MXPA06007135A - Heterocyclic derivatives as gpcr receptor agonists - Google Patents

Abstract

Compounds of Formula (I), R1-A-V-B-R2;or pharmaceutically acceptable salts thereof, are agonists of GPR116 and are useful as regulators of satiety, e.g. for the treatment of obesity, and for the treatment of diabetes.

Description

HETEROCICLIC DERIVATIVES AS AGNISTS OF THE GPCR RECEIVER Field of the Invention The present invention is directed to agonists of the G-protein-linked receptor (GPCR). In particular, the present invention is directed to GPR116 agonists which are useful as regulators against satiety, for example, for the treatment against obesity and for the treatment of diabetes. Background of the Invention Obesity is characterized by an excessive mass of adipose tissue in relation to the size of the body. Clinically, the body mass of fat is estimated by the body mass index (BMI, weight (kg) / height (m) 2), or by the circumference of the waist. Individuals are considered obese when the BMI is greater than 30 and medical consequences are established when there is overweight. From a medical point of view for some time when there is an increase in weight, especially as a result of abdominal body fat, it is associated with an increased risk of diabetes, hypertension, heart disease and other health complications, such as arthritis, dystrophy , inflammatory disease of the bladder, muscular and respiratory problems, lumbago and certain types of -cancer. The pharmacological approach for the treatment against obesity Ref.:173556 mainly concerns the reduction of body fat by altering the balance between energy consumption and expenditure. Many studies have clearly established the relationship between adiposity and the brain system involved in the homeostasis of energy regulation. Direct and indirect evidence suggests that the serotonergic, dopaminergic, adrenergic, cholinergic, endocanaboinid, opioid and histaminergic routes in addition to many neuropeptide pathways (eg, neuropeptide Y and melanocortins) are involved in the central control of energy consumption and expenditure. Hypothalamic centers are also capable of sensitizing peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, as well as peptides derived from fatty tissue. The drugs designated in the pathophysiology associated with Type I insulin dependent diabetes and non-insulin dependent Type II diabetes have many potential side effects and do not adequately combat dyslipidemia and hyperglycemia in a high proportion of patients. The treatment is generally focused on individual patients in need of carrying out diet, exercise, hypoglycemic agents and insulin, so that new antidiabetic agents are needed, particularly those that are better tolerated with fewer adverse effects.

Similarly, the metabolic syndrome (Syndrome X) that is characterized by hypertension and is associated with pathologies that include atherosclerosis, lipidemia, hyperlipidemia and hypercholesterolemia have been associated with decreased sensitivity to insulin, which generates abnormal levels of blood sugar when they change Myocardial ischemia and microvascular disorder is an established morbidity associated with the untreated or poorly controlled metabolic syndrome. Therefore, there is a continuing need for novel antidiabetic and anti-obesity agents, particularly those that are well tolerated with few adverse effects.

GPR116 is a GPCR identified as SNORF25 in WO 00/50562 which describes receptors in both humans and rats, US6,468,756 also describes the mouse receptor (access numbers AAN95194 (human), AAN95195 (rat) and ANN95196 (mouse) ) . In humans, GPR116 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the GPR116 receptor in humans indicates its potential usefulness as an objective for the treatment of obesity and diabetes. Williams J.P., Combinatorial Chemistry & High Throughput Screening, 2000, 3, 43-50 describes the compounds 4- (5-piperidin-4-yl- [l, 2,4] oxadiazol-3-yl) pyridine and 4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-d-iDpiperidin-l-carboxylic acid butylester, synthesized as part of a library of compounds designed to identify dopamine D4 ligands The compounds 4- [5- (4-butylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine and 3- [5- (4-propylcyclohexyl) - [ 1,2,4] oxadiazol-3-yl) iridine (Chem Div) and 3- [5- (4-butylcyclohexyl) - [1,4,2] oxadiazol-3-yl) pyridine (Chembridge) are / were commercially available available. No pharmaceutical utility is suggested for these compounds. The present invention relates to GPR116 agonists which are useful as peripheral regulators against satiety, for example, for the treatment against obesity and for the treatment against diabetes. Brief Description of the Invention The compounds of the formula (I): (I) or the pharmaceutically acceptable salts thereof, are agonists of GPR116 and are useful as regulators against satiety, for example, in the prophylactic or therapeutic treatment of obesity and for the treatment against diabetes. Detailed Description of the Invention The present invention is directed to a compound of the formula (I) or a pharmaceutically acceptable salt thereof: R1-A-V-B-R2 (I) wherein V is a 5-membered heteroaryl ring containing more than four atoms selected from 0, N and S, optionally substituted by C? _4 alkyl; A is -CH = CH- or (CH2) n; B is -CH = CH- or (CH2) n where one of the CH2 groups is replaced by 0, NR5, S (0) m, C (0) or C (0) NR12; n is indistinctly 0, 1, 2 or 3; m is indistinctly 0, 1 or 2; R1 is 3- or 4-pyridyl, 4- or 5-pyrimidinyl or 2-pyranizyl, any of these may optionally be substituted by one or more substitutes selected from halo, C alquilo _ alkyl, C flu _ fluoroalkyl, C2_ alkenyl, C2_ alkynyl , C3_7 cycloalkyl, aryl, OR6, CN, N02, S (0) mR6, CON (R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6) 2 / a heterocyclyl group of 4 to 7 members or a 5- to 6-membered heteroaryl group; R2 is 4- to 7-membered cycloalkyl substituted with R3, C (0) 0R3, CtO) R3 or S (0) 2R3 or 4- to 7-membered heterocyclyl containing one to two nitrogen atoms which is unsubstituted or substituted by C (0) 0R4, C (0) R3, S (0) 2R3, C (0) NHR4, PfO) (0R11) 2 or a nitrogen-containing five or six-membered heteroaryl group; R3 is C3-βalkyl, C3-βalkenyl or C3-alkynyl, any of which is substituted with more than five chlorine or fluorine atoms and contains a CH2 group which can be substituted by 0, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 7 alkylcycloalkyl, C 1-4 alkylaryl, C 1-4 alkylheterocyclyl or C 1-4 alkylheteroaryl, any of these is substituted with one or more substitutes selected from halo, C 1 alkyl, fluoroalkyl C 1, OR 6, CN, alkyl Ci-4C02, N (R6) 2 and N02; R4 is C2_s alkyl, C2_s alkenyl or C2-β alkynyl, any of these is optionally substituted with more than 5 chlorine or fluorine atoms and can contain a CH group which can be substituted by 0, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl , C 1 -C 7 alkylcycloalkyl, C 4 alkyl alkylaryl, C 1 -4 alkylheterocyclyl or C 4 alkylheteroaryl, any of these may be substituted with one or more substitutes selected from halo, C 1 alkyl, fluoroalkyl C 1, OR 6, CN, alkyl C? _4C02, N (R6) 2 and N02; R 5 is hydrogen, C (0) R 7, S (0) 2 R 8, C 3-7 cycloalkyl or C 1 alkyl optionally substituted by OR 6, C 3 cycloalkyl? , aryl, heterocyclyl or heteroaryl, wherein the cyclic groups are substituted with one or more substitutes selected from halo, C alquilo _2 alkyl, fluoroalkyl C ?2, OR6, CN, N (R6) 2 and N02; R6 is either hydrogen, C4_4alkyl, C3_7 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups can be substituted with one or more substitutes selected from halo, C4_4alkyl, fluoroalkyl C_, OR9, CN, S02CH3, N (R10) 2 and N02; or a group N (R10) 2 can form a 4- to 7-membered heterocyclic ring optionally containing another heteroatom selected from 0 and NR10; R7 is hydrogen, C ?4 alkyl, OR6, hepceroaryl or aryl N (R6) 2; R8 is C4_4alkyl, C4_4 fluoroalkyl, aryl or heteroaryl; R9 is hydrogen, C? _2 alkyl or C? _2 fluoroalkyl; R10 is hydrogen or C? _4 alkyl; R11 is phenyl; and R12 is hydrogen, C3- or C3-7 cycloalkyl; provided that the compound is not: a) 4- (5-piperidin-4-yl- [1, 2, 4] oxadiazol-3-yl) pyridine; b) 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidine-1-carboxylic acid butylester; c) 4- [5- (4-butylcyclohexyl) - [1,2, 4] oxadiazol-3-yl] pyridine; d) 3- [5- (4-butylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine; or e) 3- [5- (4-propylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine. The molecular weight of the compounds of the formula (I) is preferably less than 800, more preferably less than 600, especially less than 500. In the compounds of the formula (I) V is preferably a 5-membered heteroaryl ring containing more of three heteroatoms selected from O, N and S of the formula: where W, X and Y represent the positions of the heteroatoms or otherwise represent CH. Particular heterocyclic rings that V may represent include oxadiazole, oxazole, isoxazole, thiadiazole, thiazole and pyrazole. Preferably, two of W, X and Y are N and the other is 0. W is preferably N. Preferably, the n groups of A and B do not represent both 0. In A, n is preferably 0, 1 or 2, more preferably 0. In B, n is preferably 2 or 3, more preferably 2. When one of the CH2 groups in B is replaced, it is preferably substituted by O, NR5, S (0) mo or C (0); more preferably, it is replaced by 0 or NR5. R1 is preferably 4-pyridyl optionally substituted by 1 or 2 halo, C4-4alkyl, C4-4 fluoroalkyl, C2_4alkenyl, C2-4alkynyl, C3_7 cycloalkyl, aryl, OR6, CN, N02, S (0) jnR6 , CON (R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6), 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl groups; more preferably 4-pyridyl optionally substituted by halo, C 1 alkyl, C 1 or C 4 alkoxy; even more preferably 4-pyridyl, optionally substituted by halo, C? _4 alkyl or CN; and especially 4-pyridyl, optionally substituted by CN. When R 2 is 4- to 7-membered heterocyclyl containing one or two nitrogen atoms, the substitution is preferably on the nitrogen atom. R2 is preferably a 4- to 7-membered cycloalkyl substituted by R3 or C (0) OR3, especially R3, or 4- to 7-membered heterocyclyl which contains a nitrogen atom which is replaced by C (O) 0R4 or a heteroaryl group of 6 members containing nitrogen, more preferably a 4- to 7-membered heterocyclyl containing a nitrogen atom which is replaced by C (0) OR4. A particularly preferred R2 group is piperidinyl, especially 4-piperidinyl which is substituted on the nitrogen atom by C (0) OR4. R3 is preferably C3_3 alkyl which may contain a CH2 group substituted by O, or C3_7 cycloalkyl, more preferably R3 is C3-8 alkyl. R4 is preferably C2_ß alkyl, C2-8 alkenyl or C2_s alkynyl, any of these is substituted by more than 5 fluorine or chlorine atoms and may contain a CH group substituted by O, or C3_ cycloalkyl, aryl, 5-6 membered heteroaryl containing one or two nitrogen atoms C 1 -C 4 alkyl cycloalkyl or C 4 alkyl alkylaryl, any of these is substituted with one or more substitutes selected from halo, C 4 alkyl, C 1-4 fluoroalkyl, OR 6 and C alkyl ? _ C02. More preferably, R4 is C3_6 alkyl, optionally substituted with more than 5 fluorine or chlorine atoms, for example, 3 fluorine or chlorine atoms and may contain a CH2 group which is replaced by O, or C3_7 cycloalkyl. R5 is preferably hydrogen or C4-4 alkyl, more preferably C4-4 alkyl. R6 is preferably hydrogen, C4_4alkyl or C3_7 cycloalkyl, more preferably C alquilo_alkyl. R7 is preferably hydrogen or C? _ Alkyl. R8 is preferably C? _ Alkyl, or C? -4 fluoroalkyl. While the preferred groups of each variable are mentioned separately for each variable, the preferred compounds of this invention include those wherein several or each variable in formula (I) are selected from the preferred, most preferred listed groups. or particularly mentioned for each variable. Therefore, this invention is intended to include all preferred, most preferred or particularly mentioned combinations of the free groups. The preferences indicated above also apply, when applicable, to the compounds of formulas (la) to (le) below.

A particular group of compounds that may be mentioned are the compounds of the formula (la) and particularly acceptable salts thereof: 0 * 0 where two of W, X and Y are N and the other is O; A is -CH = CH- or (CH2) n; B is -CH = CH- or (CH2) n where one of the CH2 groups is replaced by O, NR5, S (0) m, C (O) or C (0) NR12; n is indistinctly 0, 1, 2 or 3; m is 0, 1 or 2; R1 is 3- or 4-pyridyl, 4-pyrimidinyl or 2-pyrazinyl, any of these may optionally be substituted by one or more substitutes selected from halo, C? -44alkyl fluoroalkyl C? _4, cycloalkyl C3_7, OR6a, CN , N02, SCOaR6, N (R6) 2, CON (R6) 2 or a 5- or 6-membered heteroaryl group; R2 is 4- to 7-membered cycloalkyl substituted by R3, C (0) OR3, C (0) R3 or S (0) 2R3 or 4- to 7-membered heterocyclyl which contains one to two nitrogen atoms which is substituted or unsubstituted by C (0) 0R4, C (0) R3, S (O) 2R3, C (0) NHR4, P (O) (OR1: L) 2 or a nitrogen-containing five or six-membered heteroaryl group; R3 is C3_8 alkyl, C3_s alkenyl or C3-8 alkynyl / any of these is substituted with more than five chlorine or fluorine atoms and contains a CH2 group which can be substituted by 0, or C3_7 cycloalkyl, C3-7 cycloalkylC3-7 alkyl, aryl or C 1-4 alkylaryl, wherein the cycloalkyl groups are optionally substituted with one or more substitutes selected from halo and C 1-4 alkyl and the aryl groups may be substituted with one or more substitutes selected from halo, C? _4 alkyl, fluoroalkyl C? _4, 0R6a, C00R6a, CN, N (R6b) 2 and N02; R4 is C2-8 alkyl, C2_s alkenyl or C2_s alkynyl, any of these is optionally substituted with more than 5 fluorine or chlorine atoms and may further contain a CH2 group which is substituted by 0, or C3-7 cycloalkyl, cycloalkylC3_7 alkyl , C aryl or alkylaryl, wherein the cycloalkyl groups may be optionally substituted by one or more substituents selected from halo and C 1-4 alkyl and the aryl groups are substituted with one or more substitutes selected from halo, C alkyl? _, fluoroalkyl C? _ 4 0R6a, C00R6a, CN, N (R6b) 2 and N02; R5 is indistinctly hydrogen, C1-4alkyl or C3-4 cycloalkylC3alkyl; R6a is either hydrogen, C? _4 alkyl, or C? _4 fluoroalkyl; R6b is indistinctly hydrogen, C4_4alkyl or C3_cycloalkyl_3alkyl; R11 is phenyl; and R 12 is hydrogen, C 1-4 alkyl or C 3-7 cycloalkyl; provided that the compound is not: a) 4- (5-piperidin-4-yl- [1,2,4] oxadiazol-3-yl) pyridine; b) 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidine-1-carboxylic acid butylester; c) 4- [5- (4-butylcyclohexyl) - [1, 2, 4] oxadiazol-3-yl] pyridine; d) 3- [5- (4-butylcyclohexyl) - [1, 2, 4] oxadiazol-3-yl] pyridine; or e) 3- [5- (4-propylcyclohexyl) - [1, 2, 4] oxadiazol-3-yl] pyridine.

A further group of compounds which may be mentioned as the compounds of the formula (Ib) and pharmaceutically acceptable salts thereof: R ^ AVB-R2 (Ib) where V is a 5-membered heteroaryl ring containing more than 4 heteroatoms selected from O, N and S; A is (CH2) n; - B is (CH2) n, where one of the CH2 groups can be replaced with 0, NR5, S (0) m or C (0); n is indistinctly 0, 1, 2 or 3; m is 0, 1 or 2; R1 is 3- or 4-pyridyl or 4- or 5-pyrimidinyl, of which any can be optionally substituted by one or more substitutes selected from halo, C? _4alkyl, C flu _ fluoroalkyl, C2_alkenyl, C2_4 alkynyl, C3_7 cycloalkyl, aryl, OR6, CN, N02, S { 0) mR6, CON (R6) 2, N (R6) 2, NR10R6, NR10SO2COR6, S02N (R6) 2, a heterocyclyl group of 4 to 7 members or a heteroaryl group of 5 or 6 members; R2 is 4- to 7-membered cycloalkyl substituted with R3, C (0) OR3, C (0) R3 or S (0) 2R3 or 4- to 7-membered heterocyclyl which contains one or two nitrogen atoms which is or is not substituted replaced with C (0) OR4, C (0) R3 or S (0) 2R3; R3 is C3_7 alkyl, C3.7 alkenyl or C3-7 alkynyl, of which any may contain a CH2 group which may be replaced with 0, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C3 alkyl- cycloalkyl- 7, C 4 alkyl alkylaryl, C 4 alkylheterocyclyl or C 4 alkylheteroaryl, any of these is substituted with one or more substitutes selected from halo, C 3-4 alkyl, C 1-4 fluoroalkyl, OR 6, CN, N ( R6) 2 and N02; R4 is C2_7alkyl, C2_7alkenyl, C2_7alkynyl / any of which may contain a CH2 group which can be replaced with 0, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C3_4cycloalkyl_3alkyl, alkylaryl C ? 4, C 1-4 alkylheterocyclyl or C 1-4 alkylheteroaryl, any of these is substituted with one or more substitutes selected from halo, C 1-4 alkyl, fluoroalkyl C? _4, OR6, CN, N (R6) 2 and N02; R5 is hydrogen, C (0) R7, S (C) 2R8 or C1-4 alkyl optionally substituted with OR6, C3_7 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups may be substituted with one or more substitutes selected from halo, alkyl C? -2, fluoroalkyl C? _2, OR6, CN, N (R6) 2 and N02; R6 is independently hydrogen or C1-4 alkyl, C3_7 cycloalkyl, aryl, a heterocyclyl or heteroaryl group, wherein the cyclic groups can be substituted with one or more substitutes selected from halo, C1-4 alkyl, fluoroalkyl C? _4, OR9, CN, S02CH3, N (R10) 2 and N02; or a group N (R10) 2 can form a 4- to 7-membered heterocyclic ring optionally containing another heteroatom selected from 0 and NR10; R7 is hydrogen, C1-4 alkyl, OR6, heteroaryl or aryl N (R6) 2; R8 is C ?4 alkyl, C flu _ fluoroalkyl, aryl or heteroaryl; R9 is hydrogen, C? _2 alkyl or C? -2 fluoroalkyl; and R10 is hydrogen or C? _4 alkyl; provided that the compound is not: a) 4- (5-piperidin-4-yl- [1,2,4] oxadiazol-3-yl) pyridine; b) 4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) piperidine-1-carboxylic acid butylester; c) 4- [5- (4-butylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine; d) 3- [5- (4-butylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine; or e) 3- [5- (4-propylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine.

