MX2013001785A - Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy. - Google Patents

Abstract

The present invention relates to phenalkylamine derivatives of the formula (I) or (II); or a physiologically tolerated salt thereof. The invention relates to pharmaceutical compositions comprising such phenalkylamine derivatives, and the use of such phenalkylamine derivatives for therapeutic purposes. The phenalkylamine derivatives are GlyT1 inhibitors.

Description

DERIVATIVES OF PHENALQUILAMINE, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. AND ITS USE IN THERAPY Background of the Invention The present invention relates to phenylalkylamine derivatives, pharmaceutical compositions comprising such phenylalkylamine derivatives, and the use of such phenalkylamine derivatives for therapeutic purposes. The phenylalkylamine derivatives are inhibitors of GlyT1.

Glutamatergic trajectory dysfunction has been implicated in a number of disease states in the human central nervous system (CNS) including but not limited to schizophrenia, cognitive deficits, dementia, Parkinson's disease, Alzheimer's disease and bipolar disorder. A large number of studies in animal models support the hypothesis of NMDA hypofunction in schizophrenia.

The function of the NMDA receptor can be modulated by altering the availability of the glycine coagonist. This process has the critical advantage of maintaining the activity-dependent activation of the NMDA receptor because an increase in the synaptic concentration of glycine will not cause an activation of the NMDA receptors in the absence of glutamate. Because synaptic glutamate levels remain very narrow by high affinity transport mechanisms, an increased activation of the glycine site will only improve the NMDA component of the activated synapses. 4 Two specific glycine transporters, GlyT1 and GlyT2, have been identified and shown to belong to the family of Na / CI-dependent neurotransmitter transporters that include taurine, gamma-aminobutyric acid (GABA), proline, monoamines and orphan transporters. GlyT1 and GlyT2 have been isolated from different species and show that they have only 50% identity at the amino acid level. They also have a different pattern of expression in the central nervous system of mammals, with GlyT2 being expressed in the spinal cord, brainstem and cerebellum and GlyT1 present in these regions as well as in frontal areas of the brain such as cortex, hippocampus, septum and thalamus . At the cellular level, GlyT2 has been reported to be expressed in glycine-like nerve terminals in the rat spinal cord while GlyT1 appears to be expressed preferentially in glial cells. These expression studies have led to the suggestion that GlyT2 is predominantly responsible for glycine uptake at the glycinergic synapses while GlyT1 is involved in the monitoring of glycine concentration in the vicinity of the synapses expressing the NMDA receptor. It has been shown in recent functional studies in rat that blocking GlyT1 with the potent inhibitor (N- [3- (4'-fluorophenyl) -3- (4'-phenylphenoxy) propyl]) - sarcosine (NFPS) enhances NMDA receptor activity and long-term potentiation of the rat NMDA receptor.

The molecular cloning also revealed the existence of three variants of GlyT1, called GlyT-1a, GlyT-1b and GlyT-1c, each of which shows a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and use of exons, and differ in their N-terminal regions.

The physiological effects of GlyT1 in the frontal regions of the brain together with clinical reports showing the beneficial effects of the inhibitor of GlyT1 sarcosine in the improvement of the symptoms of patients with schizophrenia suggest that the selective inhibitors of GlyT1 represent a new class of antipsychotic drugs.

Glycine transporter inhibitors are already known in the art, for example: 25 (see also Hashimoto K., Recent Patents on CNS Drug Discovery, 2006, 1, 43-53; Harsing LG et al., Current Medicinal Chemistry, 2006, 13, 1017-1044; Javitt DC, Molecular Psychiatry (2004) 9, 984-997; Lindsley, CW et al., Current Topics in Medicinal Chemistry, 2006, 6, 771-785; Lindsley CW et al., Current Topics in Medicinal Chemistry, 2006, 6, 1883-1896).

It was an object of the present invention to provide additional glycine transporter inhibitors.

