m, 4 N), 2.38 (s, 3 N), 2.21 (quint., J = 6.5 Hz, 2 N), 2.06-2.15 (m, 2 N), 1.84-1.95 (m, 4 N), 1.68-1.79 (m, 2 N), 1.32 (t, J = 7.5 Hz, 3 N).

Example 7

2 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino )acetic acid

The title compound (40 mg) was obtained as an off-white solid, following the procedures described in Example 1 starting from 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1 , 2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (200 mg, 0.399 mmol) and glycine ethyl ester hydrochloride (167 mg, 1.20 mmol); LC-MS: t _R = 0.94 min, [M + H] ⁺ = 481.03; ¹ H NMR (CD ₃ OD): δ 7.92 (s, 1 H), 7.90 (s, 1 H), 7.55 (s, 1 H), 7.31 (s, 1 H), 4.13-4.18 (m, 2 N ), 4.02 (s, 3 N), 3.66 (s, 2 N), 3.49-3.55 (m, 3 N), 2.82 (q, J = 7.3 Hz, 2 N), 2.45 (s, 3 N), 2.08 -2.17 (m, 2 N), 1.86-1.98 (m, 4 N), 1.73-1.82 (m, 2 N), 1.35 (t, J = 7.5 Hz, 3 N).

Example 8

rac-1- (2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) pyrrolidine-3-carboxylic acid

The title compound was obtained (68 mg) as a pale orange solid, following the procedures described in Example 1 based on 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1 , 2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (250 mg, 0.498 mmol) and rac-methyl 3-pyrrolidinecarboxylate hydrochloride (322 mg, 2.49 mmol); LC-MS: t _R = 0.94 min, [M + H] ⁺ = 521.05; ¹ H NMR (CD ₃ OD): 5 8.25 (s, 1 H), 7.92 (s, 1 H), 7.90 (s, 1 H), 7.54 (s, 1 H), 4.20 (t, J = 5.1 Hz , 2 N), 4.01 (s, 3 N), 3.79-3.85 (m, 1 N), 3.50-3.77 (m, 5 N), 3.21-3.31 (m, 2 N), 2.82 (q, J = 7.6 Hz, 2 N), 2.45 (s, 3 N), 2.30-2.44 (m, 2 N), 2.07-2.16 (m, 2 N), 1.87-1.97 (m, 4 N), 1.73-1.82 (m, 2 N), 1.35 (t, J = 7.5 Hz, 3 N).

Example 9

(S) -2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) acetic acid

a) A solution of (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3-ethyl-5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2, 4-oxadiazole (500 mg, 1.15 mmol), glycine ethyl ester hydrochloride (320 mg, 2.30 mmol), from which the hydrochloride was removed by filtration through a carbonate-loaded silica gel resin before use, and DIPEA (0.2 ml) in methanol (3 ml) stirred at 60 ° C for 3 days. The mixture was diluted with DCM and washed with sat. aq. NaHCO ₃ solution. Vodn. the phase is extracted once with DCM. United org. the extracts are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by prep. TLC using DCM: methanol 9: 1 to give (S) -2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl)) ethyl ester -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -2-hydroxypropyl) amino) acetic acid (60 mg) as a white solid; LC-MS: t _R = 1.03 min, [M + H] ⁺ = 537.29.

b) Ethyl ester solution (S) -2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2 -ethyl-6-methylphenoxy) -2-hydroxypropyl) amino) acetic acid (60 mg, 0.114 mmol) in THF (3 ml), methanol (3 ml) and 2 N. aq. LiOH (1 ml) was stirred at rt. for 2 hours, the solvent was evaporated and the residue was dissolved in 2 n. aq. HCl (10 ml) and extracted four times with DCM (4 × 20 ml). Org the extracts are combined, dried over MgSO ₄ , filtered and concentrated. The crude product is purified using prep. HPLC to give the title compound (31 mg) as a white solid; LC-MS *: t _R = 0.86 min, [M + H] ⁺ = 511.19; ¹ H NMR (CD ₃ OD): δ 7.88 (s, 1 H), 7.86 (s, 1 H), 7.54 (s, 1 H), 7.30 (s, 1 H), 4.30-4.36 (m, 1 N ), 4.01 (s, 3 N), 3.87-3.98 (m, 2 N), 3.63 (s, 2 N), 3.46 (dd, J ₁ = 12.5 Hz, J ₂ = 2.9 Hz, 1 N), 3.24- 3.32 (m, 2 N), 2.81 (q, J = 7.6 Hz, 2 N), 2.42 (s, 3 N), 2.07-2.17 (m, 2 N), 1.86-1.98 (m, 4 N), 1.74 -1.82 (m, 2 N), 1.32 (t, J = 7.6 Hz, 3 N).

Example 10

(S) -3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) propanoic acid

The title compound was obtained (114 mg) as a white solid, following the procedures described in Example 9 based on (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3- ethyl 5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2,4-oxadiazole (1090 mg, 2.50 mmol) and β-alanine tert-butyl ester (682 mg, 3.75 mmol); LC-MS: t _R = 0.95 min, [M + H] ⁺ = 525.15; ¹ H NMR (CDCl ₃ ): δ 7.91 (s br, 3 H), 7.75 (s, 1 H), 7.71 (s, 1 H), 7.40 (s, 1 H), 7.17 (s, 1 H), 4.46-4.59 (m, 1 N), 3.97 (s, 3 N), 3.77-3.92 (m, 2 N), 3.13-3.47 (m, 5 N), 2.74-2.88 (m, 2 N), 2.66 ( q, J = 7.3 Hz, 2 H), 2.29 (s, 3 N), 2.01-2.15 (m, 2 N), 1.80-1.93 (m, 4 N), 1.66-1.79 (m, 2 N), 1.25 (t, J = 7.5 Hz, 3 H).

Example 11

(S) -2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) acetic acid

The title compound was obtained (61 mg) as a pale brown oil, following the procedures described in Example 9 based on (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3 ethyl 5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2,4-oxadiazole (300 mg, 0.689 mmol) and sarcosine methyl ester (184 mg, 2.07 mmol); LC-MS: t _R = 0.95 min, [M + H] ⁺ = 525.04; ¹ H NMR (CDCl ₃ ): δ 8.07 (s, 2 H), 7.85 (s, 1 H), 7.83 (s, 1 H), 7.49 (s, 1 H), 4.57-4.65 (m, 1 N) , 4.01 (s, 3 Н), 3.76-3.97 (m, 4 Н), 3.49-3.58 (m, 1 Н), 3.41-3.47 (m, 1 Н), 3.19-3.29 (m, 1 Н), 3.10 (s, 3 N), 2.72 (q, J = 7.8 Hz, 2 N), 2.40 (s br, 2 N), 2.37 (s, 3 N), 2.05-2.16 (m, 2 N), 1.83-1.94 (m, 4 N), 1.69-1.79 (m, 2 N), 1.31 (t, J = 7.5 Hz, 3 N) (formic acid salt).

Example 12

(S) -1- (3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -2-hydroxypropyl) azetidine-3-carboxylic acid

The title compound was obtained (73 mg) as a pale brown oil, following the procedures described in Example 9 based on (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3 ethyl 5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2,4-oxadiazole (200 mg, 0.459 mmol) and azetidine-3-carboxylic acid methyl ester (139 mg, 0.918 mmol) ; LC-MS: t _R = 0.87 min, [M + H] ⁺ = 537.26; ¹ H NMR (CD ₃ OD): δ 8.18 (s, 2 H), 7.89 (s, 1 H), 7.87 (s, 1 H), 7.55 (s, 1 H), 7.31 (s, 1 H), 4.32-4.43 (m, 4 N), 4.21-4.28 (m, 1 N), 4.02 (s, 3 N), 3.88 (d, J = 5.0 Hz, 2 N), 3.42-3.64 (m, 4 N) , 2.81 (q, J = 7.6 Hz, 2 N), 2.42 (s, 3 N), 2.07-2.17 (m, 2 N), 1.87-1.97 (m, 4 N), 1.73-1.83 (m, 2 N ), 1.33 (t, J = 7.4 Hz, 3 N) (formic acid salt).

Example 13

2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N- (2-hydroxyethyl ) acetamide

To a solution of 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) acetic acid (780 mg , 1.65 mmol) in THF (30 ml) add HOBt (267 mg, 1.98 mmol) and then EDC HCl (379 mg, 1.98 mmol). The mixture, before ethanolamine (121 mg, 1.98 mmol) is added, is stirred at rt. within 5 minutes Stirring was continued for 3 hours. The mixture was diluted with water and sat. aq. NaHCO ₃ solution and extracted twice with EA. United org. the extracts are dried over MgSO ₄ , filtered and concentrated. The crude product is purified using prep. HPLC to give the title compound (202 mg) as a colorless oil; LC-MS: t _R = 1.07 min, [M + H] ⁺ = 481.01; ¹ H NMR (CDCl ₃ ): 5 7.90 (s, 1 H), 7.89 (s, 1 H), 7.50 (d, J = 0.5 Hz, 1 N), 7.35 (t br, J = 5.3 Hz, 1 N ), 7.30 (d, J = 0.8 Hz, 1 N), 4.39 (s, 2 N), 4.02 (s, 3 N), 3.87 (t, J = 4.9 Hz, 2 N), 3.63 (m, 2 N ), 3.51 (s, 2 N), 3.20-3.29 (m, 1 N), 2.73 (q, J = 7.6 Hz, 2 N), 2.38 (s, 3 N), 2.06-2.15 (m, 2 N) , 1.84-1.95 (m, 4 N), 1.70-1.80 (m, 2 N), 1.33 (t, J = 7.6 Hz, 3 N).

Example 14

(S) -3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) -3-oxopropanoic acid

a) A solution of (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3-ethyl-5-methyl-4- (oxiran-2-ylmethoxy) phenyl) -1,2, 4-oxadiazole (350 mg, 0.804 mmol) in 7 N. NH ₃ in methanol (15 ml) was stirred at 45 ° C for 18 hours. The solvent was evaporated and the crude product was purified by KX on silica gel, eluting with DCM: 7N. NH ₃ in methanol 94: 6 to give (S) -1-amino-3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl ) -2-ethyl-6-methylphenoxy) propan-2-ol (256 mg) as a pale yellow solid; LC-MS: t _R = 0.83 min, [M + H] ⁺ = 453.22.

b) DIPEA (38 mg, 0.291 mmol) and TBTU (33 mg, 0.102 mmol) are added to a solution of mono-ethyl malonate (13 mg, 0.097 mmol) in DMF (1 ml). Mixture, before (S) -1-amino-3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) - 2-ethyl-6-methylphenoxy) propan-2-ol (44 mg, 0.097 mmol), stirred at rt within 5 minutes Stirring is continued at rt. for 2 hours before the mixture was diluted with water and sat. aq. NaHCO ₃ and extracted twice with EA. United org. the extracts are dried over MgSO ₄ , filtered and concentrated to give crude (S) -ethyl 3 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole -3-yl) -2-ethyl-6-methylphenoxy) -2-hydroxypropyl) amino) -3-oxopropanoate (39 mg) as a yellow oil; LC-MS: t _R = 1.03 min, [M + H] ⁺ = 567.11. This substance is dissolved in methanol (5 ml) and 2 N. aq. LiOH (5 ml) and the mixture was stirred at rt for 15 hours. The reaction mixture was acidified by adding 2 N. aq. HCl and then extracted twice with EA. United org. the extracts are dried over MgSO ₄ , filtered and concentrated. The crude product is purified using prep. HPLC to give the title compound (23 mg) as a white solid; LC-MS: t _R = 1.00 min, [M + H] ⁺ = 538.98; ¹ H NMR (CD ₃ OD): δ 7.86 (s, 1 H), 7.84 (s, 1 H), 7.53 (s, 1 H), 7.29 (s, 1 H), 4.10-4.19 (m, 1 N ), 4.01 (s, 3 N), 3.83-3.93 (m, 2 N), 3.62 (dd, J ₁ = 13.7 Hz, J ₂ = 4.8 Hz, 1 N), 3.43 (dd, J ₁ = 13.8 Hz, J ₂ = 6.9 Hz, 1 N), 3.24-3.32 (m, 2 N), 2.80 (q, J = 7.5 Hz, 2 N), 2.41 (s, 3 N), 2.06-2.18 (m, 2 N) , 1.85-1.97 (m, 4 N), 1.73-1.82 (m, 2 N), 1.31 (t, J = 7.5 Hz, 3 N).