Another specific group of compounds of the invention that may be mentioned are those of the Formula (le) or one of its pharmaceutically acceptable salts: where two of W, X and Y are N and the other is 0; A is (CH2) n; B is (CH2) n, where one of the CH2 groups can be replaced with 0, NR6, S (0) m or C (0); n is indistinctly 0, 1, 2 or 3; m is 0, 1 or 2; R1 is 3- or 4-pyridyl or 4-pyrimidinyl, of which any may be optionally substituted by one or more substitutes selected from halo, C? _4 alkyl, C flu _ fluoroalkyl, C3_7 cycloalkyl, OR5, CN, N02, N (R6) 2 CON (R6) 2 or a 5- or 6-membered heteroaryl group; R2 is 4- to 7-membered cycloalkyl substituted with R3, C (0) 0R3, C (0) R3 or S (0) 2R3 or 4- to 7-membered heterocyclyl containing one or two nitrogen atoms which is or is not substituted replaced with C (0) OR4, C (0) R3 or S (0) 2R3; R3 is C3_7 alkyl, C3_7 alkenyl or C3_7 alkynyl, of which any may contain a CH2 group which may be replaced with 0, or C3-7 cycloalkyl, aryl, C4_4 alkylaryl, where the aryl may be substituted with one or more substitutes selected from halo, aryl C? _4, fluoroalkyl C? _4, OR5, CN, N (R6) 2 and N02; R4 is C2_alkyl, C2-7alkenyl, C2-7alkynyl, of which any may contain a CH2 group which can be replaced with O, or C3-7 cycloalkyl, aryl or C2- alkylaryl, where the aryl groups can be substituted with one or more substitutes selected from halo, C? _ alkyl, C1-4 fluoroalkyl, OR5, CN, N (R6) 2 and N02; R5 is indistinctly hydrogen, C1-4alkyl, fluoroalkyl C4-4; and R6 is indistinctly hydrogen and C? _4 alkyl; provided that the compound is not: a) 4- (5-piperidin-4-yl- [1,2,4] oxadiazol-3-yl) pyridine; b) 4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) piperidine-1-carboxylic acid butylester; c) 4- [5- (4-butylcyclohexyl) - [1, 2, 4] oxadiazol-3-yl] pyridine; d) 3- [5- (4-butylcyclohexyl) - [1,2,4] oxadiazol-3-yl3 pyridine; or e) 3- [5- (4-propylcyclohexyl) - [1, 2, 4] oxadiazol-3-yl] pyridine. A preferred group of compounds of the invention are the compounds of the formula (Id) and their pharmaceutically acceptable salts of: where two of W, X and Y are N and the other is O; A is -CH = CH- or (CH2) n; B is -CH = CH- or (CH2) n where one of the CH2 groups can be replaced with O, NR5, S (0) m or C (O); n is indistinctly 0, 1, 2 or 3, provided that both of n are 0; m is indistinctly 0, 1 or 2; Rx and Ry are indistinctly selected from hydrogen, halo, C? _4 alkyl, C? _4 fluoroalkyl, C_4 alkenyl, C2_4 alkynyl, C3_7 cycloalkyl, aryl, OR6, CN, N0, S (0) mR6, CON ( R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6) 2, a heterocyclyl group of 4 to 7 members and a heteroaryl group of 5 or 6 members; Z is C (0) OR4, C (0) R3, S (0) 2R3, C (0) NHR4 or a 5- or 6-membered nitrogen-containing heteroaryl group; R3 is C3_s alkyl, C3_s alkenyl or C3_8 alkynyl, of which it can be optionally substituted with up to 5 fluorine or chlorine atoms and containing a CH2 group which can be replaced by 0, or C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylC C 4 -C 7 alkyl, C 1 -4 alkylaryl, C 1 -4 alkylheterocyclyl or C 1 -4 alkylheteroaryl, of which any can be optionally substituted with one or more substitutes selected from halo, C 1 -4 alkyl, C 1-4 fluoroalkyl, OR 6, CN, C-alkyl ? 4C02, N (R6) 2 and N02; R4 is C2-8 alkyl / C2_8 alkenyl or C2_8 alkynyl, any of these is optionally substituted with more than 5 chlorine or fluorine atoms and may contain a CH2 group which -can be substituted by O, or C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C3_4-cycloalkylC3_7 alkyl, C4_4 alkylaryl, C1-4 alkylheterocyclyl or C1-4 alkylheteroaryl, any of these can be substituted with one or more selected substitutes from halo, C 1-4 alkyl, fluoroalkyl C? _4, OR6, CN, C? _4C02 alkyl, N (R6) 2 and N0; R6 is either hydrogen, C1-4alkyl, C3_7 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups are substituted with one or more substitutes selected from halo, C1-4alkyl, fluoroalkyl C4-4, OR9, CN, S02CH3 , N (R10) 2 and N02; or a group N (R10) 2 can form a 4- to 7-membered heterocyclic ring optionally containing an additional heteroatom selected from O and NR10; R9 is hydrogen, C1-2 alkyl or fluoroalkyl C? _2; and R10 is hydrogen or C? _ alkyl; Another preferred group of compounds of the invention are the compounds of the formula (le) and the pharmaceutically acceptable salts thereof: (you) where one of X and Y is N and the other is 0; Q is 0, NR5 or CH2; R is hydrogen, halo, C? _4 alkyl, C1-4 fluoroalkyl, C2_4 alkenyl, C2-4 alkynyl, C3_7 cycloalkyl, aryl, OR6, CN, N02, S (0) mR6, CON (R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6), 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl groups; R4 is C2 alkyl, C2_2 alkenyl or C2_s alkynyl, of which any of these may be optionally substituted with up to 5 chlorine or fluorine atoms and may contain a CH2 group which may be replaced with O, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl , C 1 -C 7 alkylcycloalkyl, C 4 alkyl alkylaryl, C 1 -4 alkylheterocyclyl or C 4 -4 alkylheteroaryl, any of these may be substituted with one or more substitutes selected from halo, C 1-4 alkyl, fluoroalkyl C 4, OR 6 , CN, alkyl d_4C02, N (R6) 2 and N02; R5 is C? _4 alkyl; R6 is indistinctly hydrogen, C1-4alkyl, C3-7 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups are substituted with one or more substitutes selected from halo, C4_4alkyl, fluoroalkyl C4_4, OR9, CN, S02CH3, N (R10) 2 and N02; or a group N (R10) 2 can form a 4- to 7-membered heterocyclic ring optionally containing another heteroatom selected from O and NR10; R9 is hydrogen, C? _2 alkyl or C? _2 fluoroalkyl; R10 is hydrogen or C? _4 alkyl; p is 0 or 1. In the compounds of the formula (le) R is preferably hydrogen, halo, C ?4 alkyl, C ?4 alkoxy or CN. Specific compounds of the invention that may be mentioned are those included in the Examples and their pharmaceutically acceptable salts. Particular compounds that can be mentioned are: 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethoxy) piperidin-1-carboxylic acid tert-butylester, 4- tert-butylester [5- (2-cyanopyridin-4-yl) - [1,2,4] oxadiazol-3-ylmethoxy] piperidine-l-carboxylic acid, cyclopentyl ester of 4- (3-pyridin-4-yl- [1,2 , 4] oxadiazol-5-ylmethoxy) piperidine-l-carboxylic acid, 2,2,2-trichloroethyl ester of 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethoxy) piperidin- l-carboxylic acid, 4- [ethyl- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amino] piperidine-1-carboxylic acid, cyclopentyl ester of 4- [-] acid methyl- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amino] piperidine-1-carboxylic acid, 2, 2, 2-trichloroethylester of 4-acid. { [methyl (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amino] methyl} piperidin-1-carboxylic acid and its pharmaceutically acceptable salts. As used herein, unless otherwise indicated, the term "alkyl" as well as other groups having the prefix "alk" such as, for example, alkenyl, alkynyl and the like, mean carbon chains which may be linear or branched or combinations of these. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec and tert-butyl, pentyl, hexyl, heptyl and the like. The terms "alkenyl", "alkynyl" and other similar terms include carbon chains having at least one unsaturated carbon-carbon bond. The term "fluoroalkyl" includes alkyl groups substituted by one or more fluorine atoms, for example CH2F, CHF2 and CF3. The term "cycloalkyl" means carbocycles that do not contain heteroatoms and includes monocyclic saturated carbocycles. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "halo" includes fluorine, chlorine, bromine and iodine atoms. The term "aryl" includes phenyl and naphthyl, particularly phenyl. Unless otherwise indicated, the term "heterocyclyl" and "heterocyclyl ring" includes saturated monocyclic and bicyclic rings of 4 to 10 members, for example, saturated monocyclic rings of 4 to 7 members containing up to 3 heteroatoms selected from N, O and S. Examples of heterocyclic rings include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane, tetrahydrothiophene, tetrahydrothiopyran, tiepane, thiocan, azetidine, pyrrolidine, piperidine, azepane, azocan, [l, 3] dioxane, oxazolidine, piperazine and the like. Other examples of heterocyclic rings include the oxidized forms of rings containing sulfur. Therefore, 1-tetrahydrothiophene oxide, tetrahydrothiophene 1,1-dioxide, tetrahydrothiopyran-1-oxide and tetrahydrothiopyran-1,1-dioxide are also considered heterocyclic rings. Examples of heterocyclic rings that R2 may represent include azetidine, pyrrolidine, piperidine and piperazine. The heterocyclyl groups of R2 may also contain additional heteroatoms, for example morpholine. Unless otherwise indicated, the term "heteroaryl" includes mono- and bicyclic rings of 5 to 10 members, for example, 5-6 membered monocyclic heteroaryl rings containing up to 4 heteroatoms selected from N, O and S. The examples of these heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, -pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Bicyclic heteroaryl groups include bicyclic heteroaromatic groups where a 5- or 6-membered heteroaryl ring is fused with a phenyl or other heteroaromatic group. Examples of these bicyclic heteroaromatic rings are benzofuran, benzothiophene, indole, benzoxazole, benzothiazole, indazole, benzimidazole, benzotriazole, quinoline, isoquinoline, quinasoline, quinoxaline and purine. The compounds described herein may contain one or more asymmetric centers and therefore can produce optical isomers and diastereomers. The present invention includes all these diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts. Formula (I) above is shown without a definitive stereochemistry in certain positions. The present invention includes all stereoisomers of formula (I) and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers as well as the specific isolated stereoisomers are also included. During the course of the synthetic procedures used to prepare these compounds or in the use of racemization or epimerization methods known to those skilled in the art, the products of these processes may be a mixture of stereoisomers. When a tautomer of the compound of the formula (I) exists, the present invention includes any of the possible tautomers and their pharmaceutically acceptable salts and mixtures thereof, except when specifically drawn or otherwise indicated. When the compound of the formula (I) and the pharmaceutically acceptable salts exist in the form of solvates or polymorphic forms, the present invention includes any of the polymorphic forms and possible solvates. A type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used. In this description, the term "pharmaceutically acceptable salts" refers to salts prepared from the non-toxic and pharmaceutically acceptable acids or bases. When the compound of the present invention is acidic, its corresponding salt can conveniently be prepared from pharmaceutically acceptable non-toxic bases, including organic bases and inorganic bases. Salts derived from these inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, potassium, sodium, zinc and the like salts. The ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. The salts derived from the nontoxic organic and pharmaceutically acceptable bases include salts of primary amines, secondary and tertiary as well as cyclic amines of substituted amines as the synthetic and natural substituted amines. Other non-toxic organic and pharmaceutically acceptable bases of salts that can form salts include arginine, betaine, caffeine, choline, N ', N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, gluca ina, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can conveniently be prepared from non-toxic pharmaceutically acceptable acids, including inorganic and organic acids. These acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfhydric, tartaric, p-toluenesulfonic and the like. Since the compounds of the formula (I) are intended to be used in a pharmaceutical manner, they are preferably provided in substantially pure form, for example, with a purity of at least 60%, more suitably with a purity of at least 75%, especially of minus 98% purity (% is based on weight by weight). The compounds of the formula (I) can be prepared as described below, wherein, for illustrative purposes, -V- is shown as a group of the formula: and R1, R2, R3, R4, A, B, W, X and Y are as defined above. The compounds of the formula (I), wherein X = N, Y = 0 and W = N, can be prepared according to the method illustrated in Reaction Scheme 1. The nitriles of the formula 2 can be commercially available or can be synthesized using techniques known. The compounds of formula 2 are subjected to treatment with hydroxylamine in a suitable solvent such as ethanol-water at elevated torperature to provide amidoxins of formula 3 (synthesis of amidoxins is described in more detail in AR Martin et al., J. Med. Chem., 2001, 44, 1560). The compounds of formula 3 are subsequently condensed with the acids of formula 4, which by themselves are commercially available or can be easily synthesized using known techniques. First, the condensation leads to the activation of the compounds of the formula 4, by, for example, the formation of mixed anhydride, wherein the acid is subjected to treatment with a chloroformate such as isobutylchloroformate, in the presence of a suitable base as triethylamine, in a suitable solvent such as THF or toluene, followed by the addition of compounds of the formula 3. Alternatively, the compounds of the formula 4 can be activated by the conversion of the acid halide, generated by treating the acid with, for example, oxalyl chloride in a suitable solvent such as CH2C12-DMF. The intermediates produced from the condensation of amidoximes of the formula 3 and acids of the formula 4 are dissolved in a suitable solvent such as toluene or xylene and heated under reflux with the concomitant removal of water by a Dean-Stark apparatus or by sieves. Molecules for forming oxadiazoles of the formula (I). Alternatively, the amidoximes of formula 3 may, in the first instance, be subjected to treatment with a suitable base such as, for example, sodium hydride in a suitable solvent such as THF and subsequently esters of formula 5. Heating of this mixture also generates oxadiazoles of formula (I) (this process is further illustrated in RH Mach et al., Bioorg, Med. Chem., 2001, 9, 3113). Reaction Scheme 1 : R = Me 9 The compounds of the formula (I) wherein X = 0, Y = N and W = N can be prepared according to the method described in Reaction Scheme 2. The nitriles of the formula 6 can be either commercially available or can be synthesized using known techniques. These are converted to the corresponding amidoximes of the formula 7 as described above and subsequently condensed with acids of the formula 8. they are commercially available or can be easily synthesized by those skilled in the art. This condensation is carried out in a manner analogous to that described in Reaction Scheme 1 to produce the corresponding oxadiazoles of the formula (I).

Reaction Scheme 2 The compounds of the formula (I) wherein X = N, Y = N and W = 0 can be synthesized as described in Reaction Scheme 3. The acyl chlorides of the formula 9 are either commercially available or can be synthesized using known methods. The hydrazides of formula 10 can be easily obtained by, for example, treatment with an ethanolic solution of the corresponding ester with hydrazine (for more detail see K.M. Kahn et al., Bioorg, Med. Chem., 2003, 11, 1381). The treatment of the acyl chlorides of the formula 9 with the acid hydrazides of the formula 10 in a suitable solvent, such as pyridine, yields the compounds of the formula 11 (illustrated in greater detail in VN Kerr et al., J. Am. Chem. Soc., 1960, 82, 186), which are then converted by P0C13 at elevated temperature into compounds of the formula (I) (this process is further described in SA Chen et al., J. Am. Chem. Soc, 2001, 123, 2296). Similarly, the compounds of the formula (I) wherein X = Y = W = N can be prepared by means of the condensation of amidrazone analogue of 10 with an appropriate derivative of activated carboxylic acid, as 9. The reactive groups in this reaction can be interchanged, that is, an amidrazone of the formula R1-AC (= NH) NHNH2 can form a compound of the formula (I) by condensation with an activated derivative of carboxylic acid LG-C (= 0) -B-R2 where LG is halogen or oxycarbonyl (PH Olesen et al., J. Med. Chem., 2003, 46, 3333-3341). Reaction Scheme 3 or 10 The compounds of the formula (I) wherein X = N, Y = N and W = S can also be prepared from the compound of the formula 11 by heating with a Lawesson reagent in a suitable solvent such as toluene or acetonitrile (D. Alker et al., J. Med. Chem., 1989, 32, 2381-2388). The compounds of the formula (I) wherein X = S, Y = N and W = N can be formed from compounds of the formula 12 (Reaction Scheme 4) which are commercially available or can be easily synthesized from the corresponding carbonyl compound and Lawesson's reagent under conventional conditions. Treatment of a compound of formula 12 with a compound of formula 13 in a suitable solvent such as dichloromethane at a temperature of about 20 ° C provides the compounds of formula 14. The compounds of formula 13 can be obtained by treating dimethylamide corresponding with a Meerwein reagent (for details see M. Brown US 3,092,637). The compounds of formula 14 are cyclized using hydroxylamine-O-sulfonic acid in the presence of a base such as pyridine in a suitable solvent such as methanol (for further details, see A. MacLeod et al., J. Med. Chem., 1990, 33, 2052).