Brief Description of the Invention where R1 is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl, trialkylsilylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl, alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl, dialkylaminocarbonylaminoalkyl, alkylsulfonylaminoalkyl, (optionally substituted arylalkyl) aminoalkyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxy, halogenated carbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, (halogenated alkyl) aminocarbonyl, arylaminocarbonyl, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy, halogenated alkoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, alkyl carbonilaminoalcoxi, arilcarbonilaminoalcoxi, alcoxicarbonilaminoalcoxi, arylalkoxy, alquilsulfonilaminoalcoxi, (halogenated alkyl) sulfonilaminoalcoxi, arilsulfonilaminoalcoxi, (arylalkyl) sulfonilaminoalcoxi, heterociclilsulfonilaminoalcoxi, heterocyclylalkoxy, aryloxy, heterocyclyloxy, alkylthio, halogenated alkylthio, alkylamino, (halogenated alkyl amino, dialkylamino, di- (halogenated alkyl) amino, alkylcarbonylamino, (halogenated alkyl) carbonylamino, arylcarbonylamino, alkylsulfonylamino, (halogenated alkyl) sulfonylamino, arylsulfonylamino or optionally substituted heterocyclyl; W is -NR8- or a bond; A1 is optionally substituted alkylene or a bond; Q is -S (0) 2- or -C (O) -; And it is -NR9- or a link; A2 is optionally substituted alkylene, alkylene-CO-, -CO-alkylene, alkylene-O-alkylene, alkylene-NR10-alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted arylene, optionally substituted heteroarylene or a bond; X1 is -O-, -NR11-, -S-, or > CH2; X4 is -O-, -NR19-, -S-, or > CH2; n is 0, 1, or 2; m is 0, 1, or 2; R6 is hydrogen, halogen, alkyl or alkoxy, or two radicals R6 together with the carbon atom to which they are attached form a carbonyl group; R 2 is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl, -CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy, halogenated alkoxy, alkoxycarbonyl, alkenyloxy, arylalkoxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, amino, alkylamino optionally substituted alkenylamino, nitro or heterocyclyl, or two R 2 radicals together with the ring atoms to which they are attached form a 5- or 6-membered ring; R3 is hydrogen or alkyl; X2 is -O-, -NR7-, -S-, > CR1 aR12b or a link; X3 is -O-, -NR7-, -S-, > CR 3aR13b or a link; R5 is optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; Y1 is > CR14aR14b or a link; Y2 is > CR15aR15b; R 4a is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, CH 2 CN, arylalkyl, cycloalkyl, -CHO, alkylcarbonyl, (halogenated alkyl) carbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenyl, -C (= NH) NH2, -C (= NH) NHCN, alkylsulfonyl, arylsulfonyl, amino, -NO or heterocyclyl; D 4a D 3 together they are optionally substituted alkylene; or R4a, R a together they are optionally substituted alkylene; or R b is hydrogen, alkyl, halogenated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, CH 2 CN, -CHO, alkylcarbonyl, (halogenated alkyl) carbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenyl, -C (= NH) NH 2, -C ( = NH) NHCN, alkyl ilsu Ifonyl, arylsulfonyl, amino, -NO or heterocyclyl; or R4a R4b together are optionally substituted alkylene, wherein an alkylene -CH2- can be substituted with an oxygen atom or -NR16; R7 is hydrogen or alkyl; " R8 is hydrogen or alkyl; ? R9 is hydrogen, alkyl, cycloalkyl, aminoalkyl, optionally substituted arylalkyl or heterocyclyl; or R9, R1 together they are alkylene; or R9 is alkylene which is bonded to a carbon atom in A2 and A2 is alkylene; R10 is hydrogen, alkyl or alkylsulfonyl; R11 is hydrogen or alkyl, or R9, R11 together they are alkylene, R12a is hydrogen, optionally substituted alkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or hydroxy; R12 is hydrogen or alkyl, or together they are optionally substituted carbonyl or alkylene, wherein an alkylene -CH2- can be substituted by an oxygen atom or -NR17-; R13a is hydrogen, optionally substituted alkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or hydroxy; R 3b is hydrogen or alkyl, or 13a p 13b together they are optionally substituted carbonyl or alkylene, wherein an alkylene -CH2- can be replaced by an oxygen atom or -NR18-; R14a is hydrogen, optionally substituted alkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclylalkyl of 3 to 12 carbon atoms, optionally substituted aryl or hydroxy; R14d is hydrogen or alkyl, or together they are optionally substituted carbonyl or alkylene, wherein one or two -CH2- of alkylene can be replaced by an oxygen atom or -NR20-; R15a is hydrogen, optionally substituted alkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or hydroxy; R15d is hydrogen or alkyl of-1 to 6 carbon atoms, or. "P 15a p 15b together they are optionally substituted carbonyl or alkylene, wherein one or two -CH2- of alkylene can be replaced by an oxygen atom or -NR20-; R16 is hydrogen or alkyl of 1 to 6 carbon atoms; R 7 is hydrogen or alkyl of 1 to 6 carbon atoms; R 8 is hydrogen or alkyl of 1 to 6 carbon atoms; R 9 is hydrogen or alkyl of 1 to 6 carbon atoms, and R20 is hydrogen or alkyl of 1 to 6 carbon atoms, or a physiologically tolerated salt thereof.

Thus the term derivative fenalquilamina used herein to denote particularly phenethylamines (Y1 is a bond) and fenpropilaminas (Y1 is > CR1 aR1 b).

Compounds of formula (I) or (II), ie derivatives fenalquilamina of formula (I) or (II) and their physiologically tolerated salts, are glycine transporter inhibitors and thus useful as pharmaceuticals.

The present invention thus also relates to compounds of formula (I) or (II) for use in therapy.

"The present invention is also related to pharmaceutical compositions comprising a carrier and a compound of formula (I) or (II).