Example 15

(S) -4 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) -4-oxobutanoic acid

The title compound was obtained (162 mg) as a pale brown oil, following the procedures described in Example 14 based on (S) -1-amino-3- (4- (5- (2-cyclopentyl-6-methoxypyridine) -4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propan-2-ol (348 mg, 0.614 mmol) and mono-methyl succinate (128 mg, 0.921 mmol) ; LC-MS: t _R = 1.05 min, [M + H] ⁺ = 553.20; ¹ H NMR (CD ₃ OD): δ 7.85 (s, 1 H), 7.83 (s, 1 H), 7.53 (s, 1 H), 7.28 (s, 1 H), 4.07-4.15 (m, 1 N ), 4.00 (s, 3 Н), 3.81-3.92 (m, 2 Н), 3.57 (dd, = 13.7 Hz, J2 = 4.8 Hz, 1 Н), 3.34-3.42 (m, 1 Н), 3.23-3.31 (m, 1 N), 2.80 (q, J = 7.6 Hz, 2 N), 2.64 (m, 2 N), 2.51-2.58 (m, 2 N), 2.41 (s, 3 N), 2.07-2.17 ( m, 2 N), 1.85-1.98 (m, 4 N), 1.72-1.82 (m, 2 N), 1.31 (t, J = 7.5 Hz, 3 N).

Example 16

2 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) ( methyl) amino) acetic acid

The title compound was obtained (24 mg) as a beige solid, following the procedures described in Example 1 based on 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2 , 4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (263 mg, 0.525 mmol) and sarcosine methyl ester hydrochloride (878 mg, 6.29 mmol); LC-MS: t _R = 0.95 min, [M + H] ⁺ = 495.25; ¹ H NMR (CDCl ₃ ): δ 7.77 (s, 1 H), 7.73 (s, 1 H), 7.41 (s, 1 H), 7.18 (s, 1 H), 3.95 (s, 3 H), 3.88 -3.95 (m, 2 N), 3.47 (s br, 3 N), 3.14-3.24 (m, 3 N), 2.98 (s br, 2 N), 2.68 (q, J = 7.0 Hz, 2 N), 2.47 (s, 3 N), 2.31 (s, 3 N), 2.02-2.11 (m, 2 N), 1.79-1.93 (m, 4 N), 1.67-1.77 (m, 2 N), 1.26 (t, J = 7.3 Hz, 3 N).

Example 17

3 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) ( methyl) amino) propanoic acid

The title compound was obtained (7 mg) as a colorless glass, following the procedures described in Example 1, starting from 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1.2, 4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (280 mg, 0.558 mmol) and ethyl 3- (methylamino) propionate (148 mg, 1.13 mmol); LC-MS: t _R = 0.94 min, [M + H] ⁺ = 509.26; ¹ H NMR (CD ₃ OD): δ 7.88 (s, 1 H), 7.86 (s, 1 H), 7.52 (s, 1 H), 7.27 (s, 1 H), 4.21 (t, J = 5.0 Hz , 2 N), 4.00 (s, 3 N), 3.56 (t, J = 5.0 Hz, 2 N), 3.42 (t, J = 6.5 Hz, 2 N), 3.23-3.30 (m, 1 N), 2.98 (s, 3 N), 2.80 (q, J = 7.5 Hz, 2 N), 2.65 (t, J = 6.5 Hz, 2 N), 2.43 (s, 3 N), 2.06-2.16 (m, 2 N) , 1.85-1.97 (m, 4 N), 1.72-1.83 (m, 2 N), 1.33 (t, J = 7.5 Hz, 3 N).

Example 18

2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino )acetic acid

The title compound (59 mg) was obtained as a pale yellow solid, by analogy with the procedures described in Example 1, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) - 1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (150 mg, 0.291 mmol) and glycine ethyl ester hydrochloride (203 mg, 1.46 mmol); LC-MS: t _R = 0.96 min, [M + H] ⁺ = 495.25; ¹ H NMR (CD ₃ OD): δ 7.88 (s, 1 H), 7.86 (s, 1 H), 7.53 (s, 1 H), 7.28 (s, 1 H), 3.98-4.03 (m, 2 N ), 4.00 (s, 3 N), 3.84 (s, 2 N), 3.38-3.44 (m, 2 N), 3.24-3.31 (m, 1 N), 2.78 (q, J = 7.6 Hz, 2 N) , 2.41 (s, 3 N), 2.23-2.32 (m, 2 N), 2.06-2.17 (m, 2 N), 1.85-1.97 (m, 4 N), 1.72-1.82 (m, 2 N), 1.32 (t, J = 7.5 Hz, 3 N).

Example 19

3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) propanoic acid

The title compound (6 mg) was obtained as a pale brownish solid, by analogy with the procedures described in Example 1, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) - 1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (100 mg, 0.194 mmol) and B-alanine ethyl ester hydrochloride (149 mg, 0.970 mmol); LC-MS: t _R = 0.96 min, [M + H] ⁺ = 509.28; ¹ H NMR (CD ₃ OD): δ 7.88 (s, 1 H), 7.87 (s, 1 H), 7.57 (s, 1 H), 7.35 (s, 1 H), 4.04 (s, 3 H), 4.01 (t, J = 6.0 Hz, 2 N), 3.36-3.46 (m, 4 N), 3.23-3.32 (m, 1 N), 2.84 (t, J = 6.4 Hz, 2 N), 2.79 (q, J = 7.6 Hz, 2 N), 2.42 (s, 3 N), 2.25-2.34 (m, 2 N), 2.07-2.19 (m, 2 N), 1.85-1.97 (m, 4 N), 1.73-1.83 (m, 2 N), 1.33 (t, J = 7.5 Hz, 3 N).

Example 20

2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) ( methyl) amino) acetic acid

The title compound (102 mg) was obtained as a pale yellow oil, by analogy with the procedures described in Example 1, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1 , 2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (150 mg, 0.291 mmol) and sarcosine methyl ester hydrochloride (203 mg, 1.46 mmol); LC-MS: t _R = 0.97 min, [M + H] ⁺ = 509.26; ¹ H NMR (CD ₃ OD): δ 7.85 (s, 1 H), 7.83 (s, 1 H), 7.51 (s, 1 H), 7.25 (s, 1 H), 3.99 (s, 3 H), 3.98 (t, J = 5.9 Hz, 2 N), 3.79 (s, 2 N), 3.50-3.58 (m, 2 N), 3.22-3.30 (m, 1 N), 3.02 (s, 3 N), 2.76 (q, J = 7.5 Hz, 2 N), 2.39 (s, 3 N), 2.28-2.37 (m, 2 N), 2.04-2.16 (m, 2 N), 1.84-1.97 (m, 4 N), 1.71-1.82 (m, 2 N), 1.31 (t, J = 7.5 Hz, 3 N).

Example 21

3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) ( methyl) amino) propanoic acid

The title compound (46 mg) was obtained as a pale yellow oil, by analogy with the procedures described in Example 1, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1 , 2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (150 mg, 0.291 mmol) and ethyl 3- (methylamino) propanoate (244 mg, 1.46 mmol); LC-MS: t _R = 0.97 min, [M + H] ⁺ = 523.26; ¹ H NMR (CD ₃ OD): δ 7.87 (s, 1 H), 7.85 (s, 1 H), 7.54 (s, 1 H), 7.31 (s, 1 H), 4.02 (s, 3 H), 3.96-4.01 (m, 2 N), 3.57-3.73 (m, 2 N), 3.48-3.56 (m, 1 N), 3.39-3.48 (m, 1 N), 3.23-3.31 (m, 1 N), 3.01 (s, 3 N), 2.94 (t, J = 6.7 Hz, 2 N), 2.78 (q, J = 7.5 Hz, 2 N), 2.41 (s, 3 N), 2.30-2.39 (m, 2 N ), 2.07-2.19 (m, 2 N), 1.84-1.96 (m, 4 N), 1.72-1.83 (m, 2 N), 1.32 (t, J = 7.5 Hz, 3 N).

Example 22

1- (3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) azetidine- 3-carboxylic acid

The title compound (29 mg) was obtained as a white solid, by analogy with the procedures described in Example 1, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1, 2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (150 mg, 0.291 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (220 mg, 1.46 mmol); LC-MS: t _R = 0.96 min, [M + H] ⁺ = 521.39; ¹ H NMR (CD ₃ OD): δ 7.89 (d, J = 1.4 Hz, 1 N), 7.87 (d, J = 1.4 Hz, 1 N), 7.55 (d, J = 1.0 Hz, 1 N), 7.31 (d, J = 1.1 Hz, 1 N), 4.24-4.40 (m, 4 N), 4.01 (s, 3 N), 3.97 (t, J = 5.8 Hz, 2 N), 3.53-3.60 (m, 2 N), 3.43-3.48 (m, 1 N), 3.26-3.31 (m, 1 N), 2.78 (q, J = 7.5 Hz, 2 N), 2.41 (s, 3 N), 2.06-2.19 (m, 4 N), 1.86-1.97 (m, 4 N), 1.72-1.83 (m, 2 N), 1.33 (t, J = 7.5 Hz, 3 N).

Example 23

2 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) ethanol

Mixture of 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (184 mg, 0.367 mmol) and ethanolamine (112 mg, 1.83 mmol) in acetonitrile (6 ml), before it is separated using prep. HPLC to give the title compound (77 mg) as a white solid, stirred at 65 ° C for 18 hours; LC-MS: t _R = 0.92 min, [M + H] ⁺ = 467.25; ¹ H NMR (CD ₃ OD): δ 7.91 (s, 1 H), 7.88 (s, 1 H), 7.62 (s, 1 H), 7.41 (s, 1 H), 4.20 (t, J = 5.0 Hz , 2 N), 4.07 (s, 3 N), 3.93 (t, J = 5.1 Hz, 2 N), 3.60 (t, J = 4.9 Hz, 2 N), 3.34-3.38 (m, 2 N), 3.24 -3.31 (m, 1 N), 2.82 (q, J = 7.5 Hz, 2 N), 2.45 (s, 3 N), 2.10-2.19 (m, 2 N), 1.85-1.97 (m, 4 N), 1.72-1.84 (m, 2 N), 1.35 (t, J = 7.5 Hz, 3 N).

Example 24

2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) ethanol

The title compound (54 mg) was obtained as a pale yellow solid, by analogy with Example 23, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4 -oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (200 mg, 0.388 mmol) and ethanolamine (72 mg, 1.16 mmol); LC-MS: t _R = 0.95 min, [M + H] ⁺ = 481.10; ¹ H NMR (CD ₃ OD): 7.92 (s, 1 H), 7.91 (s, 1 H), 7.89 (s, 1 H), 7.81 (s, 1 H), 4.27 (s, 3 H), 4.02 (t, J = 5.9 Hz, 2 N), 3.87 (m, 2 N), 3.38-3.46 (m, 2 N), 3.34-3.38 (m, 1 N), 3.23-3.28 (m, 2 N), 2.79 (q, J = 7.5 Hz, 2 N), 2.42 (s, 3 N), 2.19-2.34 (m, 4 N), 1.80-2.02 (m, 6 N), 1.33 (t, J = 7.5 Hz, 3 H).