The regioisomeric derivatives of the formula (I), wherein X = N, Y = S and W = N, can be formed in a similar manner by inverting the functionality of the reagents so that the fragment R1 contains the entity acetate and the fragment R2 contains the thiocarbonyl. The compounds of the formula (I) wherein W = 0, X = N and Y = CH can be formed from the compounds of the formula (Reaction Scheme 5). The compounds of formula 15 are commercially available or can be synthesized using conventional techniques. The chlorides of formula 16 are commercially available or can be easily formed by chlorinating the corresponding ketone using conventional conditions, for example, passing chlorine gas through a methanol solution of the ketone (for more details see R. Gallucci and R. Going, J. Org. Chem., 1981, 46, 2532). Mixing a compound of the formula 15 with a chloride of the formula 16 in a suitable solvent such as toluene, heating for example at a temperature of about 100 ° C provides the compounds of the formula (I) (for more information, see A Hassner et al., Tetrahedron, 1989, 45, 6149). The compounds of the formula (I) wherein W = 0, X = CH and Y = N can be formed in a similar manner by reversing the functionality of the reagents so that the R1 fragment contains a haloketone entity and the R2 fragment contains the C (0) NH2.

Reaction Scheme 5 RS NH2 * «^? 2 - R ^ S ^ B ^ 15 16 I Alternatively, the compounds of (I) wherein X = S, W = N and Y = CH can also be formed from the compound of formula 16. Heat a compound of formula 15 with phosphorous pentasulfide, followed by the addition of a compound of formula 16 followed by a longer period of heating provides the compounds of formula (I) (for, additional details see R. Kurkjy and E. Brown, J. Am. Chem. Soc., 1952, 74, 5778). The regioisomeric compounds where X = CH, W = N and Y = S can be formed in a similar manner by reversing the functionality of the reagents, so that the fragment R1 contains the entity haloketone and the fragment R2 contains the C (0) NH2. The compounds of the formula I wherein W = N, X = 0 and Y = CH can be formed from the compounds of the formula 15 and the formula 17 (Reaction Scheme 6) under conditions similar to those described for the Reaction scheme 5. Compounds of formula I wherein W = S, X = N and Y = CH can be formed from the compounds of formula 15 and formula 17 using conditions involving the phosphorous pentasulfide described above.

Reaction Scheme 6 The compounds of the formula (I) wherein X = 0, Y = N and Y = CH and where X = N, X = 0 and W = CH can be formed from compounds of the formula 20 (Reaction Scheme 7). Acylation of the compounds of the formula 18 with a compound of the formula 19wherein Q is alkoxide or chloride, can occur under conventional conditions, for example, deprotonation of ketone 18 with a suitable base, such as lithium diisopropylamide or potassium ethoxide in a suitable solvent such as tetrahudrofuran, generally at low temperature. Treatment of compound 20 with hydroxylamine, in a suitable solvent such as ethanol at elevated temperature, for example 75 ° C, provides compounds of formula (I) as a mixture of both regiosiomers of isozaxol. Using conventional separation techniques such as chromatography on silica gel, the individual isomers can be isolated (for further details see M. Rowly et al., J. Med. Chem., 1997, 40, 2374). Reaction Scheme 7 R1-. what WlB * 18 19 20 The compounds of the formula (I) wherein X = S, Y = N and W = CH can be formed by the hydrogenation of a compound of the formula (I) wherein X = 0, Y = N and W = CH, with platinum and a suitable solvent such as ethanol, followed by heating with phosphorous pentasulfide to provide compounds of the formula (I) wherein X = S, Y = N and W = CH (for more details, see G. Wiegand et al., J. Med. Chem., 1971, 14, 1015). For details on the regioisomer synthesis, where X = N, Y = S and W = CH, see also G. Wiegand ibid). The compounds of the formula (I) wherein X = N, Y = N and W = CH can be formed from compounds of the formula 20. The treatment of compounds of the formula 20 with hydrazine in a suitable solvent such as methanol produces compounds of the formula (I) wherein X = N, Y = N and W = CH (this process is illustrated in more detail in Baker et al., J. Med. Chem., 1997, 40, The compounds of the formula (I ) where X = CH, Y = N and W = N can be synthesized as described in Reaction Scheme 8. Bromides of formula 23 are either commercially available or can be synthesized from the corresponding ketone by, for example, the treatment of an aqueous solution of the ketone with Br2 and HBr (as described by JY Becker et al., Tetrahedron Lett., 2001, 42, 1571.) The amidines of the formula 22 can be synthesized by known methods, for example by the treatment of the corresponding alkylimidates of the formula 21 with ammonia in a suitable solvent as for example, ethanol (as described in detail in D. A. Pearson et al., J. Med. Chem., 1996, 39, 1372). The imidates of the formula 21 can in turn be generated by, for example, the corresponding nitrile treatment with HCl in a suitable solvent such as methanol (for more details see JP Lokensgard et al., J. Org. Chem., 1985, 50 , 5609). The reaction of amidines of formula 22 with bromide of formula 23 in a suitable solvent such as DMF, provides compounds of formula (I) (illustrated in NJ Liverton et al., J. Med. Chem., 1999, 42, 2180 ).

Reaction Scheme 8 21 s Oalkyl 22R-NH2 - * The regioisomeric compounds wherein X = N, Y = CH and W = N can be formed in a similar manner by reversing the functionality of the reagents so that the R1 fragment contains the amidine entity and R2 contains the bromide. The compounds of the formula (I) wherein X = CH, Y = CH and W = N can be synthesized as illustrated in Reaction Scheme 9. The diketones of the formula 25 are easily accessible by, for example, the condensation of Commercially available ketones of formula 24 which are readily synthesized using known techniques, with bromides of formula 23 and a suitable solvent such as benzene using an appropriate catalyst. Illustrative examples are described in OG Kulinkovich et al., Synthesis, 2000, 9, 1259. Using a Paal-Knorr ration, the diketones of formula 25 can be treated with, for example, ammonium carbonate in a suitable solvent such as ethanol a High temperature . (for more details see R. A. Jones et al., Tetrahedron, 1996, 52, 8707) to produce the compounds of the formula (I).

Reaction Scheme 9 The compounds of the formula (I) wherein R2 contains either a sulfonamide or carbamate group can be synthesized as described in Reaction Scheme 10. The compounds of the formula 26, wherein P represents a suitable protecting group, for example , tert-butoxycarbonyl (Boc), can be synthesized as described in Reaction schemes 1-9 above. The protecting group is first removed under suitable conditions to produce the compounds of the formula 27. In the case of the Boc group, this can be achieved by treatment of the compounds of the formula 26 with a suitable acid such as trifluoroacetic acid, in an appropriate solvent such as CH2C12. The treatment of the compounds of formula 27 with chloroformates of formula 28, which are generally commercially available or can be easily synthesized in a suitable solvent such as CH2C12 in the presence of a suitable base, as triethylamine, provide the compounds of the formula (I). Similarly, the compounds of the formula 27 can be reacted with sulfonyl chlorides of the formula 29, which are generally commercially available or which can be easily synthesized in a suitable solvent such as CH2C12 in the presence of a suitable base such as triethylamine to produce the compounds of the formula (I). The compounds of the formula (I) wherein R2 contains a urea entity can be prepared by reacting the compound of formula 13 with an isocyanate of the formula 0 = C = N-R4. Furthermore, the compounds of the formula (I) wherein R 2 is a 4-7 membered heterocyclyl substituted with a heteroaryl group can be prepared by reacting the amine 27 with the appropriate heteroarylchloride or bromide under catalysis with Pd (0) in the presence of a suitable base and ligand (Urgaonkar, S .; Hu, J.-H .; Verkade, J. G. J. Org. Chem., 2003, 68, 8416-8423).

Reaction Scheme 10 The compounds of the formula (I) wherein R2 contains an amide group can be synthesized from the compound of the formula 27 and a suitable acid (R3COOH) or an activated derivative thereof, in an amide bond forming reaction. The compounds of the formula (I) wherein R2 contains an ester entity can be synthesized as is. illustrates - in Reaction Scheme 11. Compounds of formula 30 wherein R is a group, alkyl, for example a methyl group, can be synthesized using preferably the processes in Reaction Schemes 1-9. First, the alkyl group is removed under appropriate conditions to produce the compounds of the formula 31. For example, when R = Me, the compounds of the formula 30 can be hydrolyzed in the presence of a suitable alkali, for example LiOH in a suitable solvent as water-methanol. The acids of the formula 31 are condensed with alcohols of the formula 32 which are commercially available or can be synthesized using known techniques. For example, condensation can be achieved by treating the compounds of the formula 31 with alcohols of the formula 32 in the presence of a thionyl chloride, yielding the compounds of the formula (I): Reaction Scheme 11 The compounds of the formula (I) wherein R3 contains an ester group can also be synthesized from a compound of the formula 30 as illustrated in Reaction Scheme 12. The compounds of the formula 30 can be converted to the corresponding alcohol 33 by action of a suitable reducing agent, for example diisobutylaluminum hydride in a suitable solvent such as CH2C12 and then can be treated, first with a suitable base as sodium hydride, in a suitable solvent such as THF and followed by an appropriate alkylating agent as the alkyl halide of the formula '34 to produce the compounds of the formula (I): Reaction Scheme 12 The compounds of the formula (I) wherein B contains a group NR5 where R5 is hydrogen, can be further transformed into compounds of the formula (I) wherein R5 is C (0) R7, S (0) 2R8 or a C1 alkyl group -4 optionally substituted using conventional techniques known to those skilled in the art for acylation, sulfonation and reductive amination, respectively. The compounds of the formula (I) wherein R 1 is pyridyl optionally substituted with CN can be prepared from the corresponding unsubstituted pyridine by the Reissert reaction (Fife, W.K. J. Org. Chem., 1983, 48, 1375-1377). Similar reactions can be used to prepare the compounds wherein R 1 is pyridyl optionally substituted with halogen (Walters, M. A; Shay, J. J. Tetrahedron Lett. 1995, 36, 7575-7578). Compounds wherein R 1 is pyridyl optionally substituted with halogen can be transformed into the corresponding compounds wherein R 1 is pyridyl optionally substituted with C 1 to 4 alkyl by cross-coupling reactions catalysed by transition metal (Fürstner, A., et al., J. Am. Chem. Soc., 2002, 124, 13856-13863). Other compounds of the formula (I) can be prepared by analogous methods to those described above or by methods known per se. In the examples, more details are found for the preparation of the compounds of the formula (I). The compounds of the formula (I) can be prepared individually or with libraries of compounds comprising at least 2, for example 5 to 1000 compounds and more preferably 10 to 100 compounds of the formula (I). Compound libraries can be prepared by a combinatorial "split and mix" approach or by multiple parallel synthesis using either a solid phase chemistry or solution, using methods known to those skilled in the art.

During the synthesis of the compounds of the formula (I), the labile functional groups in the intermediate compounds, for example, hydroxyl, carboxyl and amino groups can be protected. The protecting groups can be removed at any stage during the synthesis of the compounds of the formula (I) or they can be present in the final compound of the formula (I). A comprehensive mention of the ways in which the various labile functional groups can be protected and methods for cleaving the resulting protective derivatives is provided, for example in Protective Groups in Organic Chemistry, TW Greene and PGM Wuts (1991) Wiley-Interscience, New York, 2nd edition Any of the novel intermediaries as defined above is also included within the scope of the invention. As indicated above, the compounds of the formula (I) are useful as GPR116 agonists, for example for the treatment and / or prophylaxis against obesity and diabetes. For this use, the compounds of the formula (I) are generally administered in the form of a pharmaceutical composition. The invention also provides a compound of the formula (I), including the compounds of the c) to e) statutes or a pharmaceutically acceptable salt thereof for use as a pharmaceutical product.

The invention also provides a pharmaceutical composition comprising a compound of the formula (I), including the compounds of stipulations c) to e), combined with a pharmaceutically acceptable carrier. Preferably, the composition comprises a pharmaceutically acceptable carrier and a non-toxic and therapeutically effective amount of a compound of formula (I), including the compounds of stipulations c) to e) or a pharmaceutically acceptable salt thereof. Moreover, the invention also provides a pharmaceutical composition for the treatment against a disease by regulating GPR116, as regulators of the feeling of satiety, for example resulting in the prophylactic or therapeutic treatment against obesity or for the treatment against diabetes, comprising a pharmaceutically acceptable carrier and a non-toxic, therapeutically effective amount of the compound of the formula (I), including the compounds of the provisions a) to e) or a pharmaceutically acceptable salt therein. The pharmaceutical compositions may optionally comprise other adjuvants or therapeutic ingredients. The compositions include compositions suitable for oral, rectal, topical and parenteral administration (including subcutaneous, intramuscular and intravenous), although the most appropriate route in any case will depend on the particular host and nature and severity of the conditions for which the ingredient is administered. active. The pharmaceutical compositions may conveniently be presented in a unit dosage form and prepared by any of the methods well known in the pharmaceutical art. During practice, the compounds of the formula (I), including the compounds of the a) to e) statutes, or their pharmaceutically acceptable salts, can be combined as the active ingredient by intimately mixing in a pharmaceutical carrier according to conventional techniques for the preparation of pharmaceutical compounds. The carrier can have a wide variety of forms depending on the form of preparation desired for administration, for example oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions can be presented as discrete units suitable for oral administration, such as capsules, dragees or tablets each containing the predetermined amount of the active ingredient. In addition, the compositions may be in the form of a powder, granules, solution or suspension in an aqueous liquid, such as a non-aqueous liquid with an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms discussed above, the compound of the formula il), including the compounds of the stipulations a) to e) one of its pharmaceutically acceptable salts, can also be administered by means of administration devices and / or controlled release means. The compositions can be prepared by any of the pharmaceutical methods. In general, these methods include a step to associate the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can conveniently be shaped to acquire the desired presentation. The compounds of formula (I), including the compounds of stipulations a) to e) or their pharmaceutically acceptable salts, may also be included in pharmaceutical compositions combined with one or more therapeutically active compounds. The pharmaceutical carrier used can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, alabaster, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil and water. Examples of gaseous carriers include nitrogen and carbon dioxide.

In preparing the compositions for their oral dosage form, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavorings, preservatives, dyes and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; While . that carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to formulate oral solid preparations such as powders, capsules and tablets. Due to their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, the tablets can be coated by conventional aqueous or non-aqueous techniques. A tablet containing the composition of this invention can be prepared by compression or molding as optionally or more adjuvants and accessory ingredients occur. Compressed tablets can be prepared by compressing, in a suitable apparatus, the active ingredient in the form of free fluidity as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. The molded tablets may be made by molding in a suitable apparatus as a mixture of the wetted composite powder with an inert liquid diluent.