Example 25

2 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propane-1,3-diol

The title compound (66 mg) was obtained as a white solid by analogy with Example 23 starting from 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole -3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (227 mg, 0.453 mmol) and serinol (165 mg, 1.81 mmol); LC-MS: t _R = 0.91 min, [M + H] ⁺ = 497.11; ¹ H NMR (CD ₃ OD): δ 7.80 (s, 1 H), 7.78 (s, 1 H), 7.46 (s, 1 H), 7.20 (s, 1 H), 4.00 (t, J = 5.2 Hz , 2 N), 3.97 (s, 3 N), 3.71 (dd, J ₁ = 11.1 Hz, J ₂ = 5.3 Hz, 2 N), 3.62 (dd, J ₁ = 11.0 Hz, J ₂ = 6.0 Hz, 2 H), 3.19-3.29 (m, 1 N), 3.14 (t, J = 5.2 Hz, 2 N), 2.85 (quint., J = 5.6 Hz, 1 N), 2.77 (q, J = 7.5 Hz, 2 H), 2.38 (s, 3 N), 2.04-2.16 (m, 2 N), 1.83-1.95 (m, 4 N), 1.70-1.81 (m, 2 N), 1.30 (t, J = 7.5 Hz, 3 H).

Example 26

2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) propane-1,3-diol

The title compound (54 mg) was obtained as a pale brown oil by analogy with Example 23 starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4- oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (200 mg, 0.388 mmol) and serinol (106 mg, 1.16 mmol); LC-MS: t _R = 0.93 min, [M + H] ⁺ = 511.28; ¹ H NMR (D ₆ -DMSO): δ 7.79 (s, 2 H), 7.54 (s, 1 H), 7.27 (s, 1 H), 4.38-4.45 (m, 2 H), 3.94 (s, 3 N), 3.88 (t, J = 6.1 Hz, 2 N), 3.36-3.45 (m, 2 N), 3.23-3.33 (m, 1 N), 2.81 (t, J = 6.7 Hz, 2 N), 2.71 (q, J = 7.5 Hz, 2 N), 2.52-2.58 (m, 1 N), 2.34 (s, 3 N), 1.98-2.10 (m, 2 N), 1.86-1.94 (m, 2 N), 1.76-1.85 (m, 4 N), 1.63-1.73 (m, 2 N), 1.23 (t, J = 7.5 Hz, 3 N).

Example 27

rac-3 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl ) amino) propane-1,2-diol

Mixture of 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (195 mg, 0.389 mmol) and rac-2,2-dimethyl-1,3-dioxolane-4-methanamine (51 mg, 0.389 mmol) in acetonitrile (6 ml) was stirred at 65 ° C for 16 hours. The mixture was separated using prep. HPLC to give rac-2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) ethanamine (180 mg) as a white solid. This substance is dissolved in 2 N. aq. HCl (1 ml) and dioxane (5 ml) and stirred at 60 ° C for 1 h. The solvent was evaporated and the crude product was purified using prep. TLC, eluting with DCM containing 15% methanol, and then using prep. HPLC to give the title compound (16 mg) as a white solid; LC-MS: t _R = 0.91 min, [M + H] ⁺ = 497.11; ¹ H NMR (CD ₃ OD): δ 7.82 (s, 1 H), 7.80 (s, 1 H), 7.48 (s, 1 H), 7.22 (s, 1 H), 4.00 (t, J = 5.0 Hz , 2 N), 3.98 (s, 3 N), 3.82-3.89 (m, 1 N), 3.53-3.63 (m, 2 N), 3.20-3.30 (m, 1 N), 3.08 (t, J = 5.0 Hz, 2 N), 2.88 (dd, J ₁ = 12.1 Hz, J ₂ = 3.7 Hz, 1 N), 2.70-2.81 (m, 3 N), 2.38 (s, N), 2.05-2.15 (m, 2 H), 1.84-1.95 (m, 4 N), 1.69-1.81 (m, 2 N), 1.30 (t, J = 7.5 Hz, 3 N).

Example 28

rac-3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl ) amino) propane-1,2-diol

The title compound (94 mg) was obtained as a pale brownish oil, by analogy with Example 27, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4- oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (200 mg, 0.388 mmol) and rac-2,2-dimethyl-1,3-dioxolan-4-methanamine (153 mg, 1.16 mmol); LC-MS: t _R = 0.93 min, [M + H] ⁺ = 511.28; ¹ H NMR (D ₆ -DMSO): δ 7.80 (s, 2 N), 7.55 (s, 1 H), 7.28 (s, 1 H), 4.55 (d br, J = 4.0 Hz, 1 H), 3.95 (s, 3 N), 3.88 (t, J = 6.1 Hz, 2 H), 3.50-3.58 (m, 1 N), 3.24-3.32 (m, 2 N), 2.67-2.79 (m, 4 N), 2.63 (dd, J ₁ = 11.7 Hz, J ₂ = 4.5 Hz, 1 N), 2.47 (dd, J ₁ = 11.8 Hz, J ₂ = 7.0 Hz, 1 N), 2.34 (s, 3 N), 1.99- 2.08 (m, 2 N), 1.87-1.95 (m, 2 N), 1.76-1.87 (m, 4 N), 1.64-1.73 (m, 2 N), 1.23 (t, J = 7.5 Hz, 3 N) .

Example 29

N- (3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) -2 hydroxyacetamide

a) A solution of 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl methanesulfonate (1.30 g, 2.52 mmol) in 7 N. NH ₃ in methanol (30 ml) was stirred at 55 ° C for 24 hours. The mixture was concentrated and dried to give crude 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2 , 4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propan-1-amine (1.24 g) as a pale yellow foam; LC-MS: t _R = 0.95 min, [M + H] ₊ = 437.33.

b) To a solution of 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propan-1 amine (200 mg, 0.458 mmol), glycolic acid (52 mg, 0.687 mmol) and DIPEA (178 mg, 1.37 mmol) in DMF (5 ml) add TBTU (191 mg, 0.596 mmol). The mixture, before it is diluted with EA (50 ml) and washed twice with sat. aq. NaHCO ₃ solution (50 ml) and, further, with brine (50 ml), stirred at rt within 18 hours. Org. the extract is dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product is purified using prep. HPLC to give the title compound (116 mg) as a pale yellow oil; LC-MS: t _R = 1.14 min, [M + H] ⁺ = 495.25; ¹ H NMR (CD ₃ OD): δ 7.85 (s, 1 H), 7.83 (s, 1 H), 7.53 (s, 1 H), 7.28 (s, 1 H), 4.01 (s, 2 H), 4.00 (s, 3 N), 3.94 (t, J = 6.1 Hz, 2 N), 3.57 (t, J = 6.9 Hz, 2 N), 3.24-3.31 (m, 1 N), 2.77 (q, J = 7.6 Hz, 2 N), 2.38 (s, 3 N), 2.05-2.16 (m, 4 N), 1.86-1.96 (m, 4 N), 1.72-1.82 (m, 2 N), 1.31 (t, J = 7.5 Hz, 3 N).

Example 30

N- (3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) -2 hydroxy-N-methylacetamide

a) 3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N-methylpropan- 1-amine (941 mg) was obtained by analogy with example 29 based on 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) - 2-ethyl-6-methylphenoxy) propyl methanesulfonate (700 mg, 1.36 mmol) and a 2 M solution of methylamine in THF (20 ml); LC-MS: t _R = 0.96 min, [M + H] ⁺ = 451.29.

b) The title compound (155 mg) was obtained as a pale yellow oil, by analogy with Example 29, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2, 4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N-methylpropan-1-amine (206 mg, 0.458 mmol) and glycolic acid (52 mg, 0.687 mmol); LC-MS: t _R = 1.19 min, [M + H] ₊ = 509.40; ¹ H NMR (CD ₃ OD): δ 7.84-7.86 (m, 1 H), 7.81-7.84 (m, 1 H), 7.51-7.53 (m, 1 H), 7.26-7.28 (m, 1 N), 4.35 (s, 0.7 N), 4.25 (s, 1.3 N), 4.00 (s, 3 N), 3.91 (q, J = 5.8 Hz, 2 N), 3.69 (m, 1.3 N), 3.55-3.61 (m , 0.7 N), 3.24-3.31 (m, 1 N), 3.06 (s, 1.05 N), 3.04 (s, 1.95 N), 2.72-2.79 (m, 2 N), 2.38 (s, 3 N), 2.07 -2.19 (m, 4 N), 1.85-1.96 (m, 4 N), 1.71-1.83 (m, 2 N), 1.28-1.35 (m, 3 N) (1: 2 mixture of atropisomers).

Example 31

3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) -3-oxopropanoic acid

To a solution of 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propan-1-amine (200 mg, 0.458 mmol), monoethyl malonate (91 mg, 0.687 mmol) and DIPEA (178 mg, 1.37 mmol) in DMF (5 ml) add TBTU (191 mg, 0.596 mmol). The mixture was stirred at rt. for 18 hours. The solution was diluted with EA (50 ml) and washed twice with sat. aq. NaHCO ₃ solution (50 ml) and then with brine (50 ml). Org the extract was dried over Na ₂ SO ₄ , filtered and concentrated to give crude ethyl 3 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole-3 -yl) -2-ethyl-6-methylphenoxy) propyl) amino) -3-oxopropanoate (298 mg) as a yellow oil; LC-MS: t _R = 1.19 min, [M + H] ⁺ = 551.38. This substance is dissolved in methanol (2 ml), THF (2 ml) and 2 N. aq. LiOH (1 ml). The solution was stirred at rt. for 2 hours, before it is concentrated, diluted with DCM (20 ml), and washed with 2 N. aq. HCl (10 ml). Vodn. the phase is extracted three times with DCM (3 × 20 ml). The combined organic extracts were dried over mgSO ₄ , filtered and concentrated. The crude product is purified using prep. HPLC to give the title compound (105 mg) as a white solid; LC-MS: t _R = 1.14 min, [M + H] ⁺ = 523.21; ¹ H NMR (CD ₃ OD): δ 7.82 (s, 1 H), 7.79 (s, 1 H), 7.49 (s, 1 H), 7.23 (s, 1 H), 3.99 (s, 3 H), 3.92 (t, J = 6.2 Hz, 2 N), 3.52 (t, J = 6.9 Hz, 2 N), 3.31 (s, 2 N), 3.22-3.31 (m, 1 N), 2.75 (q, J = 7.5 Hz, 2 N), 2.36 (s, 3 N), 2.04-2.15 (m, 4 N), 1.85-1.95 (m, 4 N), 1.73-1.82 (m, 2 N), 1.29 (t, J = 7.5 Hz, 3 N).

Example 32

4 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) -4-oxobutanoic acid

The title compound (106 mg) was obtained as a white solid, by analogy with Example 31, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole -3-yl) -2-ethyl-6-methylphenoxy) propan-1-amine (200 mg, 0.458 mmol) and monomethyl succinate (96 mg, 0.687 mmol); LC-MS: t _R = 1.13 min, [M + H] ⁺ = 537.22; ¹ H NMR (CD ₃ OD): δ 7.81 (s, 1 H), 7.79 (s, 1 H), 7.48 (s, 1 H), 7.22 (s, 1 H), 3.98 (s, 3 H), 3.90 (t, J = 6.2 Hz, 2 N), 3.47 (t, J = 7.0 Hz, 2 N), 3.21-3.30 (m, 1 N), 2.74 (q, J = 7.5 Hz, 2 N), 2.63 (t, J = 7.0 Hz, 2 N), 2.51 (t, J = 6.7 Hz, 2 N), 2.36 (s, 3 N), 2.02-2.14 (m, 4 N), 1.83-1.95 (m, 4 H), 1.71-1.80 (m, 2 N), 1.29 (t, J = 7.5 Hz, 3 N).

Example 33

3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) ( methyl) amino) -3-oxopropanoic acid

The title compound (103 mg) was obtained as a pale yellow oil, by analogy with Example 31, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4- oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N-methylpropan-1-amine (206 mg, 0.458 mmol) and monoethyl malonate (91 mg, 0.687 mmol); LC-MS: t _R = 1.16 min, [M + H] ⁺ = 537.37; ¹ H NMR (CD ₃ OD): δ 7.81-7.84 (m, 1 H), 7.78-7.81 (m, 1 H), 7.49-7.50 (m, 1 H), 7.23-7.24 (m, 1 N), 3.99 (s, 3 N), 3.88-3.95 (m, 2 N), 3.66-3.74 (m, 2 N), 3.59-3.62 (m, 0.3 N), 3.52-3.54 (m, 0.7 N), 3.23- 3.30 (M, 1 N), 3.16 (s, 2.1 N), 3.05 (s, 0.9 N), 2.75 (q, J = 7.5 Hz, 2 N), 2.37 (s, 0.9 N), 2.36 (s, 2.1 H), 2.06-2.22 (m, 4 N), 1.84-1.95 (m, 4 N), 1.73-1.81 (m, 2 N), 1.26-1.33 (m, 3 N) (mixture of atropisomers).

Example 34

4 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) ( methyl) amino) -4-oxobutanoic acid

The title compound (168 mg) was obtained as a pale yellow oil, by analogy with Example 31, starting from 3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4- oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N-methylpropan-1-amine (206 mg, 0.458 mmol) and monomethyl succinate (96 mg, 0.687 mmol); LC-MS: t _R = 1.16 min, [M + H] ⁺ = 551.37; ¹ H NMR (CD ₃ OD): δ 7.80-7.83 (m, 1 H), 7.77-7.80 (m, 1 H), 7.47-7.49 (m, 1 H), 7.22-7.24 (m, 1 H), 3.98 (s, 3 N), 3.94 (t, J = 5.9 Hz, 0.8 N), 3.87 (t, J = 6.4 Hz, 1.2 N), 3.70-3.75 (m, 0.8 N), 3.63-3.68 (m, 1.2 N), 3.21-3.30 (m, 1 N), 3.16 (s, 2 N), 3.01 (s, 1 N), 2.60-2.80 (m, 6 N), 2.37 (s, 1.2 N), 2.35 ( s, 1.8 N), 2.06-2.23 (m, 4 N), 1.84-1.96 (m, 4 N), 1.71-1.82 (m, 2 N), 1.26-1.33 (m, 3 N).

Example 35

4- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) butanoic acid

a) 2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenol (900 mg) is obtained as a white solid substances by analogy with example 1, stage a), starting from 2-cyclopentyl-6-methoxy-isonicotinic acid (3.00 g, 13.6 mmol) and 3-chloro-4, N-dihydroxy-5-methoxy-benzamidine (3.08 g, 14.24 mmol); LC-MS: t _R = 1.18 min, [M + H] ⁺ = 401.98.

b) The title compound (182 mg) was obtained as a colorless oil, by analogy with Example 6, starting from 2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4 -oxadiazol-3-yl) -6-methoxyphenol (225 mg, 0.56 mmol) and ethyl 4-bromobutyrate (169 mg, 0.84 mmol); LC-MS: t _R = 1.12 min, [M + H] ⁺ = 488.17; ¹ H NMR (CDCl ₃ ): 6 7.86 (d, J = 1.9 Hz, 1 N), 7.62 (d, J = 1.8 Hz, 1 N), 7.50 (d, J = 0.8 Hz, 1 N), 7.30 ( d, J = 0.9 Hz, 1 N), 4.17 (t, J = 5.9 Hz, 2 N), 4.02 (s, 3 N), 3.99 (s, 3 N), 3.20-3.29 (m, 1 N), 2.78 (t, J = 7.3 Hz, 2 N), 2.06-2.21 (m, 4 N), 1.84-1.95 (m, 4 N), 1.69-1.79 (m, 2 N).

Example 36

4- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) -N- (2-hydroxyethyl ) butanamide

The title compound (51 mg) was obtained as a colorless oil, by analogy with Example 13, starting from 4- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2, 4-oxadiazol-3-yl) -6-methoxyphenoxy) butanoic acid (75 mg, 0.154 mmol) and ethanolamine (11 mg, 0.184 mmol); LC-MS: t _R = 1.06 min, [M + H] ⁺ = 531.15; ¹ H NMR (CDCl ₃ ): δ 7.86 (d, J = 1.8 Hz, 1 N), 7.62 (d, J = 1.8 Hz, 1 N), 7.49 (s, 1 N), 7.30 (s, 1 N) , 6.23 (s br, 1 N), 4.17 (t, J = 5.7 Hz, 2 N), 4.02 (s, 3 N), 3.99 (s, 3 N), 3.76 (t, J = 4.8 Hz, 2 N ), 3.48 (q, J = 5.4 Hz, 2 N), 3.19-3.29 (m, 1 N), 2.60 (t, J = 7.2 Hz, 2 N), 2.14-2.22 (m, 2 N), 2.06- 2.15 (m, 2 N), 1.84-1.95 (m, 4 N), 1.69-1.80 (m, 2 N).

Example 37

3 - ((2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) amino ) propanoic acid

The title compound was prepared by analogy with Example 1 starting from 2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6- methoxyphenol; LC-MS: t _R = 0.86 min, [M + H] ⁺ = 517.17.

Example 38

N- (3- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) propyl) -2 hydroxyacetamide

The title compound was prepared by analogy with Example 29 starting from 2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6- methoxyphenol; LC-MS: t _R = 1.08 min, [M + H] ⁺ = 517.19; ¹ H NMR (CDCl ₃ ): 5 7.88 (d, J = 1.7 Hz, 1 N), 7.64 (d, J = 1.7 Hz, 1 N), 7.50 (s, 1 N), 7.31 (s, 1 N) , 7.02 (s br, 1 N), 4.19 (t, J = 5.6 Hz, 2 N), 4.16 (s, 2 N), 4.02 (s, 3 N), 4.01 (s, 3 N), 3.70 (q , J = 6.1 Hz, 2 N), 3.20-3.29 (m, 1 N), 2.03-2.16 (m, 4 N), 1.84-1.95 (m, 4 N), 1.70-1.80 (m, 2 N).

Example 39

4 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) butanoic acid

The title compound (88 mg) was obtained as a beige solid, by analogy with Example 1, starting from 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole -3-yl) -2-ethyl-6-methyl-phenoxy) ethyl methanesulfonate (292 mg, 0.582 mmol) and tert-butyl γ-amino butyrate hydrochloride (263 mg, 1.34 mmol); LC-MS: t _R = 0.93 min, [M + H] ⁺ = 509.27; ¹ H NMR (D ₆ -DMSO): δ 7.79 (s, 2 N), 7.53 (s, 1 N), 7.26 (s, 1 N), 4.04 (s br, 2 N), 3.94 (s, 3 N ), 3.90 (t, J = 5.4 Hz, 2 N), 3.23-3.33 (m, 1 N), 2.99 (t, J = 5.4 Hz, 2 N), 2.66-2.77 (m, 4 N), 2.35 ( s, 3 N), 2.30 (t, J = 7.0 Hz, 2 N), 1.99-2.09 (m, 2 N), 1.75-1.88 (m, 4 N), 1.62-1.73 (m, 4 N), 1.23 (t, J = 7.5 Hz, 3 N).

Example 40

4- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) butanoic acid

a) A mixture of 3-chloro-4-hydroxy-5-methyl-benzonitrile (1.15 g, 6.87 mmol) and Cs ₂ CO ₃ (13.43 g, 41.2 mmol) in DMF (45 ml) was stirred at rt. 30 minutes before tert-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) was added. The orange suspension was stirred at 65 ° C for 72 hours. Another portion of tert-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) was added and stirring was continued at 65 ° C for 24 hours. The mixture was diluted with water (150 ml) and extracted three times with DCM (3 × 50 ml) and EA (3 × 50 ml). Org the extracts are combined, dried over MgSO ₄ , filtered and concentrated. The crude product is purified by silica gel gel chromatography, eluting with heptane: EA: methanol to give tert-butyl 4- (2-chloro-4-cyano-6-methylphenoxy) butanoate (645 mg) as a colorless oil; LC-MS: t _R = 1.01 min, [M + H] ⁺ = mass cannot be detected; ¹ H NMR (D ₆ -DMSO): δ 7.94 (d, J = 1.7 Hz, 1 N), 7.75 (d, J = 1.3 Hz, 1 N), 3.95 (t, J = 6.3 Hz, 2 N), 2.46 (t, J = 7.2 Hz, 2 N), 2.30 (s, 3 N), 1.98 (quint., J = 6.6 Hz, 2 N), 1.41 (s, 9 N).

b) A solution of tert-butyl 4- (2-chloro-4-cyano-6-methylphenoxy) butanoate (640 mg, 2.07 mmol), triethylamine (418 mg, 4.13 mmol) and hydroxylamine hydrochloride (215 mg, 3.10 mmol) in ethanol (5 ml) was stirred at 65 ° C for 72 hours. The mixture is concentrated and the crude product is purified using prep. HPLC to give tert-butyl 4- (2-chloro-4- (N-hydroxycarbamimidoyl) -6-methylphenoxy) butanoate (145 mg) as a pale gray solid; LC-MS: t _R = 0.65 min, [M + H] ⁺ = 343.20.

c) A mixture of 2-cyclopentyl-6-methoxy-isonicotinic acid (33 mg, 0.149 mmol), TBTU (50 mg, 0.156 mmol) and DIPEA (62 mg, 0.479 mmol) in DMF (2 ml) before being added tert-butyl 4- (2-chloro-4- (N-hydroxycarbamimidoyl) -6-methylphenoxy) butanoate (51 mg, 0.149 mmol) was stirred at rt. within 15 minutes The mixture was stirred at rt. for 1 h, before another portion of TBTU (50 mg, 0.156 mmol) was added. Stirring is continued at rt. for 2 hours. The mixture was heated to 110 ° C and stirring was continued for another hour. The mixture is concentrated and the crude product is purified using prep. HPLC to give tert-butyl 4- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) butanoate (33 mg) as a colorless glass; LC-MS: t _R = 1.28 min, [M + H] ⁺ = 528.37.

d) Solution of tert-butyl 4- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) butanoate (90 mg, 170 μmol) in DCM (5 ml), before adding TFA (1 ml), cooled to 0 ° C. The mixture was stirred at 0 ° C for 10 minutes, then at rt. within 30 minutes The mixture, before another portion of TFA (1 ml) is added, is again cooled to 0 ° C. Stirring is continued at rt. for 2 hours. The mixture is concentrated and the crude product is purified using prep. HPLC to give the title compound (59 mg) as a white solid; LC-MS: t _R = 1.14 min, [M + H] ⁺ = 472.29; ¹ H NMR (CDCl ₃ ): δ 8.13 (s br, 1 H), 8.02 (d, J = 1.4 Hz, 1 H), 7.88 (d, J = 0.7 Hz, 1 H), 7.47 (s, 1 N ), 7.25 (s, 1 N), 4.05 (t, J = 5.9 Hz, 2 H), 4.00 (s, 3 N), 3.17-3.28 (m, 1 N), 2.74 (t, J = 7.3 Hz, 2 H), 2.39 (s, 3 N), 2.21 (quint., J = 6.5 Hz, 2 N), 2.05-2.15 (m, 2 N), 1.81-1.95 (m, 4 N), 1.68-1.80 ( m, 2 N).