Preferably, each tablet contains approximately 0. 05 mg to 5 g of active ingredient and each dragee or capsule preferably contains from about 0.05 mg to 5 g of the active ingredient. For example, a formulation that is intended for oral administration in humans may contain from about 0.5 mg to 5 g of active ingredient, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to 95% of the total composition . Unit dosage forms generally contain between about 1 mg to 2 mg of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 100 mg. The pharmaceutical compositions of the present invention which are suitable for parenteral administration can be prepared as solutions or suspensions of active compounds in water. A suitable surfactant can be included, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures of these - in oil. In addition, a preservative may be included to prevent the harmful growth of microorganisms. The pharmaceutical compositions of the present invention suitable for injectable use include dispersions or sterile aqueous solutions. Moreover, the compositions may be in the form of sterile powders for the extemporaneous preparation of these dispersions or sterile injectable solutions. In all cases, the final injectable form must be sterile and flow effectively to be easily applied with a syringe. The pharmaceutical compositions should be stable under storage and manufacturing conditions; therefore, they should preferably be stored to avoid the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a dispersion medium or solvent containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof. The pharmaceutical compositions of the present invention may be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. In addition, the compositions may be in suitable form for use in transdermal devices. These formulations can be prepared using a compound of the formula (I) or a pharmaceutically acceptable salt thereof by means of conventional processing methods. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water, together with about 5% by weight to 10% by weight of the compound to produce a cream or ointment with the desired consistency. The pharmaceutical compositions of this invention may be in a form suitable for rectal administration when the carrier is a solid. It is preferred that the mixture forms dosage suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by mixing the composition with the softened or molten carriers followed by cooling and forming into molds. In addition to the aforementioned carrier ingredients, the pharmaceutical compositions described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. . Moreover, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof can also be prepared in the form of a liquid or powder concentrate. Generally, dose levels within the range of 0.01 mg / kg to about 150 mg / kg of body weight per day are useful for treatment against the conditions indicated above or alternatively from about 0.5 mg to about 7 g per patient per day. For example, obesity can be effectively treated by administration of about 0.01 to 50 mg of compound per kilogram of body weight per day or alternatively, about 0.5 mg to 3.5 grams per patient per day. However, it is understood that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, general health status, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and severity of the particular disease that undergoes therapy. The compounds of the formula (I), including the compounds of stipulations a) to e) can be used in the treatment against diseases or conditions in which GPR116 has a function. Therefore, the invention also provides a method for treatment against a disease or condition wherein GPR116 has a function comprising a step of administering to a patient in need, an amount of a compound of the formula (I), including the compounds of stipulations a) to e) or one of their pharmaceutically acceptable salts. The diseases or conditions where GPR116 has a function include obesity and diabetes. Within the context of the present application, the treatment against obesity is intended to encompass treatment against diseases or conditions such as obesity and other eating disorders associated with excessive food intake, for example by reducing appetite and body weight, maintaining the reduction of weight and prevention of rebounding and diabetes (including Type I and Type II diabetes, decreased glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidemia). And the treatment of patients with a normal sensitivity to ingested fats that lead to functional dyspepsia. The invention also provides a method for regulating the feeling of satiety comprising a step of administering to a patient in need thereof, an effective amount of a compound of formula (I), including the compounds of stipulations a) to e) or one of its pharmaceutically acceptable salts. The invention also provides a method for treating obesity comprising a step of administering to a patient in need thereof., an effective amount of a compound of the formula (I), including the compounds of the stipulations a) to e) or a pharmaceutically acceptable salt thereof. The invention also provides a method for the treatment against diabetes, including Type 1 and Type 2 diabetes comprising a step of administering to a patient in need, an effective amount of a compound of the formula (I), including the compounds of the stipulations a) to e) or one of its pharmaceutically acceptable salts. The invention also provides a compound of the formula (I), including the compounds of the stipulations a) to e) or a pharmaceutically acceptable salt thereof for use in the treatment against a condition as defined above. The invention also provides a compound of formula (I), including the compounds of stipulations a) to e) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment against a condition as described above. In the methods of the invention, the term "treatment" includes both therapeutic and prophylactic treatment. The compounds of formula (I), including the compounds of stipulations a) to e) or their pharmaceutically acceptable salts, can be administered alone or in combination with one or more therapeutically active compounds.

The other therapeutically active compounds can be for the treatment against the same disease or condition as the compounds of the formula (I), including the compounds of the stipulations a) to e) or a different disease or condition. The therapeutically active compounds can be administered simultaneously, circumferentially or separately. The compounds of formula (I), including the compounds of stipulations a) to e), can be administered with other active compounds for the treatment of obesity and / or diabetes, for example, insulin and insulin analogues, gastric lipase inhibitors, inhibitors. of pancreatic lipase, sulfonylurea and analogues, biguanides, a2 agonists, glitazones, PPAR-? agonists. PPAR-a / agonists? mixed, RXR agonists, fatty acid oxidation inhibitors, α-glucosidase inhibitors, β-agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents such as, for example, pancreatic lipase inhibitors, antagonists MCH-1 and CB-1 antagonists (or inverse agonists), amylin antagonists, lipoxygenase levels, analogs -ofspectin, glucokinase activators, glucagon antagonists, insulin signaling agonists, PTB1B inhibitors, gluconeogenesis inhibitors, antilipolytic agents , GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic / dopaminergic anti-obesity drugs, CRF antagonists, CRF binding proteins, thyromimetic inhibitors, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE inhibitors -1 and sorbitol dehydrogenase inhibitors. The combination therapy comprising administering a GPR116 agonist and at least one other anti-obesity agent represents another aspect of the invention. The present invention also provides a method for treatment against obesity in a mammal as a human, this method comprising administering an effective amount of a GPR116 agonist of another anti-obesity agent to a mammal in need thereof. The invention also provides the use of a GPR116 agonist and an anti-obesity agent for the treatment of obesity. The invention also provides the use of the agonist GPR116 in the manufacture of a medicament for use in combination with another anti-obesity agent for the treatment against obesity. The GPR116 agonist and the other anti-obesity agent can be administered simultaneously, sequentially or individually.

Simultaneous administration includes the administration of a formulation that includes both the agonist GPR116 and the other anti-obesity agents or the simultaneous or separate administration of different formulations of each agent. When the pharmacological profiles of the GPR116 agonist and the other antiobesity agent permit, co-administration of both agents is preferred. The invention also provides the use of a GPR116 agonist and another anti-obesity agent in the manufacture of a medicament for the treatment of obesity. The invention also provides a pharmaceutical composition comprising a GPR116 agonist and another anti-obesity agent of a pharmaceutically acceptable carrier. The invention also encompasses the use of these compositions in the methods described above. GPR116 agonists that can be used in combination therapies according to this aspect of the invention include those compounds described herein and those described in WO 04/065380 and WO 04/076413. GPR116 agonists have particular use in combination with centrally acting antiobesity agents since these combinations can avoid the risk of adverse side effects that can be found if two centrally acting antiobesity agents are administered in combination. The other anti-obesity agent to be used in the combination therapies according to this aspect of the invention is preferably a CB-1 regulator, for example a CB-1 antagonist or inverse agonist. Examples of CB-1 regulators include SR141716 (rimonabant) and SLV-319 ((4S) - (-) -3- (4-chlorophenyl) -N-methyl-N- [(4-chlorofenyl) sulfonyl] -4 -f-4,4-dihydro-lH-pyrazole-1-carboxamide), as well as those compounds described in EP 576357, EP 656354, WD 03/018060, WD 03/020217, WO 03/020314, WO 026647, WD 03/026648, WD 03/027076, WD 03/040105, WO 03/051850, WD 03/051851, WO 03/053431, WO 03/063781, WO 03/075660, WO 03/077847, WO 03/078413, WD 03/082190, WD 03/082191, WO 03/082833, WO 03/084930, WO 03/084943, WO 03/086288, WO 03/087037, WO 03/088968, WO 04/012671, WO 04/013120, WO 04/026301, WO 04/029204, WO 04/034968, WD 04/035566, WD 4/037823, WD 04/052864, WD 04/058145, WD 04/058255, WO 04/060870, WD 04/060888, WD 04/069837, WO 04/069837, WO 04/072076, WD 04/072077, WD 04/078261 and WO 04/108728 and the references described here. Other diseases or conditions where it is suggested that GPR116 has a function and include those described in documents WD 00/50562 and US 6, 468, 756, for example cardiovascular disorders, hypertension, respiratory disorders, pregnancy abnormalities, gastrointestinal disorders, immune disorders, usculoskeletal disorders, depression, phobias, anxiety, mood disorders and Alzheimer's disease. All publications, including, but not limited to, the patents and patent applications cited in this specification, are incorporated herein by reference as if each individual publication were specifically and individually incorporated by reference herein and set forth in its entirety. The invention will be described with reference to the following examples which are for illustrative purposes and should not be construed as limiting the scope of the present invention. EXAMPLES Materials and Methods. Column chromatography was carried out on Si02 (40-63 mesh) unless otherwise specified. The LCMS data are obtained as follows: Cía Atlantis 3μ column (2 .1 x 30 .0 mm, flow velocity = 0 85 ml / min) eluting with a H20-MeCN solution containing 0. 1% HCC ^ H for 6 minutes with UV detection at 220 nm.

Gradient information: 0.0-0.3 minutes 100% H2O; 0.3-4.25 minutes; Gradual elevation to 10% H2O-90% CH3CN; 4.25min-4.4min; Gradual elevation to 100% CH3CN; 4.4-4.9min; it is maintained at 100% MeCN; 4.9-6.0 Iran: Returns to 90% H; 2 ?. The mass spectrum is obtained using an ionization source by electroaspersion in either positive ion mode (ES +) or negative ion (ES "). The spectrum of Chemical Ionization of Atmospheric Pressure (APCl) is obtained in an instrument FinniganMat SSQ 70 0C. The XH NMR spectrum is recorded on a Varian Mercuri 400 spectrometer operating at 400 MHz. Chemical shifts are recorded as ppm relative to tetramethylsilane (d = 0). HPLC is carried out using a Phenomenex ™ lOμ Cis column (210 x 21 mm) eluting with a H20-CH3CN solution at 20 ml / minute, with UV detection at 220 nm. Typical gradient: 0-0.5 minutes 10% CH3CN-90% H20; 0 .5min-10min, gradually raise to 90% CH3CN-10% H20 and maintain 90% CH3CN-10% H20 for 5 minutes; 15min-16min, returns to 10% CH3CN-90% H20. The synthesis of the following compounds was previously recorded: 3- (2-cyanopyridin-4-yl) propyl acetate; P. L. Omstein et al. , J. Med. Chem., 1991, 34, 90-97; (N-droxycarbamimidoylmethyl) carbamic acid tert-butylester: WO 03/082861; N-hydroxyisonicotinamidine and N-droxinixorinamidine: A. R. Martin et al. , J. Med. Chem., 2001, 44, 1560-1563. N-hydroxy-2-pyridin-3-ylacetamidine and N-idroxy-2-pyridin-4-ylacetamidine: WD 01/047901; 4-mercaptopiperidine-l-carboxylic acid tert-butylester: U.S. Patent 5,317,025; 4-Pentylcyclohexanecarbonitrile: J.C. Liang and J. O. Cross, Mol. Cryst. Liq. Cryst. , 1986, 133, 235-244; 4- (3-Bromo-2-oxopropyl) piperidine-l-carboxylic acid ethyl ester: WD 04/013137. Abbreviations and acronyms: Ac: acetyl; Boc: tert-butoxycarbonyl; t-Bu: tert-butyl; CDl: 1,1 '-carbonyldiimidazole; dba: dibenzylidene ketone; DMF: N, N-dimethylformamide; Et: ethyl; HPLC: high performance liquid chromatography; IH: isohexane, LDA: lithium diisopropylamide; mCPBA: 3-chloroperoxy-oceanic acid; Me: methyl; ODC: pyridinium dichromate; RP_HPLC: reversed phase high efficiency liquid phase liquid chromatography; RT: retention time; rt: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMS: trimethylsilyl. Preparation 1: 4-carboxymethoxypiperidine-1-carboxylic acid tert-butylester Sodium hydride (596 mg of 60% dispersion in oil, 14.9 mmol) is added in portions to a stirred solution of tert-butyl-4-hydroxypiperidine-1-carboxylate (1.0 g, 5 mmol) in anhydrous THF (20 ml). at room temperature. After a period of 15 minutes, bromoacetic acid (1.38 g, 9.94 mmol) is introduced and stirring is continued for 5 hours. An additional amount of bromoacetic acid (5 mmol) and sodium hydride (5 mmol) is added and stirring is continued for 24 hours. The reaction is quenched with water (2 ml) and diluted with EtOAc (20 ml), washed with saturated aqueous NaHCO3 (20 ml). Using dilute HCl, the aqueous phase is acidified to pH 2 and the precipitate is extracted into EtOAc (50 ml). The organic phase is dried (MgSO 4), evaporated and the residue is purified by flash chromatography (5% AcOH in IH-EtOAc, 7: 3 to 1.1) to yield the title acid: RT = 2. 89 minutes; m / z (ES +) (260 .3 [M + H] +. Preparation 2: 2-chloro-N-hydroxyisonicotinamidine A solution of sodium carbonate (382 mg, 1.36 mmol) and ammonium hydroxide hydrochloride salt (502 mg, 7.22 mmol) in water (10 mg) in 2-chloro-4-cyanopyridine (1.0 g, 7.22 mmol) is added. ) and the mixture is heated to 80 ° C. Then a sufficient amount of ethanol (10 ml) is added to produce a homogeneous solution. After a period of 18 hours, the solution is cooled and the ethanol is removed in vacuo. The solid precipitate is collected by filtration, washed with ethanol and CH2C12 and then dried, yielding the title compound: RT = 0.86min; m / z (ES +) = 172.1 [M + H] +. Preparation 3: trans-4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) cyclohexanecarbocyclic acid methyl ester A solution of cyclohexane-1,4-dicarboxylic acid monomethyl ester (1.053 g, 5.66 mmol) and triethylamine (800 μl, 5.66 mol) in toluene (30 ml) is cooled to 0 ° C and isobutyl chloroformate (735) is introduced dropwise. μl, 5.66 mmol). The mixture is stirred at room temperature for 30 minutes whereupon it is activated, powdered molecular sieves of 3Á (5 g) and N-hydroxyisonicotinamidine (705 mg, 5.14 mmol) are added. The mixture is refluxed for 18 hours, cooled and filtered through celite. The solvent is removed in vacuo and the residue is purified by flash chromatography (IH-EtOAc, 1: 1) to yield the title compound; RT = 3.20 minutes; m / z (ES +) = 288.2 [M + H] +. Preparation 4: trans-A- (3-pyridin-4-yl [1, 2, 4] oxadiazol-5-yl) cyclohexanecarboxylic acid Water (0.5 ml) and lithium hydroxide (9.2 mg, 0.22 mmol) are added to a stirred solution of 4- (3-pyridin-4-yl [1,2,4] oxadiazol-5-yl) cyclohexanecarboxylic acid methyl ester. (Preparation 3, 30 mg, 104 μmol) in THF (1.5 ml). The mixture is heated at 60 ° C for 1.5 hours and cooled and the THF is removed in vacuo. Water (5 ml) is added, the aqueous precipitate is washed with EtOAc (5 ml) and carefully acidified with ÍM HCl to pH 4. The resulting precipitate is extracted in 3% MeOH in EtOAc (2x15 ml) and the combined organic phases dry (MgSO4) and evaporate to yield the title compound; RT = 2742 m / z (ES +) = 274.2 [M + H] +. Preparation 5: cis- [3- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) cyclopentyl] methanol Sodium hydride (100 mg, from a 60% dispersion in oil, 2.5 mmol) is added to a solution of N-hydroxynicotinamidine (344 mg, 2.5 mmol) in anhydrous THF (3 ml) and the mixture is heated at reflux for one hour. Cis-methyl-3-hydroxymethylcyclopentane-1-carboxylate (396 mg, 2.5 mmol) is added in a single portion and heating is continued for 18 hours. After cooling, the solution is filtered through celite and the filtrate is concentrated in -empty. The residue is purified by flash chromatography (IH-EtOAc, 1: 1 to 0: 1) to yield the title compound: RT = 2. 59 min, m / z (ES +) = 246.1 [M + H] +. Preparation 6: trans- - (3-pyridin-4-yl- [1,2,4] oxadiazol-5-i1) cyclohexylmethane A solution of trans-4- (3-pyridin-4-yl [1, 2, 4] oxadiazol-5-yl) cyclohexanecarboxylic acid methylester (Preparation 3, 200 mg, 0.696 mmol) was cooled to -3 ° C in Dry CH2C12 (13 ml) and isobutylaluminum hydride (1.59 ml of 1M solution in toluene, 1.59 mmol) is introduced dropwise. After a period of 30 minutes, the reaction is quenched with 2M HCl (6 ml), the mixture is warmed to room temperature and partitioned between 2M HCl (10 ml) "and CH2C12 (10 ml) The aqueous phase is neutralized using 2M NaOH and then extracting with CH2C12 (4x20 ml) The combined organic phases are dried (MgSO4) and evaporated to yield the title compound: RT = 2.59 minutes, / z (? S +) = 260.2 [M + H ] +. Preparation 7: trans-N-hydroxy-4-pentylcyclohexylamidine A solution of potassium carbonate (2.49 g, 18 mmol) and H2 H2OH.HCl (2.50 g, 36 mmol) in water (15 mL) in trans-4-pentylcyclohexanecarbonitrile (4.30 g, 24 mmol) is added and the mixture is mixed. heat at 80 ° C. A sufficient amount of ethanol (approximately 45 ml) is added to produce a homogeneous solution. After a period of 10 hours, the solution is cooled, diluted with water (200 ml) and the solid material is collected by filtration. The solid is dissolved in EtOAc (150 ml) and the resulting solution is washed with brine (50 ml) and dried (MgSO 4). The solvent is reduced to a volume of 15 ml and hexane (60 ml) is added to precipitate the title compound, which is collected by filtration: RT = 2.86 minutes, m / z (ES +) = 213.2 [M + H] +. Preparation 8: tert-butylester (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) carbamic A solution of tert-butoxycarbonylaminoacetic acid (1.0 g, 5.71 mmol) and triethylamine is cooled to 0 ° C. (802 μl, 5.71 mmol) in toluene (30 ml) and isobutylchloroformate (740 μl) is introduced dropwise.5.71 mmol). The reaction mixture is stirred at 0 ° C for 10 minutes and at room temperature for 30 minutes, whereupon N-hydroxyisonicotinamidine (652 mg, 4.76 mmol) and powdered molecular sieves of 3Á (4 g) are added. After heating under reflux for 12 hours the reaction is cooled, filtered through celite and the solvent is removed in vacuo. The residue is dissolved in EtOAc (200 ml) and washed with water (30 ml) and saturated aqueous? AHC? 3 (30 ml), then dried (MgSO.sub.0). The solvent is removed and the residue is purified by flash chromatography (IH-EtOAc, 2: 3) to yield the title compound: RT = 2.97 minutes; m / z (ES +) = 277.1 [M + H] +.