Example 41

2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) acetic acid

a) tert-Butyl 2- (2-chloro-4- (N-hydroxycarbamimidoyl) -6-methylphenoxy) acetate is obtained by analogy with tert-butyl 4- (2-chloro-4- (N-hydroxycarbamimidoyl) -6-methylphenoxy ) butanoate (example 40); LC-MS: t _R = 0.57 min, [M + H] ⁺ = 315.2.

b) The title compound was obtained as a white solid based on the above tert-butyl 2- (2-chloro-4- (N-hydroxycarbamimidoyl) -6-methylphenoxy) acetate and 2-cyclopentyl-6-methoxy-isonicotinic acid analogies with example 40; LC-MS: t _R = 1.16 min, [M + H] ⁺ = 444.24; ¹ H NMR (CDCl ₃ ): δ 8.99 (s br, 1 N), 8.07 (d, J = 1.8 Hz, 1 N), 7.94 (d, J = 1.2 Hz, 1 N), 7.48 (s, 1 N ), 7.27 (s, 1 Н), 4.75 (s, 2 Н), 4.01 (s, 3 Н), 3.18-3.30 (m, 1 Н), 2.47 (s, 3 Н), 2.05-2.17 (m, 2 N), 1.82-1.95 (m, 4 N), 1.69-1.81 (m, 2 N).

Example 42

2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methyl-phenoxy) -N- (2 -hydroxyethyl) acetamide

The title compound was obtained in the form of beige wax, starting from the compound of Example 41, by analogy with Example 13; LC-MS: t _R = 1.09 min, [M + H] ⁺ = 487.24; ¹ H NMR (CDCl ₃ ): δ 8.01 (s, 1 H), 7.89 (s, 1 H), 7.47 (t br, J = 5.3 Hz, 1 H), 7.44 (s, 1 H), 7.22 (s , 1 N), 4.48 (s, 2 N), 3.99 (s, 3 N), 3.84 (t, J = 4.9 Hz, 2 N), 3.61 (q, J = 5.4 Hz, 2 N), 3.16-3.27 (m, 1 N), 3.05 (s br, 1 N), 2.39 (s, 3 N), 2.04-2.15 (m, 2 N), 1.81-1.93 (m, 4 N), 1.68-1.78 (m, 2 N).

Example 43

3 - ((2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) amino ) propanoic acid

a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (704 mg, 3.18 mmol) in DMF (5 ml) was added TBTU (1.43 g, 4.45 mmol) and a Huning base. The mixture, before 3-chloro-4- (2,2-diethoxyethoxy) -N-hydroxy-5-methylbenzimidamide (907 mg, 2.86 mmol) was added, was stirred at rt. within 15 minutes Stirring before another portion of 3-chloro-4- (2,2-diethoxyethoxy) -N-hydroxy-5-methylbenzimidamide (503 mg, 1.59 mmol) and TBTU (510 mg, 1.59 mmol) was added continued for 18 hours. Stirring is continued for 4 hours. The mixture is diluted with EA (100 ml) and washed with water (50 ml). The wash liquid was extracted three times with EA (3 × 50 ml). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in dioxane (35 ml), and the resulting solution was stirred at 110 ° C for 18 hours. The solvent was evaporated and the crude product was purified by HPLC on silica gel, eluting with heptane: EA 7: 3 to give 3- (3-chloro- 4- (2,2-diethoxyethoxy) -5-methylphenyl) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole (1.01 g) as a yellow oil; LC-MS: t _R = 1.43 min, [M + H] ⁺ = 502.29; ¹ H NMR (CDCl _3): δ 8.06 (d, J = 1.9 Hz, 1 H), 7.92 (d, J = 1.4 Hz, 1 H), 7.50 (d, J = 0.9 Hz, 1 H), 7.29 ( d, J = 1.1 Hz, 1 N), 4.94 (t, J = 5.3 Hz, 1 N), 4.08 (d, J = 5.3 Hz, 2 N), 4.02 (s, 3 N), 3.77-3.86 (m , 2 N), 3.64-3.73 (m, 2 N), 3.19-3.29 (m, 1 N), 2.44 (s, 3 N), 2.08-2.14 (m, 2 N), 1.83-1.94 (m, 4Н ), 1.71-1.77 (m, 2 N), 1.28 (t, J = 7.1 Hz, 6 N).

b) A solution of 3- (3-chloro-4- (2,2-diethoxyethoxy) -5-methylphenyl) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazole (1.01 g, 2.01 mmol) in dioxane (15 ml) and 2 M aq. H ₂ SO ₄ (5 ml) was stirred at 80 ° C for 3 hours. The mixture was extracted with EA (100 ml) and org. the extract is washed twice with brine (2 × 35 ml), dried over MgSO ₄ , filtered and concentrated to give crude 2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1 , 2,4-oxadiazol-3-yl) -6-methylphenoxy) acetaldehyde (1.02 g) as a yellow oil; LC-MS: t _R = 1.11 min, [M + H] ⁺ = 428.19. Part of this substance (345 mg, 0.806 mmol), before β-alanine (72 mg, 0.806 mmol) is added, is dissolved in DCM (10 ml), methanol (10 ml) and acetic acid (0.7 ml). The mixture, before Na (BH ₃ CN) (23 mg, 0.364 mmol) was added, was degassed and placed under argon. A clear solution, before the reaction is quenched by adding water (2 ml), is stirred at rt for 2 hours. The mixture is concentrated and the crude product is purified using prep. HPLC to give the title compound (77 mg) as a brownish solid; LC-MS: t _R = 0.95 min, [M + H] ⁺ = 501.23; ¹ H NMR (CDCl ₃ ): δ 8.53 (s br, 2 H), 7.83 (s, 1 H), 7.67 (s, 1 H), 7.33 (s, 1 H), 7.07 (s, 1 H), 4.20-4.30 (m, 2 N), 3.95 (s, 3 N), 3.39-3.49 (m, 2 N), 3.25-3.36 (m, 2 N), 3.12-3.22 (m, 1 N), 2.64- 2.75 (m, 2 N), 2.32 (s, 3 N), 2.02-2.12 (m, 2 N), 1.78-1.91 (m, 4 N), 1.68-1.78 (m, 2 N).

Example 44

1- (2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

The title compound was obtained as a beige solid using azetidine-3-carboxylic acid in analogy to Example 43; LC-MS: t _R = 0.95 min, [M + H] ⁺ = 514.06.

Example 45

2 - ((2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) amino ) ethanol

The title compound was obtained in the form of beige wax using ethanolamine in analogy to Example 43; LC-MS: t _R = 0.93 min, [M + H] ⁺ = 473.23; ¹ H NMR (CDCl ₃ ): δ 8.03 (d, J = 1.8 Hz, 1 N), 7.89 (d, J = 1.3 Hz, 1 N), 7.46 (s, 1 N), 7.25 (s, 1 N) , 4.12 (t, J = 5.0 Hz, 2 N), 4.00 (s, 3 N), 3.74 (t, J = 5.0 Hz, 2 N), 3.18-3.27 (m, 1 N), 3.10 (t, J = 5.0 Hz, 2 N), 2.93 (t, J = 5.2 Hz, 2 N), 2.54 (s br, 2 N), 2.41 (s, 3 N), 2.04-2.14 (m, 2 N), 1.81- 1.93 (m, 4 N), 1.67-1.79 (m, 2 N).

Example 46

4- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N- (2-hydroxyethyl ) butanamide

The title compound was prepared starting from Example 6 by analogy with Example 13; LC-MS: t _R = 1.10 min, [M + H] ⁺ = 509.49; ¹ H NMR (CDCl ₃ ): δ 7.85 (s, 1 H), 7.83 (s, 1 H), 7.49 (s, 1 H), 7.28 (s, 1 H), 6.29 (t, J = 5.0 Hz, 1 N), 4.00 (s, 3 N), 3.87 (t, J = 5.9 Hz, 2 N), 3.73-3.79 (m, 2 N), 3.45-3.52 (m, 2 N), 3.18-3.27 (m , 1 N), 3.03 (s br, 1 H), 2.72 (q, J = 7.5 Hz, 2 H), 2.54 (t, J = 7.3 Hz, 2 H), 2.35 (s, 3 H), 2.15- 2.24 (m, 2 H), 2.04-2.14 (m, 2 H), 1.82-1.96 (m, 4 H), 1.66-1.78 (m, 2 H), 1.30 (t, J = 7.5 Hz, 3 H) .

Example 47

(S) -3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) propanoic acid

The title compound was prepared from (S) -5- (2-cyclopentyl-6-methoxypyridin-4-yl) -3- (3-ethyl-5-methyl-4- (oxiran-2-ylmethoxy) phenyl) - 1,2,4-oxadiazole and ethyl 3- (methylamino) propanoate by analogy with example 9; LC-MS: t _R = 0.95 min, [M + H] ⁺ = 539.53; ¹ H NMR (CDCl ₃ ): δ 7.84 (s, 1 H), 7.82 (s, 1 H), 7.48 (s, 1 H), 7.27 (s, 1 H), 6.49 (s br, 2 H), 4.52-4.60 (m, 1 N), 4.00 (s, 3 N), 3.90-3.96 (m, 1 N), 3.84-3.90 (m, 1 N), 3.41-3.51 (m, 2 N), 3.18- 3.39 (m, 3 N), 2.97 (s, 3 N), 2.68-2.80 (m, 4 N), 2.36 (s, 3 N), 2.04-2.14 (m, 2 N), 1.82-1.94 (m, 4 N), 1.68-1.78 (m, 2 N), 1.30 (t, J = 7.5 Hz, 3 H).

Example 48

(R) -3 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) propanoic acid

The title compound was prepared by analogy with example 47; LC-MS: t _R = 0.94 min, [M + H] ⁺ = 539.35.

Example 49

3 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) -3-oxopropanoic acid

a) 2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethanamine (2.10 g) prepared from 2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl methanesulfonate (2.14 g, 4.27 mmol) and 7 n. ammonia in methanol by analogy with example 29; LC-MS: t _R = 0.91 min, [M + H] ⁺ = 464.29.

b) The title compound was prepared from the above amine and mono-tert-butyl malonate by analogy with Example 31; LC-MS: t _R = 1.11 min, [M + H] ⁺ = 509.21; ¹ H NMR (CDCl ₃ ): δ 7.54 (s, 1 H), 7.47 (s, 1 H), 7.21 (s, 1 H), 6.95 (s, 1 H), 4.99 (s br, 2 H), 3.85 (s, 3 N), 3.68-3.77 (m, 2 N), 3.57-3.65 (m, 2 N), 3.41 (s, 2 N), 3.02-3.12 (m, 1 N), 2.50 (q, J = 7.0 Hz, 2 N), 2.12 (s, 3 N), 1.93-2.03 (m, 2 N), 1.70-1.85 (m, 4 N), 1.61-1.70 (m, 2 N), 1.12 (t , J = 7.4 Hz, 3 N).

Example 50

4 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) -4-oxobutanoic acid

The title compound was prepared by analogy with Example 49 using monomethyl succinate; LC-MS: t _R = 1.17 min, [M + H] ⁺ = 537.25.

Example 51

2 - ((2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) amino )acetic acid

The title compound was prepared starting from 2-cyclopentyl-6-methoxy-isonicotinic acid, 3-chloro-4- (2,2-dimethoxyethoxy) -N-hydroxy-5-methoxybenzimidamide and ethyl glycinate by analogy with example 43 and 1 ( saponification); LC-MS: t _R = 0.88 min, [M + H] ⁺ = 503.11.