Preparation 9. C- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) methylamine Trifluoroacetic acid (6.5 ml) is added to a solution of (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) carbamic acid tert-butylester (Preparation 8, 420 mg, 1.52 mmol in CH2C12 (10 ml) and the mixture is stirred at room temperature for 2 hours.The solvent is evaporated and the residue is dissolved in EtOAc (100 ml) After washing with saturated aqueous Na2CÜ3 (25 ml), the aqueous phase becomes to extract with 5% MeOH in CH2C12 (7x25 ml) and the combined organic phases are dried (MgSO4) The solvent is removed to yield the title compound: RT = 0.25 minutes, m / z (ES +) = 177.1 [M + H] + Preparation 10: 3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethylcarbonic acid isobutyl ester Isobutylchloroformate (11.67 ml, 90 mmol) is added to a solution of hydroxyacetic acid (3.42 g, 45 mmol) and triethyl amine (12.65 ml, 90 mmol) in toluene (220 ml) at 0 ° C. After being stirred at room temperature for one hour, N-hydroxyisonicotinamidine (6.17 g, 45 mmol) in powder of 3 A (20 g) molecular is added. After heating under reflux for 18 hours, the cooled mixture is mixed through celite, the solvent is evaporated and the residue is purified by flash chromatography (IH-EtOAc, 1: 1) to yield the title compound: RT = 3.51 minutes; m / z (ES +) = 278.0 [M + H] +. Preparation 11: (3-pyridin-4-yl- [1, 2,] oxadiazol-5-yl) methanol A stirred solution of 3-pyridin-4-yl- [1,2,4-oxadiazol-5-ylmethylcarbonic acid isobutyl ester (Preparation 10, 5.94 g, 21.45 mmol) in methanol (75 ml) at room temperature is subjected to treatment. with 2M aqueous sodium hydroxide (11.8 ml, 23.6 ml). After a period of 10 minutes, the solvent is removed and the residue is purified in flash chromatography. { EtOAc) to yield the title compound: RT = 1.30 minutes; m / z (ES +) = 178.0 [M + H] +. Preparation 12: methanesulfonic acid of 3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl ester Methanesulfonyl chloride (0.50 mL, 6.50 mmol) is added to a stirred solution of (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) methanol (1 g, 5.65 mmol) and triethylamine (0.953 mL, 6.78 mmol) in CH2C12 (30 mL) at 0 ° C. After a period of 10 minutes, water (20 ml) is added and the aqueous phase is extracted with CH2C12 (20 ml). The combined organic phases are dried and evaporated (MgSO 4) to yield the title compound: RT = 2.32 minutes; m / z (? S +) = 256.0 [M + H] +. Preparation 13: 4-carbamoylmethoxypiperidine-1-carboxylic acid tert-butylester A solution of 4-carboxyethoxypiperidine-l-carboxylic acid tert-butylester (Preparation 1, 14.13 g, 54.7 mmol) and triethylamine (7.68 mL, 65.6 mmol) in anhydrous THF (250 mL) is cooled to 0 ° C and introduced drop by drop isobutylchloroformate. { 8.51 ml, 65.6 mmol). After being stirred at 0 ° C for 30 minutes, the reaction mixture is cooled to -20 ° C and rapidly added by means of a cannula to a solution of 0.7M ammonia in anhydrous CH2C12 (250 mL, 180 mmol) at -70 ° C. The reaction is warmed to room temperature and stirred for one hour. The mixture is diluted with CH2C12 (250 ml) and washed with saturated aqueous NaHCO3 (200 ml), 0.5M HCl (200 ml) and brine (200 ml) then dried (MgSO4). The solvent is evaporated and the residue is purified by flash chromatography (IH-THF 3: 7) to yield the title compound: 5H (CDC13) 1.49 (9H, s), 1.53-1.60 (2H, m), 1.85-1.92 (2H,), 3.11 (2H, m), 3.58 (HH, m), 3.76-3.83 (2H, m), 3.98 (2H, s), 6.19 (1H, bs), 6.56 (HH, bs). Preparation 14: 4-cyanomethoxypiperidine-1-carboxylic acid tert-butylester A solution of 4-carbamoylmethoxypiperidine-l-carboxylic acid tert-butylester (Preparation 13, 235 mg, 0.91 mmol) and triethylamine (140 μl, 1 mmol) in anhydrous CH2C12 (5 ml) is added at 0 ° C and added dropwise. drop a solution of trichloroacetyl chloride (174 mg, 0.96 mmol) in anhydrous CH2C12. The reaction mixture is stirred at room temperature for one hour, the solvent is removed and the residue is purified by flash chromatography (IH-EtOAc, 1: 1) to yield the title compound: dp (CDCl 3) 1.50 (9H, s), 1.58-1.65 (2H, m), 1.89-1.95 (2H, m), 3.20 (2H, m), - 3.74-3.79 (3H,), 4.33 (2H, s).

Preparation 15: 4- (N-hydroxycarbamidoylmethoxy) piperidine-1-carboxylic acid tert-butylester Add a solution of potassium carbonate (119 mg, 0.86 mmol) and NH20H.HC1 (119 mg, 1.71 mmol) in water (0.5 mL) in 4-cyanomethoxy-pipperidine-l-carboxylic acid tert-butylester (Preparation 14, 206 mg, 0.857 mmol) in ethanol (2 ml). The mixture is heated at 75 ° C for 0.75 hours, cooled and the ethanol evaporated. The residue is diluted with EtOAc (50 ml) and washed with water (2x10 ml) and brine (10 ml) and dried (MgSO 4). The solvent is dried and removed to yield the title compound: dH (CDC13) 1.50 (9H, s), 1.50-1.60 (2H, m), 1.85-1.92 (2H, m), 3.13 (2H,), 3.56 (ÍH, m), 3.77- 3.84 (2H, m), 4.05 (2H, s), 4.82 (2H, bs); RT = 2.70 minutes, m / z (ES +) = 274 .0 [M + H] +.

Preparation 16: 4- tert-butylester. { 2-oxo-2- [N'- (pyridine-4-carbonyl) hydrazin] ethoxy} piperidin-l-carboxylic A solution of 4-carboxyethoxypiperidine-1-carboxylic acid tert-butylester (Preparation 1, 1.25 g, 4.82 irmol), ethyl- (3-dimethylaminopropyl) carbodiimide (924 mg, 4.82 mmol) is stirred at room temperature for 10 minutes. N-hydroxyze zotriazole (651 mg, 4.82 mmol) in anhydrous CH2C12 (30 ml). Isonicotinic acid hydrazide (601 mg, 4.38 mmol) is added in a single portion and the stirring is continued for an additional 18 hours. The reaction mixture is diluted with CH2C12 (150 ml) and washed with water (30 ml), saturated aqueous aHC03 (30 ml) and brine (30 ml). After drying (MgSO4), the solvent is removed to yield the title compound: RT = 2.89 minutes; m / z (ES +) = 379.1. { M + H] +. Preparation 17: 4- [5-. { piperidin-4-yloxymethyl) - [1,2, 4] oxadiazol-3-yl] pyridine 4- (3-pyridin-4-yl) - [1,2, 4] oxadiazol-5-ylmethoxy) piperidine-1-carboxylic acid (Example 1) is removed using the procedure described in Example 51, yielding the title compound : RT = 1.84 minutes; m / z (ES +) = 261.2 [M + H] +. Preparation 18: 4-thiocarbamoylmethoxypiperidine-1-carboxylic acid tert-butylester A solution of 4-carbamoylmethoxypiperidine-1-carboxylic acid tert-butylester (Preparation 13, 67.5 mg, 260 μmol) and Lawesson's reagent (116 mg, 287 μmol) in dimethoxyethane (1.5 ml) is stirred at room temperature for 24 hours. . The solvent is evaporated and the residue is purified by flash chromatography (5% MeOH in CH2C12) to yield the title compound: dH (CDC13) 1.50 (9H, s), 1.55-1.63 (2H,), 1.88-1.95 (2H , m), 3.12 (2H, ddd), 3.59-3.66 (HH, m), 3.79-3.87 (2H, m), 4.40 (2H, s), 7.65 (HH, bs), 8.04 (HH, bs).

Preparation 19: N'- (pyridine-4-carbonyl) hydrazide of trans-4-phenyl-cyclohexanecarboxylic acid The isonicotinic acid hydrazine is reacted with 4-pentylcyclohexanecarboxylic acid in a manner similar to that described in Preparation 16 to yield the title compound: RT = 4.79 minutes; m / z (ES +) = 318.0 [M + H] +.

Preparation 20: 3- (2-cyanopyridin-4-yl) propionic acid A solution of K2C03 (1.67 g, 12.1 mmol) in H20 (30 mL) is added to a stirred solution of 3- (2-cyanopyridin-4-iD-propylacetate (4.94 g, 24.2 mmol) in MeOH (130 mL). After a period of 25 minutes, the MeOH is removed under reduced pressure, then the aqueous phase is extracted three times with EtOAc The combined organic extracts are dried (MgSO 4), filtered and concentrated to produce a residue which is purified by chromatography on column (IH-EtOAc, 1: 3) to give 4- (3-hydroxypropyl) pyridine-2-carbonitrile: m / z (? S +) = 163.1 [M + H] +. A solution of this alcohol is subjected to treatment (500 mg, 3.1 mmol) in DMF (200 ml) with PDC (7 g, 18.6 mmol) and H20 (0.5 ml) The reaction is stirred for 16 hours, before being partitioned between H20 and EtOAc. twice with EtOAc, then the combined organic extracts are washed with brine, dried (MgSO.sub.4), filtered and concentrated to yield the title compound: m / z (ES +) = 177.0 [M + H] +. 21: 4- (3-aminomethyl- [1, 2, 4] oxadiazol-5-yl) pyridine-2-carbonitrile Net3 (6.6 ml, 47.3 mmol) is added to a stirred solution of 2-cyanoisonicotinic acid (7.00 g, 47.3 mmol) in toluene (500 ml). The mixture is cooled to 0 ° C before being treated with isobutyl chloroformate (6.1 ml, 47.3 mmol). Stirring is continued at 0 ° C for 10 minutes, then the mixture is warmed to room temperature for one hour, before being treated with (N-hydroxycarbamimidoylmethyl) carbamic acid tert-butylester (7.44 g, 39.4 mmol) and molecular sieves. dry 4Á (40 g). The reaction is refluxed for 16 hours. Upon cooling, the mixture is filtered through celite, washed with EtOAc. The combined filtrates are concentrated in vacuo, then the residue is dissolved in EtOAc. The MeOH solution is washed with saturated aqueous Na2CO3 saturated and brine, before drying (MgSO4). Filtration, evaporation of the solvent and column chromatography (IH-EtOAc, 7: 3) produce [5- (2-cyanopyridin-4-yl) - [, 2,4] oxadiazole-3-butyl ester. ilmethyl] carbamic: m / z (ES +) = 603.2 [2M + H] +. A stirred solution of this carbamate (1.95 g, 6.5 mmol) in CHC13 (50 mL) is treated with TMS- (2.2 mL, 15.6 mmol). After a period of 10 minutes, the reaction is subjected to treatment with MeOH (2.5 ml, 62.2 mmol), then the stirring continues for an additional 10 minutes. The solvents are evaporated under reduced pressure and then the residue is dissolved in MeOH and taken up in Si02. Column chromatography (EtOAc then EtOAc-MeOH, 9: 1) yields the title compound: m / z (ES +) = 202.0 [M + H] +. Preparation 22: 4- (3,5-dioxo-5-pyridin-4-ylphenyl) piperidine-l-carboxylic acid tert-butylester CDl (0.63 g, 3.9 mmol) is added to a solution of 4- (2-carboxyethyl) piperidine-l-carboxylic acid tert-butylester (1.00 g, 3.9 mmol) in anhydrous THF (7.6 mL), then the mixture is mixed. Stir for 45 minutes. In a separate container, 4-acetylpyridine (0.49 g, 4.1 mmol) is slowly added to a stirred solution of LDA (2.04 mL of 2.0 M solution in heptane-THF-ethylbenzene, 4.1 mmol) in anhydrous THF (15.3 mL) at - 78 ° C. After a period of 45 minutes, the acylimidazole solution is added slowly by means of a cannula to 4-acetylpyridine lithiated maintaining the temperature at -78 ° C. The reaction is warmed to room temperature over a period of two hours, before being diluted with EtOAc (150 mL). The solution is washed with 10% aqueous citric acid (2x15 ml), saturated aqueous NaHCO3 (2x15 ml) and brine (20 ml) before drying (MgSO4). Filtration, concentration and purification by RP-HPLC yield the title compound: m / z (ES +) = 261.2 [M-Boc + H] +. Preparation 23: 4- (2,4-dioxo-4-pyridin-4-ylbutoxy) piperidine-1-carboxylic acid tert-butylester Condensation of 4-acetypiridine with 4-carboxyethoxy-pipiperidine-l-carboxylic acid ter-butylester (Preparation 1), using the protocol described in Preparation 22, yields the title compound: m / z (ES +) = 263.2 [M-Boc] + H] +.

Preparation 24: 4- (2,4-dioxo-4-pyridin-4-butyl) piperidine-l-carboxylic acid tert-butylester Condensation of 4-acetylpyridine with tert-butylester of -carboxymethylpiperidine-1-carboxylic acid, using the protocol described in Preparation 22, yields the title compound: m / z (ES +) = 247.2 [M-Boc + H] +.

Preparation 25: 4- [3- (piperidin-4-yloxymethyl) [1,2,4] oxadiazol-5-yl] pyridine-2-carbonitrile To a stirred solution of 4- [5- (2-cyanopyridin-4-yl) - [1, 2, 4] oxadiazol-3-ylmethoxy] piperidine-1-carboxylic acid tert-butylester (Example 42, 2.0 g, 5.2 mmol) in chloroform (100 ml) under an argon atmosphere, trimethylsilyl iodide (2.95 ml, 20.8 mmol) is added and the reaction mixture is stirred for one hour. MeOH is added until the solution is formed and then sodium thiosulfate (6.6 g, 41. 5 mmol) and the reaction mixture is stirred vigorously for 10 minutes. The solids are removed by filtration and the filtrate is adsorbed on silica gel. Purification by column chromatography (DCM-MeOH, 9: 1) produces the title compound: RT = 1.92 minutes; m / z (ES +) = 286.0 [M + H] +.

Example 1: 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethoxy) piperidine-l-carboxylic acid tert-butylester To a stirred solution of triethylamine (123 μl, 0.87 mmol) and 4-carboxyethoxy-pipiperidine-l-carboxylic acid tert-butylester (Preparation 1, 227 mg, 0.87 mmol) in toluene (10 ml) is treated with isobutylchloroformate (113 μl). 0.87 mmol). After a period of 20 minutes, powdered activated molecular sieves of 3A (0.7 g) and N-hydroxyisonicotinamidine (100 mg, 0.73 mmol) are added and the reaction mixture is heated under reflux for 18 hours. Upon cooling, the mixture is filtered through celite, the solvent is removed in vacuo and the residue is purified by flash chromatography (IH-EtOAc, 7:13) to yield the title compound: RT = 3.29 minutes; m / z (ES +) = 361.3 [M + H] +; dp (CDC13) 1.40 (9H, s), 1.55-1.63 (2H, m), 1.80-1.92 (2H, m), 3.05-3.15 (2H, m), 3.64-3.79 (3H, m), 4.80 (2H , s), 7.90 (2H, d), 8.75 (2H, d). The [1,2,4] oxadiazoles in Table 1 are synthesized from the appropriate amidoxime and the corresponding acid, in a manner similar to that described in Example 1.

Table 1 0 The compounds in Table 2 were prepared according to the method described in Example 1.

Table 2 Example 16: trans-A- [3- (4-pentylcyclohexyl) - [1,2,4] oxadiazol-5-yl] pyridine-2-carboxylic acid methylamide A stirred solution of trans-A- [5- (4-pentylcyclohexane) - [1,2,4] oxadiazol-3-yl] pyridine (Example 11, 100 mg, 0.33 mmol) and H2SO4 is cooled to 0 ° C. 17.8 μl, 0.33 mmol) in N-methylformamide (2 ml). FeS04.7 H20 solid (23 mg, 83 μmol) is added followed by H2O2 (63 μl of a 27% solution in water, 0.5 irmol) and the mixture is stirred at 0 ° C for 2 hours. A 1M solution of aqueous sodium citrate (1 ml) is added and the mixture is extracted with CH2C12 (2x5ml). The combined organic phases are washed with water (2x5 ml), saturated aqueous aHCC (2x5 ml) and brine (5 ml) which are dried (MgSO4). The solvent is removed and the residue is purified by flash chromatography (IH-EtOAc, 17: 3 to 7: 3) to yield the title compound: RT = 4.86 minutes, m / z (ES +) = 357.4 [M + H] +. Example 17: trans-4- [5 - (4-pentylcyclohexyl) - [1, 2,4] oxadiazol-3-yl] pyridine-2-carboxylic acid amide A stirred solution of trans-4- [5- (4-pentylcyclohexane) - [1, 2, 4] oxadiazol-3-yl] pyridine (Example 11) and H2SO4 in formamide with FeS04.7 H20 and H202 is treated. in a manner similar to that described in Example 16 to produce the title compound: RT = 4.66 minutes, m / z (ES +) = 343.4 [M + H] +. Example 18: fcrans-4- [3- (4-pentylcyclohexyl) - [1, 2, 4] oxadiazol-5-yl] pyridine A solution of isonicotinic acid (36.2 mg, 290 μmol) and triethylamine (30 mg, 290 μmol) in anhydrous THF (3 ml) is cooled to 0 ° C and isobutylchloroformate (39 mg, 280 μmol) is added. The mixture is stirred at room temperature for one hour and a single portion of trans-N-hydroxy-4-pentylcyclohexylamidine is added.

(Preparation 7, 50 mg, 235 μmol) solid. After a period of 45 minutes, the reaction is diluted with EtOAc (12 ml), washed with saturated aqueous aHC03 (3 ml) and brine (6 ml), then dried (MgSO4). After evaporation of the solvent, the residue is dissolved in toluene (5 ml) and the solution is heated under slight reflux for two hours. The solvent is removed and the residue is purified by flash chromatography (IH-EtOAc), 2: 1 to yield the title compound: RT = 4.97 minutes, m / z (ES +) = 300.3 [M + H] +. The [1,2,4] ixadiazoles are synthesized in Table 3 by reacting the appropriate acid with trans-N-hydroxy-4-pentylcyclohexylamidine (Preparation 7) in a manner similar to that described in Example 18.

Table 3 Tcans-2-fluoro-4- [3- 5.07 318.2 (4-pentylcyclohexyl) - [M + H] + [1,2,4] axadiazol-5-yl] pyridine cans-2-imidazole-l- 4.49 366. 2 il-5- [3- (4- [M + H] + pentylcyclohexyl) - [1,2,4] oxadiazol-5-yl] pyridine 2? Ans-2-methyl-4- [3- 5.05 314.2 ( 4-pentylcyclichexyl) - [M + H] + [1,2,4] oxadiazol-5-yl] pyridine Trans-3-pEthyl-4- [3- '5.16 314.2 (4-pentylcyclizole) - [M + H] + [1,2,4] axadiazbl-5-yl] pyridine Trans-4-. { 2- [3- (4- -4.62 326.2 Pentylcyclohexyl) - [M + H] + [1,2,4] cxadiazol-5-yl] vinyl > pyridine Example 41: 4- (5-pyridin-4-yl- [1,2,4] oxadiazol-3-ylmethoxy) piperidine-l-carboxylic acid tert-butylester A solution of isonicotinic acid (31 mg, 250 μmol) and triethylamine (51 mg, 500 μmol) in anhydrous THF is cooled to 0 ° C and isobutylchloroformate (34 mg, 250 μmol) is added. The reaction is stirred at room temperature for 0.5 hour and tert-butylester of solid 4- (N-hydroxycarbamidoylmethoxy) piperidine-1-carboxylic acid is added in a single portion (Preparation 15, 54.5 mg, 200 μmol). After stirring for 40 minutes, the solvent is removed, EtOAc is added to the residue and the mixture is passed through a small plug of silica, eluting with EtOAc. After evaporation, the residue is dissolved in toluene (4 ml) and heated under reflux for 15 hours. Then the solvent is evaporated and the residue is purified by flash chromatography (EtOAc) to yield the title compound: RT = 3.65 minutes; m / z (ES +) = 361.2. { M + H] +. The [1, 2,4] oxadiazoles are synthesized in Table 4 by condensing the appropriate acid with a suitable amidoxime, in general form to that described in Example 41.

Table 4 Example 51; 4- (5-piperidin-4-yl- [1, 2, 4] oxadiazol-3-yl) pyridine Trifluoroacetic acid (20 ml) is added to a stirred solution of 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidine-l-carboxylic acid tert-butylester (Example 2). 1.64 g, 4.96 mmol) in CH2C12. (35 ml). After a period of 2.5 hours at room temperature, the solvent is evaporated under reduced pressure. The residual solid is suspended in EtOAc (150 ml) and washed with saturated aqueous Na 2 CO 3 (20 ml). The aqueous phase is separated and extracted with EtOAc (3x30 ml). The combined organic extracts are dried (MgSO4) and evaporated under reduced pressure to yield the title compound: RT = 3.48 minutes; m / z (ES +) = 231.2 [M + H] +.

Example 52: 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidine-l-carboxylic acid tert-butylester A solution of pyridine (18μl, 0.22 mmol) and 4- (5-piperidin-4-yl- [1, 2,4] oxadiazol-3-yl) pyridine (Example 51, 50 mg, 0.22 mmol) is subjected to treatment. in CHC12. { 4 ml) with isobutylchloroformate (54 mg, 0.43 mmol). The reaction is stirred at room temperature for 18 hours and then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase is separated, evaporated and the residue is purified by flash chromatography (IH-ETOAc, 1: 1 to 0: 1) to yield the title compound: RT = 3.42 minutes; m / z (ES +) = 331.2 [M + H] '+ The [1, 2, 4] oxadiazoles are synthesized in Table 4 in a manner similar to that described in Example 52. Table 4 Example 55: 3, 3-dimethyl-l- [4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] butan-1-one A pyridine solution (18 μl, 0.22 mmol) and 4- (5-piperidin-4-yl- [1, 2, 4] oxadiazol-3-yl) pyridine (Example 51, 50 mg, 0.22 mmol) is subjected to treatment. in CH2C12 (4 ml) with 3,3-dimethylbutanoyl chloride (58 mg, 0.43 mmol). The reaction is stirred at room temperature for 18 hours and then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase is separated, evaporated and the residue is purified by flash chromatography (IH-EtOAc, 1: 1 to 0: 1) to yield the title compound: RT = 3.11 minutes; m / z (ES +) = 329.3 [M + H] +.

Example 56: 2-Cyclopentyl-l- [4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] ethanone 4- [5- (Piperidin-4-yloxymethyl) - is reacted. { 1,2,4-oxadiazol-3-yl] pyridine (Example 51) with cyclopentylacetyl chloride in a manner similar to that described in Example 55, to produce the title compound: RT = 3.44 minutes; m / z (ES +) = 341.3 [M + H] +.

Example 57: 4-. { 5- [1- (butan-1-sulfonyl) piperidin-4-yl] [1,2,4] oxadiazol-3-yl} pyridine A solution of pyridine (18 [mu] l, 0.22 mmol) and 4- (5-piperidin-4-yl- [1,2,4] oxadiazol-3-yl) pyridine (Example 51, 50 mg, 0.22 mmol) in CH2C12 (4 ml) is subjected to treatment with butan-1-sulfonyl chloride (56 μl, 0.43 mmol). The reaction is stirred at room temperature for 18 hours and then quenched with saturated aqueous NaHCO3 (1 mL). The organic phase is separated, dried (MgSO 4) and evaporated. The residue is dissolved in EtOAc (5 ml) and extracted into 2M HCl (10 ml). The aqueous phase is basified using 2M NaOH to pH = 8 and extracted with CHC12 (2x10 ml). The combined organic phases are dried (MgSO 4) and evaporated to yield the title compound: RT = 3.29 minutes; m / z (ES +) = 351.2 [M + H] +. Example 58: 4- (3-pyridin-4-yl [1, 2, 4] oxadiazol-5-yl) iperidine-1-carboxylic acid propylamide 1-Propylisocyanate (13 μl, 137 -μmol) is added to a solution of 4-. { 5-piperi-din-4-il-. { 1,2,4] oxadiazol-3-yl) pyridine (Example 51, 15.8 mg, 69 μmol) in CH2C12 (0.7 ml). After being stirred for 18 hours at room temperature, the solvent is removed to yield the title compound: RT = 2.72 minutes; m / z (ES +) = 361.3 [M + H] +.

Example 59: 4- (3-pyridin-4-yl [1,2,4] oxadiazol-5-yl) piperidine-l-carboxylic acid tert-butylamide The tert-butyl isocyanate was reacted with 4- (5-piperidin-4-yl- [1,2,4] oxadiazol-3-yl) pyridine (Example 51) in a similar manner to that described in Example 58 to produce the compound of title: RT = 3.04 minutes; / z (ES +) = 330.3 [M + H] +. The carbamate esters in Table 5 are produced by the reaction of 4- [5- (piperidin-4-yloxymethyl) - [1,2,4] oxadiazol-36-yl] pyridine (Preparation 17) with the appropriate chloroformate, in a manner similar to that described in Example 52.

Table 5 Reaction 4- [5- ([iperidin-4-yloxymethyl] - [1,2,4] oxadiazol-3-yl] pyridine (Preparation 17) is reacted with the appropriate acid chloride in a similar manner to that described in Example 55, to produce the amides in Table 6.

Table 6 4- [5- (Piperidin-4-yloxymethyl] - [1,2,4] oxadiazol-3-yl] pyridine (Preparation 17) is reacted with the appropriate sulfonyl chloride in a manner similar to that described in Example 57, to produce the sulfonamides in Table 7.

Table 7 The compounds in Table 8 are synthesized by reacting 4- [5- (piperidin-4-yloxymethyl] - [1,2,4] oxadiazol-3-yl] pyridine (Preparation 17) with the appropriate isocyanate in a manner similar to that described in Example 58.

Table 8 Example 101: trans-4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) cyclohexanecarboxylic acid propylester Thionyl chloride (11.5 μL, 0.1 mmol) is added to a solution of trans-4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) cyclohexanecarboxylic acid (Preparation 4, 22 mg , 0.08 mmol) in 1-propanol (2 ml). The mixture is refluxed for 2 hours, cooled and the solvent removed in vacuo. The residue is dissolved in EtOAc (10 mL), washed with saturated aqueous NaHCO3 (3 mL) and brine (5 mL) and dried (MgSO4). Removal of the solvent gives the title compound: RT = 3.04 minutes; m / z < ES +) = 330.3 [M + H] +. The esters in Table 9 are synthesized in a similar manner as that described in Example 101.

Table 9 Example 104: trans-4- [5- (4-propoxymethylcyclohexyl). { 1,2,4] oxadiazol-3-yl] pyridine A solution of trans-4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) cyclohexylmethanol (Preparation 6, 50 mg, 00.19 mmol) in THF (2.5 mL) is stirred with hydride of sodium (27 mg of 60% dispersion in oil, 0.68 mmol) for one hour and then 1-bromopropane (70 μL, 0.77 mmol) and tetrabutylammonium iodide (7 mg, 19 μmol) are added. The mixture is stirred at room temperature for 72 hours and the solvent is removed and the residue is dissolved in CH2C1 (10 ml). After washing with water (3 ml) the organic phase is dried (MgSO 4) and evaporated. Purification of the residue by flash chromatography (IH-EtOAc, 7: 3) yields the title compound: RT = 3.92 minutes; m / z < ES +) = 302.3 ÍM + H] +.

Example 105: trans-4- [5- (4-Butoxymethylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine A solution of 4- (3-pyridin-4-yl [1,2,4] oxadiazol-5-yl) cyclohexylmethanol (Preparation 6) in THF is subjected to treatment with sodium hydride, 1-bromobutane and tetramethylammonium iodide as described for Example 104, to produce the title compound: RT = 4.16 minutes; m / z (ES +) = 316.3 [M + H] +.

Example 106: cis-4- [5- (3-Butoxymethylcyclopentyl) [1,2,4] oxadiazol-3-yl] pyridine A solution of cis- [3- (3-pyridin-4-yl- [1, 2,] oxadiazol-5-yl] cyclopentyl] methanol (Preparation 5, 40 mg, 0.16 mmol) in anhydrous THF is subjected to treatment. (2 ml) with sodium hydride (23 mg of 60% dispersion in oil, 0.57 mmol) and tetrabutylammonium iodide (6 mg, 16 μmol), After stirring the mixture at room temperature for 10 minutes, 1-bromobutane is introduced (59 μl, 0.65 mmol) and stirring continued for 72 hours The solvent is removed in vacuo, the solvent is dissolved in CH2C12 (20 ml) and washed with water (2x5 ml) The organic phase is dried (MgSO4) and evaporated, flash chromatography (IH-EtOAc, 7: 3) yields the title compound: RT = 3.99 minutes; / z (ES +) = 302.3 [M + H] +. Example 107: cis-4- [5- (3-propoxymethylcyclopentyl) - [1,2,4] oxadiazol-3-yl] pyridine It is reacted cis. { 3- (3-pyridi-4-yl- [1, 2, 4] oxadiazol-5-yl) cyclopentyl] methanol (Preparation 5) with 1-bromopropane in the presence of tetrabutylammonium iodide, using a procedure similar to that described in Example 106, to yield the title compound: RT = 3.69 minutes; m / z (ES +) = 288.3 [M + H] +. Example 108: cis-4- [5- (3-butoxymethylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine Cis-methyl-3-hydroxymethylcyclohexane-1-carboxylate is reacted with N-hydroxy-isonicotinamidine, using the reaction conditions described in Preparation 5, to produce cis-4- [3- (3-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl) cyclohexyl] methanol: RT = 2.70 minutes; m / z (ES +) = 246.1 [M + H] +. This is subsequently rented with 1-bromobutane under conditions similar to those described in Example 106 to produce the title compound: RT = 4.11 minutes; m / z (ES +) = 316.3 [M + H] +. Example 109: 4- (3-pyridin-4-yl [1, 2, 4] oxadiazol-5-yl, toxy) -3,4,5,6-tetrahydro-2 H- [1,3 '] bipyridinyl Sodium tert-butoxide (86 mg, 900 μmol) is added to a solution of 3-chloropyridine (23 mg, 200 μmol), 4- [5- (piperidin-4-yloxymethyl) - [1,2,4] oxadiazole -36-yl] iridine (Preparation 17, 65 mg, 250 μmol), Pd2dba3 (4 mg, 4 μmol) and 2,8, 9-trisobutyl-2,5,8, 9-tetraaza-1-phosphabicyclo [3.3. 3] undecane (6 mg, 16 μmol) in toluene (3 ml) and the resulting mixture is heated at 80 ° C for 48 hours. After cooling and filtering through celite, the solvent is removed and the residue is purified by HPLC to yield the title compound: RT = 2.64 minutes; m / z (ES +) = 338.0 [M + H] +. The compounds in Table 10 are prepared in a manner similar to that described in Example 109. Table 10 Example 112: (4-Pentylcyclohexyl) - (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amine A solution of C- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) methylamine (Preparation 9, 50 mg, 248 mmol), 4-pentylcyclohexanone is stirred for 18 hours at room temperature. (64 ml, 340 mmol) and sodium tetracetoxyborohydride (9 mg, 450 mmol) in CH2C12 (4 ml). The reaction is quenched by the addition of 2M aqueous sodium hydroxide (2 ml) and the mixture is diluted with EtOAc (25 ml). The organic phase is separated, washed with brine (5 ml) and dried (MgSO4). The solvent is removed and the residue is purified by flash chromatography (IH-EtOAc, 1: 1) to yield the title compound: RT = 3.12 minutes; m / z (ES +) = 329.3 [M + H] +. The amines in Table 11 are synthesized in a manner similar to that described in Example 112.

Table 11 Example 117: methyl- (4-pentylcyclohexyl) - (3-pyridin-4-yl- [1,2,4] oxadoiazol-5-ylmethyl) amine A solution of (4-pentylcyclohexyl) - (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amine (Example 112, 30.9 mg, 94 μmol) in dichloroethane (1.3 ml) at room temperature with formaldehyde (8.4 ml of 37% aqueous solution, 103 μmol) and sodium triacetoxyborohydride (28 mg, 132 μmol). After being stirred for 48 hours, the solvent is removed and 2M aqueous sodium hydroxide (1 ml) is added. The mixture is extracted into EtOAc (25 ml) which is dried (MgSO 4) and evaporated. The residue is purified by flash chromatography (IH-EtOAc, 7: 3) to yield the title compound: RT = 3.37 minutes; m / z (ES +) = 343.2. { M + H] +. eleven The amines in Table 12 are synthesized in a manner similar to that described in Example.117.

Table 12 Example 127: 4- [Methyl- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amino] piperidine-1-carboxylic acid cyclopentyl ester The tert-butoxycarbonyl group of 4- [methyl- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amino] piperidine-1-carboxylic acid tert-butylester (Ejepplo 119) removed using the procedure described in Ejepplo 51 to produce methylpiperidin-4-yl (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amine: RT = 0.65 minutes; m / z (ES1") = 274.0 [M + H] +. Derivatization of methylpiperidin-4-yl- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amine with cyclopentylchlorofen Ormate, using the procedure described for Example 52, produces the title compound: RT = 3.02 minutes; m / z (ES +) = 3S6.0 [M + H] +. Example 128: 2, 2, 2-trichloroethyl ester of 4- {Methyl- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethyl) amino] methyl} - piperidine-1-carboxylic acid The tert-butoxycarbonyl group of the fuc-butyl ester of 4-acid. { methyl (3-pyridin-4-yl [1,2,4] oxadiazol-5-ylethyl) amino] methyl} piperidine-1-carboxylic acid (Example 124) is removed using the procedure described in Example 51 to produce methylpiperidin-4-ylmethyl- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-ylmethyl) amine : RT = 0.75 minutes; m / z (ES +) = 288.0 [M + H] +. Derivatization of methylpiperidin-4-ylmethyl (3-pyridin-4-yl [l, 2,4] oxadiazol-5-ylmethyl) amine with 2,2,2-trichloroethylchloroformate using process described for Example 52, produces the title compound: RT = 3.51 minutes; m / z (ES +) = 461.9 [M + H] +. Example 129: 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethoxymethyl) piperidine-l-carboxylic acid tert-butylester.