Example 52

1- (2- (2-Chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) azetidine- 3-carboxylic acid

The title compound was prepared starting from 2-cyclopentyl-6-methoxy-isonicotinic acid, 3-chloro-4- (2,2-dimethoxyethoxy) -N-hydroxy-5-methoxybenzimidamide and ethyl azetidine-3-carboxylate by analogy with the example 43 and 1 (saponification); LC-MS: t _R = 0.88 min, [M + H] ⁺ = 528.92; ¹ H NMR (CDCl ₃ ): δ 7.79 (d, J = 1.5 Hz, 1 N), 7.57 (d, J = 1.4 Hz, 1 N), 7.45 (s, 1 N), 7.24 (s, 1 N) , 5.96 (s br, 1 N), 4.55-4.64 (m, 2 N), 4.44-4.54 (m, 2 N), 4.32-4.38 (m, 2 N), 4.00 (s, 6 N), 3.65- 3.74 (m, 1 N), 3.58-3.65 (m, 2 N), 3.18-3.27 (m, 1 N), 2.05-2.14 (m, 2 N), 1.82-1.94 (m, 4 N), 1.75 ( m, 2 N).

Example 53

2- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) acetic acid

a) To a solution of 2-cyclopentyl-N-hydroxy-6-methoxy-isonicotinamidine (870 mg, 3.70 mmol), 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.00 g, 3.70 mmol) and DIPEA (1.44 g, 11.1 mmol) in DCM (30 ml) add TBTU (1.43 g, 4.44 mmol). The mixture, before it is diluted with EA (150 ml) and water (50 ml), is stirred at rt within 1 h. Org. the phase is separated, washed with sat. aq. NaHCO ₃ solution (50 ml) and then with brine (50 ml), dried over MgSO ₄ , filtered and concentrated. The remaining pale brown oil was dissolved in dioxane (40 ml) and then stirred at 115 ° C for 48 h The solvent was evaporated and the crude product was purified by chromatography on silica gel eluting with 1: 9 heptane: EA to give 4- [5- (4-benzyloxy-3-ethyl-5-methyl-phenyl) - [1,2,4 ] oxadiazol-3-yl] -2-cyclopentyl-6-methoxy-pyridine (1040 mg) as a pale yellow oil; LC-MS ∗∗: t _R = 1.11 min, [M + H] ⁺ = 470.26.

b) Pd / C (150 mg, 10% Pd) is added to a solution of 4- [5- (4-benzyloxy-3-ethyl-5-methyl-phenyl) - [1,2,4] oxadiazol-3-yl] -2-cyclopentyl-6-methoxy-pyridine (1040 mg, 2.22 mmol) in THF (20 ml) and methanol (20 ml). The mixture is stirred under a pressure of 1 bar H ₂ at KT within 24 hours. The catalyst was removed by filtration and the filtrate was concentrated and dried to give 4- [3- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -2-ethyl-6-methyl-phenol (672 mg) as an off-white solid; LC-MS ∗∗: t _R = 0.97 min, [M + H] ⁺ = 380.27.

c) The title compound is obtained from the above phenol using ethyl bromoacetate in analogy to Example 5; LC-MS: t _R = 1.15 min, [M + H] ⁺ = 438.21; ¹ H NMR (CDCl ₃ ): δ 7.87 (s, 1 H), 7.83 (s, 1 H), 7.42 (s, 1 H), 7.22 (s, 1 H), 6.85 (s br, 1 H), 4.41 (s, 2 N), 3.97 (s, 3 N), 3.13-3.25 (m, 1 N), 2.73 (q, J = 7.5 Hz, 2 N), 2.36 (s, 3 N), 2.01-2.13 (m, 2 N), 1.81-1.93 (m, 4 N), 1.66-1.76 (m, 2 N), 1.29 (t, J = 7.5 Hz, ЗН).

Example 54

4- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) butanoic acid

The title compound was prepared by analogy with Example 53 using ethyl 4-iodobutyrate in step c); LC-MS: t _R = 1.21 min, [M + H] ⁺ = 465.99; ¹ H NMR (CDCl ₃ ): δ 8.53 (s br, 1 H), 7.92 (s, 1 H), 7.91 (s, 1 H), 7.48 (s, 1 H), 7.29 (s, 1 H), 4.00 (s, 3 N), 3.91 (t, J = 6.1 Hz, 2 N), 3.16-3.27 (m, 1 N), 2.69-2.79 (m, 4 N), 2.39 (s, 3 N), 2.17 -2.26 (m, 2 N), 2.04-2.14 (m, 2 N), 1.82-1.95 (m, 4 N), 1.67-1.79 (m, 2 N), 1.32 (t, J = 7.5 Hz, 3 N )

Example 55

2 - ((2- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) amino )acetic acid

The title compound was prepared from 4- [3- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -2-ethyl-6-methyl- phenol (Example 53, Step b), by analogy with Example 1, using tert-butyl glycinate; LC-MS: t _R = 0.93 min, [M + H] ⁺ = 481.12.

Example 56

2 - ((2- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) ( methyl) amino) acetic acid

The title compound was prepared from 4- [3- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -2-ethyl-6-methyl- phenol (Example 53, Step b), by analogy with Example 1, using sarcosine methyl ester; LC-MS: t _R = 0.95 min, [M + H] ⁺ = 495.23; ¹ H NMR (CDCl ₃ ): δ 7.84 (s, 1 H), 7.81 (d, J = 1.6 Hz, 1 H), 7.40 (s, 1 H), 7.20 (d, J = 0.7 Hz, 1 N) , 6.42 (s br, 1 N), 4.18-4.24 (m, 2 N), 3.96 (s, 3 N), 3.88 (s, 2 N), 3.66-3.73 (m, 2 N), 3.11-3.21 ( m, 1 N), 3.10 (s, 3 N), 2.70 (q, J = 7.5 Hz, 2 N), 2.36 (s, 3 N), 2.00-2.11 (m, 2 N), 1.79-1.92 (m , 4 N), 1.65-1.77 (m, 2 N), 1.28 (t, J = 7.5 Hz, 3 N).

Example 57

3 - ((2- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid

The title compound was prepared from 4- [3- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -2-ethyl-6-methyl- phenol (Example 53, Step b), by analogy with Example 1, using β-alanine ethyl ester; LC-MS: t _R = 0.94 min, [M + H] ⁺ = 495.20.

Example 58

1- (2- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

The title compound was prepared from 4- [3- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -2-ethyl-6-methyl- phenol (Example 53, Step b), by analogy with Example 1, using azetidine-3-carboxylic acid methyl ester; LC-MS: t _R = 0.95 min, [M + H] ⁺ = 507.21.

Example 59

2 - ((3- (4- (3- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) propyl) amino )acetic acid

The title compound was prepared from 4- [3- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -2-ethyl-6-methyl- phenol (Example 53, Step b), by analogy with Example 1, using 3-bromo-propanol and glycine tert-butyl ester; LC-MS: t _R = 0.97 min, [M + H] ⁺ = 495.24; ¹ H NMR (CDCl ₃ ): δ 7.84 (s, 1 H), 7.80 (s, 1 H), 7.41 (s, 1 H), 7.22 (s, 1 H), 3.97 (s, 3 H), 3.91 (t, J = 5.3 Hz, 2 N), 3.66 (s, 2 N), 3.34-3.41 (m, 2 N), 3.13-3.23 (m, 1 N), 2.68 (q, J = 7.4 Hz, 2 H), 2.35-2.43 (m, 2 N), 2.33 (s, 3 N), 2.02-2.11 (m, 2 N), 1.81-1.93 (m, 4 N), 1.67-1.76 (m, 2 N) , 1.29 (t, J = 7.5 Hz, 3 N); ¹³ C NMR (CDCl ₃ ): δ 175.7, 170.8, 167.7, 165.0, 164.2, 158.8, 137.9, 136.7, 131.9, 129.0, 127.3, 120.0, 111.9, 105.5, 70.0, 53.5, 50.0, 47.5, 45.4, 33.3, 27.2 , 25.9, 22.8, 16.5, 14.7.

Example 60

2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) acetic acid

a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid hydrazide (870 mg, 3.70 mmol), 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.00 g, 3.70 mmol) and DIPEA (1.44 g, 11.1 mmol) in DCM (30 ml) add TBTU (1.43 g, 4.44 mmol). The mixture, before it is diluted with EA (150 ml) and water (50 ml), is stirred at rt. within 1 h. Org. the phase is separated, washed with sat. aq. a solution of ManSO ₃ (50 ml) and then brine (50 ml), dried over MgSO ₄ , filtered and concentrated. The remaining pale yellow oil was dissolved in THF (50 ml) and Burgess reagent (1.23 g, 5.18 mmol) was added. The mixture, before it is diluted with EA (200 ml) and washed twice with water (50 ml), is stirred at 110 ° C for 15 minutes under microwave radiation. Org the extract was dried over MgSO ₄ , filtered and concentrated, and the crude product was purified by KX on silica gel eluting with 1: 9 heptane: EA to give 4- [5- (4-benzyloxy-3-ethyl-5-methyl-phenyl) - [1,3,4] oxadiazol-2-yl] -2-cyclopentyl-6-methoxy-pyridine (750 mg) as a pale yellow oil; LC-MS ∗∗: t _R = 1.06 min, [M + H] ⁺ = 470.21.

b) Pd / C (150 mg, 10% Pd) is added to a solution of 4- [5- (4-benzyloxy-3-ethyl-5-methyl-phenyl) - [1,3,4] oxadiazol-2-yl] -2-cyclopentyl-6-methoxy-pyridine (750 mg, 1.60 mmol) in THF (20 ml) and methanol (20 ml). The mixture is stirred under a pressure of 1 bar H ₂ at KT within 24 hours. The catalyst was removed by filtration and the filtrate was concentrated and dried to give 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,3,4] oxadiazol-2-yl] -2-ethyl-6-methyl-phenol (495 mg) as a white solid; LC-MS ∗∗: t _R = 0.91 min, [M + H] ⁺ = 380.25; ¹ H NMR (D ₆ -DMSO): δ 1.20 (t, J = 7.5 Hz, 3 N), 1.65-1.74 (m, 2 N), 1.76-1.88 (m, 4 N), 1.99-2.09 (m, 2 N), 2.29 (s, 3 N), 2.69 (q, J = 7.5 Hz, 2 N), 3.94 (s, 3 N), 7.26 (d, J = 1.0 Hz, 1 N), 7.50 (d, J = 0.8 Hz, 1 N), 7.76 (d, J = 2.0 Hz, 1 N), 7.78 (d, J = 2.0 Hz, 1 N).

c) The title compound is obtained from the above phenol using ethyl bromoacetate in analogy to Example 5; LC-MS: t _R = 1.03 min, [M + H] ⁺ = 438.33.

Example 61

4- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) butanoic acid

The title compound was prepared by analogy with Example 60 using ethyl 4-iodobutyrate in step c); LC-MS: t _R = 1.09 min, [M + H] ⁺ = 466.38; ¹ H NMR (D ₆ -DMSO): δ 7.88 (s, 1 H), 7.87 (s, 1 H), 7.52 (s, 1 H), 7.29 (s, 1 H), 3.94 (s, 3 N) , 3.84 (t, J = 6.3 Hz, 2 N), 3.21-3.31 (m, 1 N), 2.70 (q, J = 7.5 Hz, 2 N), 2.43 (t, J = 7.3 Hz, 2 N), 2.34 (s, 3 N), 1.96-2.09 (m, 4 N), 1.76-1.88 (m, 4 N), 1.63-1.74 (m, 2 N), 1.23 (t, J = 7.5 Hz, 3 N) .