Sodium hydride (19.5 g, 0.49 mmol) is added to a solution of (3-? Iridin-4-yl- [1, 2, 4] oxadiazol-5-yl) methanol (Preparation 11, 86 mg, 0.49 mmol) in Anhydrous THF (3 ml). After being stirred at room temperature for 5 minutes, 15-crown-5 (97 μL, 0.49 mmol) is added followed by the 4-methanesulfonyloxymethylpiperidine-1-carboxylic acid tert-butylester (143 mg, 0.487 mmol). The reaction mixture is heated in a microwave oven (750 W) at 100 ° C for 15 minutes, cooled and the solvent evaporated. The residue is taken up in CH2C12 (100 ml), washed with water (10 ml), dried (MgSO4) and the solvent is evaporated. The residue is purified by flash chromatography (IH-EtOAc, 1: 1) to yield the title compound: RT = 3.67 minutes; m / z (ES +) = 375.2 [M + H] +. Example 130: 4- (3-pyridin-4-yl- [1, 2,4] oxadiazol-5-ylmethyl) 5-methyl, carboxylic acid tert-butylester ) 3-Pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl ethyl ester of methanesulfonic acid is added (Preparation 12, 56 mg, 0.22 mmol) and potassium carbonate (30 mg, 0.22 mmol) were added to a solution of tert-butylester of piperazine-1-carboxylic acid (37 mg, 0.2 mmol) in 1-acetonitrile (4 mL). The stirred mixture is heated under reflux for 18 hours, the solvent is removed and 1 residue is dissolved in EtOAc-water (90:10, 150 ml). The organic phase is separated, washed with brine, dried and the solvent removed to provide a removal that is ) purified by flash chromatography (IH-EtOAc, 4: 1) to yield the title compound: RT = 3.26 minutes; m / z (ES +) = 346.1 [M + H] +. Example 131: 4- (3-pyridin-4-yl- [1, 2,4] oxadiazol-5-ylmethylsulfanyl) piperidine-l-carboxylic acid tert-butylester T-BuOK (92 mg, 823 μmol) and 3-pyridin-4-yl- [1,2, 4] oxadiazol-5-ylmethyl ester of methanesulfonic acid are added.

(Preparation 12, 150 mg, 588 μmol) to a stirred solution of 4-mercaptopiperidine-l-carboxylic ter-butylester (191 g, 881 μmol) in anhydrous THF (10 ml). After 100 minutes, the reaction mixture is diluted with Et20 before washing with NaHCO3 and brine. The organic layer is dried (MgSO 4), filtered and concentrated, then the residue is purified by column chromatography (IH-EtOAc, 3: 2) to give the title compound: RT = 3.77 minutes; m / z (ES +) = 377.2 [M + H] +. Example 132: tert-butylester 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethanesulfonyl) piperidine-l-carboxylic acid MCPBA (111 mg 65% purity, 418 μmol) is added to a stirred solution of 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl-methylsulfonyl) tert-butylester. ) piperidine-1-carboxylic acid (Example 131, 105 mg, 279 μmol) in CH2C12 (7 ml). After 110 minutes, the reaction is quenched with saturated aqueous Na 2 C 3. The organic layer is washed with brine, dried (MgSO 4) and concentrated. Column chromatographic purification (4: 1 EtOAc-IH) gives the title compound: RT = 3.40 minutes; m / z (? S +) = 353.1. { M + H] +. Example 133: 4- (5-pyridin-4-yl) - [1, 3,4] oxadiazol-2-ylmethoxy) piperidine-l-carboxylic acid tert-butylester Triethylamine (149 μl, 1.06 mmol) is added to a stirred solution of 4- tert-butylester. { 2-oxo-2 -. [N '- (pyridine-4-carbonyl) hydrazino] ethoxy} piperi din-1-carboxylic (Preparation 16, 200 mg, 0.53 mmol) and 2-chloro-l, 3-dimethyl-2-ir dazolinium hexafluorophosphate (147 pg, 0.53 rrmol) in CH ^^ (10 ml). After 18 hours at room temperature, the solvent is reduced to a small volume and this mixture is purified by rapid chromatography (EtOAc). providing the title compound: RT = 3.42 minutes; m / z (? S +) = 361.1 [M + H] +.

Example 134: 3-pyridin-4-yl- [1,2,4] oxadiazole-5-carboxylic acid (4-pentylcyclohexyl) amoda A solution of 3-pyridin-4-yl- [1,2,4] oxadiazole-5-carboxylic acid ethyl ester (50.5 mg, 0.23 mmol) and 4-pentylcyclohexylamine (39 mg, 0.23 mmol) in toluene is treated. anhydrous (2 ml) with trimethylaluminium (345 μl of 2M solution in hexanes, 0.69 mmol). After stirring at room temperature for 18 hours, saturated aqueous NaHCO3 (2 ml) is added and the mixture is diluted with CH2C12 (25 ml). The organic phase is separated, washed with brine (5 ml) and dried ( MgSO 4). The solvent is evaporated and the residue is purified by flash chromatography to give the title compound: RT = 4.14 minutes; m / z (ES +) = 343.2 [M + H] +. Example 135: [4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-ylmethoxy) piperidin-1-yl] phosphonic acid diphenylester A solution of pyridine (31 μl, 0.38 mmol) and 4- [5-. { piperidin-4-yloxymethyl) - [1, 2, 4] oxadiazol-3-yl] -pyridine (Preparation 17, 49 mg, 0.19 mmol) with phosphorochlorhydric acid diphenylester (103 mg, 0.38 mmol). The reaction is stirred at room temperature for 18 hours and then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase is separated, evaporated and the residue is purified by HPLC to give the title compound: RT = 3.79 minutes; m / z (ES +) = 493.1 [M + H] +. Example 136: 4- (4-pyridin-4-yl-thiazol-2-ylmethoxy) piperidine-l-carboxylic acid tert-butylester A solution of 2-bromo-l-pyridin-4-yl-ethanone bromohydride (35 mg, 124 μmol) and 4-thiocarbamoylmethoxypiperidine-1-carboxylic acid tert-butylester is heated at 60 ° C for 1.5 hours (Preparation 18). , 34 mg, 124 μmol) in methanol (2 ml). The reaction mixture is diluted with EtOAc (60 ml), washed with saturated aqueous Na-HC03. (15 ml) and brine (15 ml) then dried (MgSO 4): The solvent is removed and the residue is purified by flash chromatography (EtOAc) to give the title compound: RT = 2. 95 minutes; m / z (ES +) = 37 .1. . { M + H] +.

Example 137: 4- (2-pyridin-4-yl-) -butyl ester thiazol-4-ylmethyl) piperisine-l-carboxylic acid 4- (3-Bromo-2-oxopropyl) piperidine-l-carboxylic acid tert-butylester is reacted with thioisonicotinamide in a similar manner to that described in Example 136 to provide the Title compound: RT = 3.39 minutes; / z (ES +) = 360.1 [M + H] +. Example 138: trans-4- [5- (4-pentyl-cyclohexyl) - [1,3,4] thiadiazol-2-yl] piperidine A solution of N '- (pyridine-4-carbonyl) hydrazide of 4-pentyl-cyclohexanecarboxylic acid (Preparation 19, 50 mg, 0.158 mmol) and Lawesson's reagent (127 mg, 0.32 mmol) was heated under reflux for 18 hours. toluene (2 ml). The solvent is evaporated and the residue is purified by flash chromatography (IH-? TOAc, 4: 1 then EtOAc) to give the title compound: RT = 5.02 minutes; m / z (ES +) = 316.0 ÍM + H] +.

Example 139: 4- (5-pyridin-4-yl- [1,3,4] thiadiazol-2-ylmethoxy) pyridine-l-carboxylic acid tert-butylester 4-butyl ester of the acid. { 2-oxo-2- [N '- (pyridin-4-carbonyl) hydrazino] ethoxy} piperidine-l-carboxylic acid (Preparation 16) is subjected to treatment with Lawesson's reagent in a manner similar to that described in Example 138, giving the title compound: RT = 3.47 minutes; m / z (ES +) = 377.1 [M + H] +. Example 140: 4- (5-pyridin-4-yl-4H- [1,2, 4] triazol-3-ylmethoxy) piperidine-l-carboxylic acid tert-butylester A solution of 4-carboxymethoxypiperidine-l-carboxylic acid tert-butylester (Preparation 1, 255 mg, 0.952 mmol) and triethylamine (138 μl, 0.9? 2 mmol) in toluene is added at 0 ° C and isobutylchloroformate is added (127 μl, 0.9"82 mmol) After stirring at room temperature for 45 minutes, 4-pyridinecarboximide acid hydrazide (100 mg, 0.82 mmol) and powdered 3 A molecular sieves (0.82 g) are added and the reaction is heated to reflux for 18 hours.With cooling, the mixture is filtered through celite, the filtrate is evaporated and the residue is dissolved in EtOAc (50 ml), it can be washed with saturated aqueous Na2CO3 (10 ml) and brine (10 ml), the solvent is removed and the residue is purified by flash chromatography (EtOAc then 5% MeOH in EtOAc) to give the title compound: RT = 2.81 minutes; m / z (ES +) = 360.1 [M + H] +. : 4- [2- (5-pyridin-4-yl-isoxazol-3-yl) ethyl] piperidine-l-carboxylic acid tert-butylester H0NH2.HC1 (29 mg, 418 μmol) and Na2C03 (29 mg, 277 μmol) are added to a stirred solution of 4- (3,5-dioxo-5-pyridin-4-ylpentyl) piperidine- tert-butylester. l-carboxylic acid (Preparation 22, 98 mg, 271 μmol) in EtOH. { 0.75 ml) and H20 (0.45 ml). The reaction is heated to 70 ° C (in a bath) for 4 hours and then the solvents are removed under reduced pressure. The residue is purified by RP-HPLC to give the title compound: RT = 3.57 minutes; m / z (ES +) = 358.3 [M + H] +.

Example 142: 4- (5-pyridin-4-yl-isoxazol-3-ylmethoxy) piperidine-l-carboxylic acid t-er-butylester Condensation of HONH2 with 4- (2,4-dioxo-4-pyridin-4-ylbutoxy) piperidine-l-carboxylic acid tert-butylester (Preparation 23), as described in Example 41, provides the title compound : RT = 3.34 minutes; m / z (ES +) = 360.3 [M + H] +. Example 143: 4- (5-pyridin-4-yl-isoxazol-3-ylmethyl) piperidine-l-carboxylic acid tert-butylester Condensation of HONH2 with 4- (2,4-dioxo-4-pyridin-4-ylbutyl) piperidine-l-carboxylic acid tert-butylester (Preparation 24), as described in Example 41, gives the title compound : RT = 3.47 minutes; m / z (ES +) = 344.3. { M + H] +.

Examples 144 and 145; 4- [2- (l-Methyl-5-pyridin-4-yl-lH-pyrazol-3-yl) ethyl] piperidine-l-carboxylic acid terbutyl ester and 4- [2- ( 2-methyl-5-pyridin-4-yl-2H-pyrazol-3-yl) ethyl] piperidin-1-carboxylic acid MeHNH2 (16 mg, 348 μmol) is added to a stirred solution of 4- (3,5-dioxo-5-pyridin-4-yl-pentyl) piperidine-l-carboxylic acid tert-butylester (Preparation 22, 96 mg 268 μmol) in EtOH (1 ml). The reaction is refluxed for 4 hours, then the solvents are removed under reduced pressure. The residue is purified by RP-HPLC to provide Example 144: RT = 3.22 minutes; m / z (ES +) = 371.3 [M + H] + and Example 145: RT = 2.99 minutes; m / z (ES +) = 371.3 [M + H] +. Example 146: tert-butylester of (E) -4- acid. { 5- [2- (2-cyanopyridin-4-yl) inyl] - [1,2, 4] oxadiazol-3-yl} piperidin-l-carboxylic A solution of JJTCPBA (9 .4 mg, 77% purity, 42 μmol) in CHC13 (0.5 ml) is added to a stirred solution of (E) -A- [5- (2-pyridin-4) -butyl ester of tert-butylester. -ylvinyl) - [1,2,4] oxadiazol-3-yl] piperidine-1-carboxylic acid (Example 46, 15 mg, 42 μmol) in CHC13 (1 ml) at 0 ° C. The mixture is stirred at 20 ° C for 16 hours, before being subjected to treatment with more mCPBA (25 mg, 77% purity, 11 μmol). After a period of 2 hours, the reaction is concentrated and then the residue is purified by column chromatography (EtOAc then THF) to give (E) -4- tert-butylester. { 5- [2- (1-oxypyridin-4-yl) vinyl] - [1, 2, 4] oxadiazol-3-yl} piperidin-l-carboxylic acid. m / z (ES +) = 373.3 [M + H] +. This N-oxide (13 mg, 35 μmol) is subjected to treatment with TMS-C? (14 μl, 130 μmol), Et Et 3 (10 μl, 70 μmol), CH 2 C 12 (250 μl) and Me 2 C C 0 Cl (3 μl). After 18 hours, the solvents are evaporated and the residue is purified by column chromatography (IH-EtOAc) to give the title compound: RT = 3.99 minutes; m / z (ES +) = 382.3 [M + H] +.

Example 147: 4- tert-butyl ester. { 5- [2- (2H-tetrazol-5-yl)] pyridin-4-yl] - [1,2,4] oxadiazol-3-ylmethoxy} -piperidine-l-carboxylic acid To a stirred solution of 4- [5- (2-cyanopyridin-4-yl) - [1,2,4] oxadiazol-3-ylmethoxy] piperidine-l-carboxylic acid tert-butylester (Example 42, 52 mg, 0.14 mmol) in DMF (3 ml) which is heated to 90 ° C, sodium azide (9 mg, 0.15 mmol) is added as suspension in DMF (2 ml). After 3 hours, sodium azide (18 mg, 0.29 mmol) is added in a single portion and the reaction mixture is stirred at 90 ° C for an additional 16 hours. The reaction mixture is cooled to room temperature and then all the ingredients are removed in vacuo. The residue is suspended in EtOAc and then filtered through a sinter, washed with EtOAc. The solid is partitioned between EtOAc (20 ml) and water (10 ml) containing AcOH (5 drops). The layers are separated and then the aqueous portion is extracted with EtOAc (3x20 ml). The combined organic phases are washed with brine (20 ml), dried (MgSO4), filtered and concentrated in vacuo to provide the title compound that does not need further purification: RT = 3.44 minutes; / z (ES +) = 429.1 [M + H] +.