Example 62

3 - ((2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid

The title compound was prepared starting from 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,3,4] oxadiazol-2-yl] -2-ethyl-6-methyl α-phenol (Example 60, step b), by analogy with Example 1, using β-alanine ethyl ester; LC-MS: t _R = 0.85 min, [M + H] ⁺ = 495.37; ¹ H NMR (CDCl ₃ ): δ 7.73 (s, 1 H), 7.67 (s, 1 H), 7.38 (s, 1 H), 7.12 (s, 1 H), 4.13-4.18 (m, 2 N) , 3.98 (s, 3 Н), 3.37-3.42 (m, 2 Н), 3.23-3.29 (m, 2 Н), 3.15-3.23 (m, 1 Н), 2.64-2.74 (m, 4 Н), 2.35 (s, 3 N), 2.02-2.13 (m, 2 N), 1.81-1.93 (m, 4 N), 1.67-1.78 (m, 2 N), 1.27 (t, J = 7.5 Hz, 3 N).

Example 63

1- (2- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid

The title compound was prepared from 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,3,4] oxadiazol-2-yl] -2-ethyl-6-methyl- phenol (Example 60, step b), by analogy with Example 1, using azetidine-3-carboxylic acid methyl ester; LC-MS: t _R = 0.84 min, [M + H] ⁺ = 507.37.

Example 64

(S) -1- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) -3- ((2-hydroxyethyl) amino) propan-2-ol

The title compound was prepared from 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,3,4] oxadiazol-2-yl] -2-ethyl-6-methyl- phenol (example 60, step b) by analogy with example 3; LC-MS: t _R = 0.82 min, [M + H] ⁺ = 498.24; ¹ H NMR (CDCl ₃ ): δ 7.81 (s, 1 H), 7.79 (s, 1 H), 7.44 (s, 1 H), 7.18 (s, 1 H), 4.15-4.23 (m, 1 N) , 3.99 (s, 3 N), 3.86 (d, J = 5.0 Hz, 2 N), 3.76 (t, J = 4.7 Hz, 2 N), 3.15-3.34 (m, 4 N), 2.84-2.98 (m , 4 N), 2.74 (q, J = 7.5 Hz, 2 N), 2.38 (s, 3 N), 2.02-2.12 (m, 2 N), 1.80-1.93 (m, 4 N), 1.65-1.77 ( m, 2 N), 1.29 (t, J = 7.5 Hz, 3 N).

Example 65

(S) -2 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) propane-1,3-diol

The title compound was prepared from 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,3,4] oxadiazol-2-yl] -2-ethyl-6-methyl- phenol (example 60, step b) by analogy with example 4; LC-MS: t _R = 0.82 min, [M + H] ⁺ = 527.37.

Example 66

(S) -4 - ((3- (4- (5- (2-Cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) -4-oxobutanoic acid

The title compound was prepared from (S) -2- (2-cyclopentyl-6-methoxypyridin-4-yl) -5- (3-ethyl-5-methyl-4- (oxiran-2-ylmethoxy) phenyl) - 1,3,4-oxadiazole (derived from 4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,3,4] oxadiazol-2-yl] -2-ethyl-6 -methyl-phenol (example 60, stage b) analogously to example 3, stage a) by analogy with example 14, using mono-tert-butyl succinate; LC-MS: t _R = 0.94 min, [M + H] ⁺ = 553.19; ¹ H NMR (CD ₃ OD): δ 7.83 (d, J = 1.8 Hz, 1 N), 7.79 (d, J = 1.6 Hz, 1 N), 7.43 (d, J = 0.7 Hz, 1 N), 7.16 (d, J = 0.9 Hz, 1 N), 4.08-4.15 (m, 1 N), 3.97 (s, 3 N), 3.81-3.91 (m, 2 N), 3.57 (dd, J ₁ = 13.7 Hz, J ₂ = 4.7 Hz, 1 N), 3.33-3.39 (m, 1 N), 3.19-3.28 (m, 1 N), 2.80 (q, J = 7.5 Hz, 2 N), 2.52 (s, 4 N) , 2.40 (s, 3 N), 2.04-2.14 (m, 2 N), 1.84-1.96 (m, 4 N), 1.71-1.80 (m, 2 H), 1.31 (t, J = 7.5 Hz, 3 N )

Example 67

S1P ₁ analysis of β-arrestin (Tango) recruitment to determine EC ₅₀ values

The principle of analysis:

After ligand activation, G protein-conjugated receptors (GPCRs) trigger two pathways that independently transduce signals into the cell: one via heterotrimeric GTP-binding proteins (G proteins), and one via β-arrestins. GPCR agonist-induced recruitment of β-arrestin proteins, which then bind to the carboxy-terminal domain of the activated GPCR ligand. A quantitative measure of β-arrestin recruitment can be used to evaluate the potency and effectiveness of GPCR activating ligands.

To measure the potency and effectiveness of the compounds as agonists of the S1P ₁ (EDG1) receptor, Tango ™ -EDG1 bla U2OS cells are used (Invitrogen, USA, catalog No. K1520). Tango ™ GPCR technology is based on GeneBLAzer analyzes of β-lactamase reporter cells that use the mammalian-optimized β-lactamase reporter gene (bla) in combination with FRET (resonant fluorescence energy transfer), an involved substrate. Host cells, U2OS, stably express the human S1P ₁ receptor (EDG1) / transcription factor (TF) fusion protein. Cells also express a recombinant, protease-targeted β-arrestin protein that recruits to the S1P ₁ receptor after ligand stimulation and specifically cleaves the S1P ₁ -TF fusion protein. Released TF activates the β-lactamase reporter gene (bla). To measure the activity of the reporter gene, the cells are loaded with a fluorescent substrate containing two chemically coupled fluorophores, coumarin and fluorescein. In the absence of bla expression, the substrate molecule remains unchanged, and excitation at a length of 410 nm leads to the emission of green fluorescence radiation (520 nM) due to internal FRET. In the presence of bla, the chemical bond is cleaved and the FRET is inhibited. In this case, excitation over a length of 410 nM results in a signal in the form of emission of blue fluorescence radiation (450 nm). The amount of β-arrestin recruitment is proportional to the increase in blue fluorescence.

Cell culture:

Tango ™ -EDG1 bla U2OS cells were cultured in McCoy's 5A containing 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 1 mM sodium pyruvate, 1% penicillin / streptomycin, 200 μg / ml zeocin, 50 μg / ml hygromycin and 100 μg / ml geneticin (Invitrogen, USA). The cells are trypsinized, resuspended in the medium and then counted. The cells are centrifuged, then washed with assay medium (Freestyle ™ HEK-293 expression medium (Invitrogen, USA)) and seeded at a density of 5000 cells / well in 384-well black clear plates bottom (Greiner, Germany) in 30 μl / well of assay medium.

Agonist Analysis:

Compounds (10 mM stock solution in DMSO) are diluted first in DMSO. Pre-diluted solutions of the compounds are then transferred to an analysis medium / 0.1% BSA free of fatty acids to achieve a fourfold concentrated basic solution of the compounds, which is applied to the cells to achieve final concentrations of the compounds that range from 10 μM to 0.0005 nM (0.5% final DMSO ) The cells are then incubated for 16 hours at 37 ° C and 5% CO ₂ .

Detection:

Substrate (1 μM LiveBLAzer ™ FRET substrate - B / G (with CCF4-AM), 1 mg / ml Pluronic® F-127 surfactant, 0.001% acetic acid, 4% w / w PEG 400, 3% TR-40 by volume in water (Invitrogen, USA)) is added to each well and cells are incubated for 2 hours at rt. In the dark. Plates are read using Synergy4 ™ (Biotek, USA) using excitation at a wavelength of 410 nm and emission at wavelengths of 450 nm and 520 nm.

Data analysis:

EC _{50 of the} test compound means the concentration of the compound inducing 50% of its maximum activity. For EC ₅₀ calculations, a ratio of 450 nM / 520 nM is calculated after subtracting the background (i.e., bands without cells), and the maximum effect of the compound is used as 100% and as the upper asymptote.

Agonistic activities (Tango EC ₅₀ values) were measured for all illustrative compounds, and they range from 0.02 to 69 nM with an average value of 3.3 nM. EC ₅₀ values of these compounds are shown in Table 2.

Example 68

In vivo efficacy assessment

The effectiveness of the compounds of formula (I) is evaluated by measuring the number of circulating lymphocytes after oral administration from 3 to 30 mg / kg of the compound of formula (I) to male rats with normal blood pressure. Animals are kept in controlled climatic conditions with a 12-h cycle of alternating light and dark, and provide free access to ordinary rat food and drinking water. Blood is taken before administration, as well as after 3, 6 and 24 hours after drug administration. Whole blood is subjected to hematology using the Advia Hematology system (Bayer Diagnostics, Zurich, Switzerland).

All data are presented as mean ± SEM. Statistical analysis is performed using analysis of variance (ANOVA) using Statistica (StatSoft) and the Student-Newman-Cales methodology for multiple comparisons. The null hypothesis is rejected when p <0.05.

As an example, Table 3 shows the effect of the compound of the present invention on the number of lymphocytes 6 hours after oral administration at a dose of 10 mg / kg to male Uistar rats with normal blood pressure, compared to a group of animals treated only with vehicle. The number of lymphocytes 6 hours after oral administration was measured for 49 of 66 exemplary compounds, and it was in the range of -24% -82% with an average of 63% (excluding the compounds of examples 49 and 51, which were administered at a dosage of 3 mg / kg).

Example 69

Isometric Strength Measurement

Animals are obtained from RCC Ltd (Fullinsdorf, Switzerland). Female Uistar rats are euthanized by exposure to CO ₂ . Tracheas are cut out and rings from the lower segment are obtained. Tracheal rings are suspended in tissue culture incubators (10 ml) containing Krebs-Henseleit buffer of the following composition (mM): NaCl 115; KCl 4.7; MgSO ₄ 1.2; KH ₂ PO ₄ 1.5; CaCl ₂ 2.5; NaHCO ₃ 25; glucose 10. The temperature of the solution in the bath is maintained at 37 ° C and aerated with 95% O ₂ /5% CO ₂ (pH 7.4). A resting force of 2 g (20 mN) was applied to the ring preparation, and the generated changes in force were measured using an isometric force recorder (EMKA Technologies Inc., Paris, France). The viability of the rings is assessed by exposure to a depolarizing concentration of KCl (50 μM). Tracheal narrowing is expressed as a percentage of response to KCl.

Compounds are obtained in the form of a basic solution with a concentration of 0.3 mM in pure DMSO. Compounds are added to the incubator (10 ml) in a volume of 33 μl to obtain a final concentration of DMSO in the incubator of 0.33%.

Female rat trachea contraction was measured for 14 of 66 illustrative compounds. The results are summarized in table 4.

Claims (24)

1. The compound of formula (I)

in which A means

in which the asterisks indicate a bond that is attached to the pyridine group of the formula (I);
R ¹ means cyclopentyl;
R ² means methyl, and R ⁴ means ethyl or chlorine; or
R ² means methoxy, and R ⁴ means chlorine;
R ³ means —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _n —NH - (CH ₂ ) _m —COOH, —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) - (CH ₂ ) _m —COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] - ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] -ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidin-3-carboxylic acid ) -1-yl] propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl ] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, - OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ O H) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH ( OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH , -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _n COOH, -OCH ₂ - (CH ₂ ) _n- N (CH ₃ ) -CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) -CO-CH ₂ COOH, or -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) -CO-CH ₂ CH ₂ COOH;
n independently is 1 or 2;
m independently means 1, 2 or 3; and
k is 1 or 2;
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where the stereocenter R ³ groups —O — CH ₂ CH (OH) —CH ₂ NH — CH ₂ COOH, —OCH ₂ CH (OH) —CH ₂ NH — CH ₂ CH ₂ COOH, - OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ and —OCH ₂ CH (OH) —CH ₂ NH — CO— (CH ₂ ) _n COOH is in the S configuration, or a pharmaceutically acceptable salt of such a compound. 3. The compound according to paragraph 1 or 2, where A means

in which the asterisks indicate a bond that is attached to the pyridine group of the formula (I), or a pharmaceutically acceptable salt of such a compound. 4. The compound according to claim 1 or 2, where A means

where the asterisk indicates a bond that is attached to the pyridine group of the formula (I), or a pharmaceutically acceptable salt of such a compound. 5. The compound according to claim 1 or 2, where A means

or a pharmaceutically acceptable salt of such a compound. 6. The compound according to claim 1 or 2, where R ² means methyl, and R ⁴ means ethyl or chlorine, or a pharmaceutically acceptable salt of such a compound. 7. The compound according to claim 1 or 2, where R ² means methyl, and R ⁴ means ethyl, or a pharmaceutically acceptable salt of such a compound. 8. The compound according to claim 1 or 2, where R ² means methoxy, and R ⁴ means chlorine, or a pharmaceutically acceptable salt of such a compound. 9. The compound of claim 1, wherein R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine-3- carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidin-3-carboxylic acid) -1-yl] propoxy, - OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n- NH-CO-CH ₂ COOH, -OCH ₂ - ( CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _n COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) -CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) -CO-CH ₂ COOH, or -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) -CO-CH ₂ CH ₂ COOH, or a pharmaceutically acceptable salt of such a compound. 10. The compound of claim 1, wherein R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine-3- carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, -O-CH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, —OCH ₂ CH (OH) —CH ₂ N (CH ₃ ) —CH ₂ COOH, —OCH ₂ CH (OH) —CH ₂ N (CH ₃ ) —CH ₂ CH ₂ COOH, 3 - [( azetidin-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidin-3-carboxylic acid) -1-yl] propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -O-CH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - ( CH ₂ ) _k —NH — CO — CH ₂ OH, or —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ OH, or a pharmaceutically acceptable salt of such a compound. 11. The compound of claim 1, wherein R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine-3- carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidin-3-carboxylic acid) -1-yl] propoxy, 3 - [(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N ( CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidine-3-carboxylic acid) -1 -yl] -propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -OCH ₂ CH ( OH) -CH ₂ NH-CH ₂ CH ₂ OH, -O-CH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -O-CH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _n COOH, -OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ COOH, or —OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ CH ₂ COOH, or a pharmaceutically acceptable salt of such a compound. 12. The compound of claim 1 or 2, wherein R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH- (CH ₂ ) _m -COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine- 3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidin-3-carboxylic acid) -1-yl] propoxy, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -O-CH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _k -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) _n -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _n COOH, -OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) -CO-CH ₂ COOH, or -OCH ₂ - (CH ₂ ) _n —N (CH ₃ ) —CO — CH ₂ CH ₂ COOH, or a pharmaceutically acceptable salt of such a compound. 13. The compound of claim 1 or 2, wherein R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ - (CH ₂ ) _n —NH— (CH ₂ ) _m —COOH, —OCH ₂ - (CH ₂ ) _n -N (CH ₃ ) - (CH ₂ ) _m -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] propoxy, or 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, or a pharmaceutically acceptable salt of such a compound. 14. The compound of claim 1 or 2, wherein R ³ is —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH (OH) —CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy , -OCH ₂ - (CH ₂ ) _n -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _n -NH-CH (CH ₂ OH) ₂ , -O-CH ₂ CH (OH) -CH ₂ NH — CH ₂ CH ₂ OH, or —O — CH ₂ CH (OH) —CH ₂ NH — CH (CH ₂ OH) ₂ , or a pharmaceutically acceptable salt of such a compound. 15. The compound according to paragraph 1 or 2, where m is 1 or 2, or a pharmaceutically acceptable salt of such a compound. 16. The compound of claim 1 or 2, wherein n is 1, or a pharmaceutically acceptable salt of such a compound. 17. The compound according to claim 1, in which a means

where the asterisk indicates a bond that is attached to the pyridine group of the formula (I);
R ¹ means cyclopentyl;
R ² means methyl, and R ⁴ means ethyl or chlorine; or
R ² means methoxy, and R ⁴ means chlorine; and
R ³ means —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH _2- (CH ₂ ) _1-2 -NH- (CH ₂ ) _1-2 -COOH, -OCH ₂ -CH ₂ -NH- (CH ₂ ) ₃ -COOH, -OCH ₂ - (CH ₂ ) _1-2 -N (CH ₃ ) - (CH ₂ ) _1-2 -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1-yl] ethoxy, 3 - [( azetidine-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, - OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ OH, -OC H ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ COOH, -OCH ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO - (CH ₂ ) _1-2 COOH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO- CH ₂ COOH, or —OCH ₂ - (CH ₂ ) ₂ —N (CH ₃ ) —CO — CH ₂ CH ₂ COOH, or a pharmaceutically acceptable salt of such a compound. 18. The compound of claim 1, wherein R ³ is —OCH ₂ COOH, —OCH ₂ CH ₂ CH ₂ COOH, —OCH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ CH ₂ CH ₂ CONHCH ₂ CH ₂ OH, —OCH ₂ - (CH ₂ ) _1-2 -NH- (CH ₂ ) _1-2 -COOH, -OCH ₂ -CH ₂ -NH- (CH ₂ ) ₃ -COOH, -OCH ₂ - (CH ₂ ) _1-2 -N (CH ₃ ) - (CH ₂ ) _1-2 -COOH, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidin-3-carboxylic acid) -1- yl] -ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propoxy, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ N (CH ₃ ) -CH ₂ CH ₂ COOH, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ₂ CH ₂ OH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) _1-2 -NH-CH ₂ CH (OH) -CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH ₂ CH ₂ OH, -OCH ₂ CH (OH) -CH ₂ NH-CH (CH ₂ OH) ₂ , -OCH ₂ - (CH ₂ ) ₂ -NH-CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CO -CH ₂ COOH, -OCH ₂ - (CH ₂ ) _1-2 -NH-CO-CH ₂ CH ₂ COOH, -OCH ₂ CH (OH) -CH ₂ NH-CO- (CH ₂ ) _1-2 COOH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ OH, -OCH ₂ - (CH ₂ ) ₂ -N (CH ₃ ) -CO-CH ₂ COOH, or -OCH ₂ - ( CH ₂ ) ₂ —N (CH ₃ ) —CO — CH ₂ CH ₂ COOH, or a pharmaceutically acceptable salt of such a compound. 19. The compound according to claim 1, selected from the group consisting of:
3- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -propionic acid,
1- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethyl) -azetidine-3-carboxylic acid,
(S) -1- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -3- (2-hydroxy-ethylamino) -propan-2-ol,
2 - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6 -methyl-phenoxy} -2-hydroxy-propylamino) propane-1,3-diol,
2- (4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} -acetic acids
4- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} -based acids
2 - ((2- (4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy) ethyl) amino) acetic acid,
1- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethyl) -pyrrolidine-3-carboxylic acid,
(S) -2 - ((3- (4- (5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl) -2-ethyl- 6-methyl-phenoxy) -2-hydroxypropyl) amino) acetic acid,
3 - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6 -methyl-phenoxy} -2-hydroxy-propylamino) propionic acid,
(S) -2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) - [1,2,4] oxadiazol-3-yl) -2-ethyl-6- methylphenoxy) -2-hydroxypropyl) (methyl) amino) acetic acid,
1 - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6 -methyl-phenoxy} -2-hydroxy-propyl) -azetidine-3-carboxylic acid,
2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy} -N - (2-hydroxy-ethyl) -acetamide,
semi-amide N - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl- 6-methyl-phenoxy} -2-hydroxy-propyl) -malonic acid,
semi-amide N - ((S) -3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl- 6-methyl-phenoxy} -2-hydroxy-propyl) succinic acid,
2 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) - [1,2,4] oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) (methyl) amino) acetic acid,
3 - [(2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} ethyl) methyl] amino] propionic acid,
2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) - [1,2,4] oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) propyl) amino) acetic acid
3- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propylamino) -propionic acid,
2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) - [1,2,4] oxadiazol-3-yl) -2-ethyl-6-methylphenoxy} propyl ) (methyl) amino) acetic acid,
3 - [(3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -propyl) methyl-amino] propionic acid,
1- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propyl) -azetidine-3-carboxylic acid,
2- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -ethanol,
2- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } propylamino) ethanol,
2- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -propane-1,3-diol,
2- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propylamino) -propane-1,3-diol,
3- (2- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -ethylamino) -propan-1,2-diol,
3- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propylamino) -propan-1,2-diol,
N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propyl) -2-hydroxy-acetamide,
N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl-phenoxy } -propyl) -2-hydroxy-N-methyl-acetamide,
N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} propyl) malonic acid,
N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} propyl) succinic acid,
N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -propyl) -N-methyl-malonic acid,
N- (3- {4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -2-ethyl-6-methyl- phenoxy} -propyl) -N-methyl-succinic acid,
4- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy} -based acids
4- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy} -N - (2-hydroxy-ethyl) -butyramide,
3- (2- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy } -ethylamino) -propionic acid,
N- (3- {2-chloro-4- [5- (2-cyclopentyl-6-methoxy-pyridin-4-yl) - [1,2,4] oxadiazol-3-yl] -6-methoxy-phenoxy } -propyl) -2-hydroxy-acetamide,
4 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) butanoic acid, and
4- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) butanoic acid,
or pharmaceutically acceptable salts of such compounds. 20. The compound of paragraph 1 selected from the group consisting of:
2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) acetic acid,
2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methyl-phenoxy) -N- (2 -hydroxyethyl) acetamide,
3 - ((2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) amino ) propanoic acid,
1- (2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid
2 - ((2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methylphenoxy) ethyl) amino ) ethanol
4- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) -N- (2-hydroxyethyl ) butanamide,
(S) -3 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) propanoic acid,
(R) -3 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) (methyl) amino) propanoic acid,
3 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) -3-oxopropanoic acid,
4 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) -4-oxobutanoic acid,
2 - ((2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) amino ) acetic acid
1- (2- (2-chloro-4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-3-yl) -6-methoxyphenoxy) ethyl) azetidine- 3-carboxylic acid
2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) acetic acid,
4- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) butanoic acid,
2 - ((2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) acetic acid
2 - ((2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) ( methyl) amino) acetic acid,
3 - ((2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid,
1- (2- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid
2 - ((3- (4- (3- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,2,4-oxadiazol-5-yl) -2-ethyl-6-methylphenoxy) propyl) amino ) acetic acid
2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) acetic acid,
4- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) butanoic acid,
3 - ((2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) ethyl) amino ) propanoic acid,
1- (2- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) ethyl) azetidine- 3-carboxylic acid
(S) -1- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy) -3- ((2-hydroxyethyl) amino) propan-2-ol,
(S) -2 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) propane-1,3-diol, and
(S) -4 - ((3- (4- (5- (2-cyclopentyl-6-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl) -2-ethyl-6-methylphenoxy ) -2-hydroxypropyl) amino) -4-oxobutanoic acid,
or pharmaceutically acceptable salts of such compounds. 21. A pharmaceutical composition having S1P1 / EDG1 receptor agonist activity, comprising, in an active amount, a compound according to any one of 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 22. The compound according to any one of paragraphs. 1, 2, 9-11 and 17-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 21, for use as a medicine having S1P1 / EDG1 receptor agonist activity. 23. The compound according to any one of paragraphs. 1, 2, 9-11 and 17-20, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of diseases or disorders associated with an activated immune system. 24. The use of compounds according to any one of paragraphs. 1, 2, 9-11 and 17-20, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the prevention or treatment of diseases or disorders associated with an activated immune system.