Example 148: 4- [5- (2-cyanopyridin-4-yl) - [1,4,2] oxadiazol-3-ylmethoxy] piperidine-l-carboxylic acid isopropylester To a stirred solution of 4-. { 3- (piperidin-4-yloxymethyl) - [1,2,4] oxadiazol-5-yl] pyridine-2-carbonitrile (Preparation 25, 300 mg, 1.1 mmol) in DCM (10 ml) is added triethylamine (0.3 ml) , 2.1 mmol). The resulting solution is transferred to the stirred solution of isopropylchloroformate (IM solution in 2.1 ml in PhMe, 2.1 mmol) in DCM (30 ml) and stirring is continued for 30 minutes at room temperature. The reaction mixture is diluted with EtOc (30 ml) and then washed successively with water (50 ml), saturated aqueous sodium carbonate (50 ml) and brine (50 ml). The organic phases are dried (MgSO 4) and then absorbed on silica gel. Purification by chromatography (EtOAc-LH, 1: 1) gives the title compound: RT = 3.44 minutes; m / z (ES +) = 372.04 [M + H] + Example 149: 4- [5- (2-cyanopyridin-4-yl- [1,2,4] oxadiazol-3-ylmethoxy] piperidin-1 phenylester -carboxylic To a stirred solution of 4- [3- (piperidin-4-yloxymethyl) -. { 1,2,4-oxadiazol-5-yl] pyridine-2-carbonitrile (Preparation 25, 700 mg, 2.5 mmol) in DCM (30 ml) is added triethylamine (0.7 ml, 4.9 mmol). The resulting solution is transferred to a stirred solution of phenylchloroformate (0.62 ml, 4.9 mmol) in DCM (30 ml) and stirring continued for 30 minutes at room temperature. The reaction mixture is diluted with EtOac (250 ml) and then washed successively with water (100 ml), saturated aqueous sodium carbonate (100 ml) and brine. (100 ml). The organic phases are dried (MgSO 4) then absorbed on silica gel. Purification by means of chromatography (EtOAc-LH, 1: 1 to 3: 2) gives the title compound: RT = 3.63 minutes; m / z. { ES +) = 406.01 [M + H] + The biological activity of the compounds of the invention can be analyzed by the following test systems: Yeast Indication Tests Cell-based yeast Indication Tests have been previously described in the literature ( see for example, Miret JJ et al., 2002 J. Biol. Chem., 277: 6881-6887; AMPcbell RM et al., 1999, Bioorg, Med. Chem. Lett., 9: 2413-2418, King K. et al., 1990, Science, 250: 121-123, WO 99/14344, WO 00/12704 and US 6,100,042). In summary, the yeast cells have been genetically engineered so that yeast endogenous G-alpha (GPA1) has been replaced and replaced with structured G-protein chimeras using multiple techniques. In addition, endogenous yeast alpha cell GPCR, Ste3, has been deleted to allow homologous expression of a mammalian GPCR of choice. In yeast, elements of the pheromone signaling transduction pathway, which are conserved in eukaryotic cells (eg, mitogen-activated protein kinase pathway), regulate Fusl expression. by placing ß-galactosidase (LacZ) under the control of the promoter (Fuslp), a system has been developed in which the activation of the receptor leads to an enzymatic reading. The yeast cells are transformed by an adaptation of the lithium acetate method described by Agatep et al., (Agatep, R. et al., 1998, Transformation of Saccharomyces cerevisiae by the lithium scetate / single-standed carrier DNA / polyethylene glycol (LiAc / ss-DNA / PEG) protocol, Technical Tips Online, Trends Journals, Elsevier). In summary, the yeast cells are grown overnight in tryptone plates for yeast (YT). Of the single-stranded DNA carrier (10 μg), 2 μg of each of two Fuslp-LacZ reporter plasmids (one with a URA selection marker and one with TRP), 2 μg of GPR116 (human or mouse receptor) in a vector of expression for yeast (2 μg origin of replication) and a buffer of lithium acetate / polyethylene glycol / S? TE transferred in pipette to an Eppendorf tube. The yeast expression plasmid containing the receptor / control without receptor has a LEU marker. The yeast cells are inoculated into this mixture and the reaction proceeds at 30 ° C for 60 minutes. The yeast cells are then thermally deactivated at 42 ° C for 15 minutes. The cells are washed and seeded on selection plates. The selection plates are LEU synthetically defined yeast medium, URA and TRP (SD-LUT). After incubation at 30 ° C for 2-3 days, the colonies growing on the selection plates are analyzed in the LacZ test. In order to carry out the fluorimetric enzymatic assay for β-galactosidase, the yeast cells carrying the human or mouse GPR116 receptor are grown overnight in a liquid SD-LUT medium at an unsaturated concentration (i.e. they are still dividing and had not reached the stationary phase). They are diluted in fresh medium to an optimal concentration of analysis and 90μl of yeast cells are added to 96-well black polystyrene plates (Costar). The compounds, dissolved in DMSO and diluted in a 10% DMSO solution at a concentration of 10X, are added to the plates and the plates are placed at 3 ° C for 4 hours. After 4 hours, the substrate for β-galactosidase is added in each well. In these experiments, Fluorescein di (ß-D-galactopyranoside) (FDG), a substrate for the enzyme that releases fluorescein, is used, which allows a fluorimetric reading. Add 20 μl per well of 500 μM FDG / 2.5% Tritomn XlOO (the detergent is necessary to permeabilize the cells). After incubation of the cells with the substrate for 60 minutes, 20μl per well of 1M sodium carbonate is added to finish the reaction and enhance the fluorescent signal. The plates are read in a fluorimeter at 485/535 nm. The compounds of the invention provide an increase in the fluorescent signal of at least ~ 1.5 times the background signal (i.e., the signal obtained in the presence of 1% DMSO without the compound). CAMP Analysis An expressing cell line is established for human recombinant GPR116 and the cell line is used to investigate the effect of the compounds of the invention at intracellular levels of cyclic AMP (cAMP). The cell monolayers are washed with phosphate buffered saline and stimulated at 37 ° C for 30 minutes with various concentrations of the compound in a stimulation buffer plus 1% DMSO. The cells are then lysed and the cAMP content is determined using the Perkin Elmer AlphaScreen ™ cAMP equipment (Homogeneous Amplified Proximity Assay by Luminescence). The conditions of the shock absorber and analysis are as described in the manufacturer's protocol. The compounds of the invention showed an increase in the concentration of the intracellular cAMP level and generally have an ECso of <10μM.

In vivo Feeding Study The effect of the compounds of the invention on body weight and food and water intake is examined in male Sprague-Dawley rats fed freely by reverse phase illumination. The test compounds and references are dosed by appropriate routes of administration (eg, intraperitoneally or orally) and the quantifications were carried out for the next 24 hours. The rats are housed individually in polypropylene cages with metallic mesh floor at a temperature of 21 + 4 ° C and a humidity of 55 + 20%. Polypropylene trays with cage pads are placed under each cage to detect any food spillage. The animals are kept in a reverse light-dark phase cycle (the lights are off for 8 hours from 09.30-17.30 h) during this time the room is illuminated with red light. The animals have free access to tap water and conventional diet for powdered rats during a two-week acclimation period. The diet is contained in glass feeding bottles with aluminum lid. Each lid has a 3-4 cm hole to allow access to the food. The animals, feeding jars and bottles with water are weighed (about 0.1 g) at the beginning of the dark phase. The feeding bottles and bottles with water are subsequently quantified for 1, 2, 4, 6 and 24 hours after the animals are dosed with a compound of the invention and any significant difference between the treatment groups in the baseline are compared with control animals treated with the carrier. The selected compounds of the invention showed a statistically significant hyperphagic effect at one or more points at a dose of < 100 mg / kg. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (22)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound according to formula (I), and a pharmaceutically acceptable salt thereof: R1-AVB-R2 characterized in that V represents a 5-membered heteroaryl ring containing up to four heteroatoms selected from O, N and S optionally substituted by C? -4 alkyl; A is independently -CH = CH- or (CH) n; B is -CH = CH- or (CH2) n / where one of the CH2 groups is replaced by O, NR5, S (0) m, C (0) or C (0) NR12; n is 0, 1, 2 or 3; m is independently 0 ', 1 or 2; R 1 is 3- or 4-pyridyl, 4- or 5-pyrimidinyl or 2-pyrazinyl, any of these may be optionally substituted by one or more substitutes selected from halo, C 1 _ 4 'alkyl / fluoroalkylloyl C 4 _4, C2_4 alkenyl, C2_4alkynyl, C3_cycloalkyl, aryl, OR6, CN, N02, S (0) mR6, CON (R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6) 2, heterocycle of 4 to 7 members or 5 or 6 membered heteroaryl groups;
2. R2 is 4- to 7-membered cycloalkyl substituted with R3, C (0) OR3, C (0) R3 or S (0) 2R3 or 4- to 7-membered heterocycle containing 1 or 2 nitrogen atoms substituted or unsubstituted by C (0) OR4, C (0) R3, S (0) 2R3, C (0) NHR4, P (0) (0RX1) 2 or a 5- or 6-membered heteroaryl group containing nitrogen. R3 is C3-8 alkyl C3-8 alkenyl or C3-8 alkynyl, any of these may be optionally substituted with more than 5 fluorine or chlorine atoms and may contain a CH2 group which may be substituted by O, or C3_7 cycloalkyl, aryl, heterocyclyl , heteroaryl, C 1 -C 7 alkylcycloalkyl, C 4 alkyl alkylaryl, C 4 alkylheterocyclyl, C 1 alkyheteroaryl, any of these may be optionally substituted with one or more substitutes selected from halo, alkyl. C? _, Fluoroalkyl C? _4, OR6, CN, C? _4C02 alkyl, N (R6) 2 and N02; R4 is C2_8 alkyl / C2_s alkenyl or C2_8 alkynyl / any of these may be optionally substituted with more than 5 chlorine or fluorine atoms and may contain a CH2 group which may be substituted by 0, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C alkyl? C 4 -C 7 alkylcycloalkyl, C 1-4 alkylaryl / C 1-4 alkylheterocyclyl, C 1-4 alkylheteroaryl, any of these can optionally be substituted with one or more substitutes selected from halo, C 1-4 alkyl, C 1-4 fluoroalkyl, OR 6, CN, C-alkyl ? 4C02, N (R6) 2 and N02; R5 is hydrogen, C (0) R7, S () 2R8, C3_7 cycloalkyl or C4_4alkyl optionally substituted by OR6, C3_cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups can be substituted with one or more substitutes selected from halo , alkyl C? _2, fluoroalkyl C? _2, OR6, CN, N (R €) 2 and N02; R6 is either hydrogen, C4_4alkyl, C3_cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups can be substituted with one or more substitutes selected from halo, C4_4alkyl, C4_4 fluoroalkyl, OR9, CN, S02CH3, N (R10) 2 and N02; or a group N (R10) 2 which can form a 4- to 7-membered heterocyclic ring optionally containing an additional heteroatom selected from O and NR10; R7 is hydrogen, C ?4 alkyl, OR6, N (R6) 2, aryl or heteroaryl; R8 is C4_4alkyl, C4_4 fluoroalkyl, aryl or heteroaryl; R9 is hydrogen, C? _2 alkyl or C? _2 fluoroalkyl; R10 is hydrogen, or C? _4 alkyl; R 11 is phenyl and R 12 is hydrogen, C 1-4 alkyl, or C 3-7 cycloalkyl; provided that the compound is not: a) 4- (5-piperidin-4-yl- [1,2,4] oxadiazol-3-yl] pyridine b) butylester of 4- (3-pyridin-4-yl- [1,2,4] oxadiazol-5-yl) piperidine-1-carboxylic acid; c) 4- [5- (4-butylcyclohexyl) - [1, 2, 4] oxadiazol-3-yl] pyridine; d) 3- [5- (4-butylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine; or e) 3- [5- (4-propylcyclohexyl) - [1,2,4] oxadiazol-3-yl] pyridine. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that V represents a 5-membered heteroaryl ring containing more than three heteroatoms selected from O,
3. N and S of the formula: wherein W, X and Y represent the positions of the heteroatoms or otherwise represent CH. 3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that two of W, X and Y are N and the other is O.
4. 4. A compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, characterized in that W is N.
5. 5. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that groups n of A and B none represent 0.
6. 6. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that in A, n is 0, 1 or 2.
7. 7. A compound according to any of the preceding claims or a. pharmaceutically acceptable salt thereof, characterized in that in B, n is 2 or 3.
8. 8. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that R1 is 4-pyridyl optionally substituted by 1 or 2 halo, C4_4 alkyl, C4 fluoroalkyl, C2_ alkenyl, C2_4 alkynyl, C3-7 cycloalkyl, aryl, OR6, CN, N02, S (0) mR6, CON (R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6) 2, a 4- to 7-membered heterocyclyl group or a 5- or 6-membered heteroaryl group.
9. 9. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, characterized in that R1 is 4-pyridyl optionally substituted by halo, C? Alkyl? 4, C 4 -C 4 alkoxy or CN.
10. 10. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that R2 is a 4- to 7-membered cycloalkyl substituted by R3, or a 4- to 7-membered heterocyclyl containing a nitrogen atom which is replaced by C (0) OR4.
11. 11. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that R3 is C3_8 alkyl, which may contain a CH2 group which can be replaced by O, or C3_7 cycloalkyl.
12. 12. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that R4 is C2_s alkyl, C2_s alkenyl or C2_8 alkynyl / any of these may be optionally substituted with up to 5 fluorine or chlorine atoms and may contain a CH2 group which can be replaced by O, or C3-7 cycloalkyl, aryl, 5- or 6-membered heteroaryl containing one or two nitrogen atoms, C 1 -C 4 alkyl cycloalkyl C 3-7, or C 1-4 alkylaryl, any of these can be substituted with one or more substitutes selected from halo, C 1-4 alkyl, fluoroalkyl C? _4, OR6 and C? _ C02 alkyl.
13. 13. A compound according to claim 12 or a pharmaceutically acceptable salt thereof, characterized in that R4 is C3-6 alkyl optionally substituted with up to 5 fluorine or chlorine atoms and which may contain a CH2 group which may be substituted by 0, or cycloalkyl.
14. 14. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, characterized in that R5 is C? _ Alkyl.
15. 15. A compound characterized in that it is of the formula (I) as defined in any of Examples 1, 3 to 8, 10 to 13, 16 to 50 or 52 to 149, or a pharmaceutically acceptable salt thereof,.
16. 16. A compound according to claim 1, having the formula (Id) or a pharmaceutically acceptable salt thereof: (Ed) characterized in that two of W, X and Y are N and the other is O; A is independently -C-H = CH- or (CH2) n; B is -CH = CH- or (CH2) n "where one of the CH2 groups is replaced by O, NR5, S (0) m or C (O); n is 0, 1, 2 or 3; m is independently 0, 1 or 2; Rx and R? they are unspecifically selected from hydrogen, halo, C? _4 alkyl, C? _ flu fluoroalkyl, C2_ alkenyl, C2_4 alkynyl, C3_7 cycloalkyl, aryl, OR6, CN, N02, S (0) mR6, N (R6) 2, CON (R6) ) 2, NR10COR6, NR10SO2R6, S02N (R6) 2, a heterocyclyl group of 4 to 7 members and a heteroaryl group of 5 or 6 members; Z is C (0) OR4, C (0) R3, S (0) 2R3, C (0) NHR4 or a heteroaryl group containing nitrogen in 5 or 6 members; R3 is C3-8 alkyl / C3_s alkenyl or C3_s alkynyl, any of these may be optionally substituted with up to 5 fluorine or chlorine atoms and may contain a CH2 group which may be substituted by O, or C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl C 4 -C 7 alkyl, C 4 alkyl alkylaryl, C 1 -4 alkylheterocyclyl or C 4 alkylheteroaryl any of these may be optionally substituted with one or more substitutes selected from halo, C 4 alkyl, C 1-4 fluoroalkyl, OR 6, CN, alkyl C? _ 4C02, N (R6) 2 and N02; R4 is C2_s alkyl, C2_s alkenyl or C2_skynyl, any of these can be optionally substituted with up to 5 fluorine or chlorine atoms and can contain a CH2 group which can be substituted by O, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C alkyl? _4 C 3-7 cycloalkyl, C 1-4 alkylaryl, C 1-4 alkylheterocyclyl or C 1-4 alkylheteroaryl, any of these may be optionally substituted with one or more substitutes selected from halo, C 1-4 alkyl, C 1-4 fluoroalkyl, OR 6, CN, C-alkyl ? -4C02, N (R6) 2 and N02? R5 is hydrogen or C? _4 alkyl; R6 is either hydrogen or C ?4 alkyl, C3_7 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups are substituted with one or more substitutes selected from halo, C1-4 alkyl, C1-4 fluoroalkyl, OR9, CN, S02CH3, N (R10) 2 and N02; or a group N (RX0) 2 can form a 4- to 7-membered heterocyclic ring optionally containing an additional heteroatom selected from O and NR10; R9 is hydrogen, C? _2 alkyl or C? _2 fluoroalkyl; and R10 is hydrogen or C1-4 alkyl.
17. 17. A compound according to claim 1, having the formula (le) or a pharmaceutically salt of the s or: characterized in that one of X and Y is N and the other is O; Q is 0, NR5 or CH2; (you) R is hydrogen, halo, C? -4 alkyl, C1-4 fluoroalkyl, C2_4 alkenyl, C2_4 alkynyl, C3_7 cycloalkyl, aryl, OR6, CN, N02, S (0) mR6, CON (R6) 2, N (R6) 2, NR10COR6, NR10SO2R6, S02N (R6) 2, a heterocyclyl group of 4 to 7 members or a heteroaryl group of 5 or 6 members; R4 is C2_s alkyl, C2_8 alkenyl or C2_8 alkynyl, any of these may be optionally substituted with up to 5 chlorine or fluorine atoms and may contain a CH2 group which is substituted by 0, or C3_7 cycloalkyl, aryl, heterocyclyl, heteroaryl, alkyl C ? C4_7cycloalkyl, C? _4 alkylaryl, C? _ Alkylheterocyclyl or C? _ Alkylheteroaryl, any of these is substituted with one or more substitutes selected from halo, C? _4 alkyl, C1-4 fluoroalkyl, OR6, CN, C1- alkyl 4 C02, N (R6) 2 and N02; R5 is C? _4 alkyl; R6 is either hydrogen or C ?4 alkyl, C3_7 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the cyclic groups can be substituted with one or more substitutes selected from halo, C? _4 alkyl, fluoroalkyl C ?4, OR9, CN, S02CH3, N (R10) 2 and N02; or a group N (R10) 2 can form a heterocyclic ring optionally containing an additional heteroatom selected from 0 and NR10; R9 is hydrogen, C? _2 alkyl or C? _2 fluoroalkyl; R 10 is hydrogen or C 1-4 alkyl and p is 0 or 1.
18. 18. A pharmaceutical composition comprising a compound according to any of claims 1 to 17, characterized in that it includes the compounds of stipulations c) to e), or a salt pharmaceutically acceptable thereof; and a pharmaceutically acceptable carrier.
19. 19. A method for the treatment of a disease or condition wherein GPR116 has a role comprising the step of administering to a subject in need thereof an effective amount of a compound according to any of claims 1 to 17, characterized because it includes the compounds of stipulations a) to e), or a pharmaceutically salt thereof.
20. 20. A method for the regulation of satiety comprising the step of administering to a patient in need thereof, an effective amount of a compound according to any of claims 1 to 17, characterized in that it comprises the compounds of the stipulations to ) ae) or a pharmaceutically acceptable salt thereof.
21. 21. A method for treatment against obesity comprising the step of administering to a patient in need thereof, an effective amount of a compound according to any of claims 17, characterized in that it comprises the compounds of the stipulations a) ae) or a pharmaceutically acceptable salt thereof.
22. 22. A method for treatment against diabetes comprising the step of administering to a patient in need thereof, an effective amount of a compound according to any of claims 1 to 17, characterized in that it comprises the compounds of the stipulations to ) ae) or a pharmaceutically acceptable salt thereof.