In particular, the compounds, ie, the phenalkylamine derivatives and their physiologically tolerated salts, are inhibitors of the GlyT1 glycine transporter.

The present invention thus also relates to compounds of formula (I) or (II) for use in inhibiting the glycine transporter.

The present invention also relates to the use of the compounds of formula (I) or (II) in the manufacture of a medicament for inhibiting the GlyT1 glycine transporter and corresponding methods for inhibiting the GlyTL glycine transporter.

Inhibitors of glycine transport and in particular GlyT1 glycine transporter inhibitors are known to be useful in treating a variety of neurological and psychiatric disorders.

The present invention is likewise related to the compounds of formula (I) or (II) for use in treating a neurological or psychiatric disorder.

The present invention is further related to the compounds of formula (I) or (II) for use in treating pain.

The present invention also relates to the use of the compounds of formula (I) or (II) in the manufacture of a medication to treat a neurological or psychiatric disorder and corresponding methods to treat the disorders. The present invention also relates to the use of the compounds of formula (I) or (II) in the manufacture of a medicament for treating pain and corresponding methods for treating pain.

Detailed description of the invention Provided that the tetralin and indane derivatives of formula (I) or (II) of a given constitution can exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective enantiomers, diastereomers and essentially pure tautomers of the compounds of formula (I) or (II) and / or their salts.

According to one embodiment, an enantiomer of the phenylalkylamine derivatives of the present invention has the following formula: where R1, W, A1, Q, Y, A2, X1, X4, n, m, R6, R2, R3, X2, X3, R5 > Y1 ,, - Y2 > R a- R b are as defined herein.

According to another embodiment, an enantiomer of the. Phenylalkylamine derivatives of the present invention has the following formula: where R1, W, A1, Q, Y, A2, X1, X4, n, m, R6, R2, R3, X2, X3, R5, Y1, Y2, R4a, Rb are as defined herein.

Physiologically tolerated salts of the phenylalkylamine derivatives of formula (I) or (II) are especially acid addition salts with physiologically tolerated acids. The Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, acid, phosphoric acid, sulfuric acid, alkylsulfonic acids of 1 to 4 carbon atoms, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S- (+) acid Sulfonic camferon, aromatic sulfonic acids, such as benzenesulfonic and toluenesulfonic acid, di and tricarboxylic acids and hydroxycarboxylic acids having between 2 and 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid , tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other usable acids are described, for example * in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 et seq., Birkháuser Verlag, Basel and Stuttgart, 1966. Physiologically tolerated salts of the phenalkylamine derivatives also include salts of a physiologically tolerated anion with phenalkylamine derivatives wherein one or more than one nitrogen atom is quaternized, for example, with an alkyl residue (for example methyl or ethyl).

The present invention further relates to compounds of formula (I) or (II) as defined herein, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, 2C by 13C, 14N by 5N, 60 by 1sO) and preferably where at least one hydrogen atom has been replaced by a deuterium atom.

Of course, such compounds contain more of the respective isotope than the natural occurrence and therefore are present in the compounds (I) anyway.

Stable isotopes (eg, deuterium, 13C, 15N, 180) are non-radioactive isotopes that contain one or more additional neutrons than the abundant isotope normally of the respective atom. The deuterated compounds have been used in pharmaceutical research to investigate in vivo the metabolic fate of the compounds by evaluating the mechanisms of action of metabolic trajectories of the non-deuterated parent compound (Blake et al J. Pharm. Sci. 64, 3, 367 -391 (1975)). Such metabolic studies are important in the design of safe, effective drugs, because it was proved that the active compound in vivo administered to the patient or that the metabolites produced from the parent compound are toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985, Kato et al, J. Labelled Comp.R. Radiopharmaceut., 36 (0): 927-932 (1995), Kushner et al, Can. J. Physiol. Pharmacol., 77, 79-88 (1999).

The incorporation of a substitution particularly of the heavy atom of deuterium with hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. This effect is generally insignificant if the label is placed in a metabolically inert position of the molecule.

Stable isotope labeling of a drug can alter its physicochemical properties such as pKa and lipid solubility. These changes can influence the fate of the drug in different stages throughout its passage through the body. It can change its absorption, distribution, metabolism or excretion. Absorption and distribution are processes that depend mainly on the molecular size and lipophilicity of the substance. These effects and alterations may affect the pharmacokinetic response of the drug molecule if isotopic substitution affects a region involved in a ligand-receptor interaction.

The metabolism of the drug, can give rise to large isotopic effects if the rupture of a chemical bond to a deuterium atom is the limiting stage of the speed in the process. Although some of the physical properties of a molecule labeled with a stable isotope are different from those of the non-labeled one, the chemical and biological properties are the same, with one important exception: due to the increased mass of the heavy isotope, any bond that it involves the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this link is the speed limiting step, the reaction will proceed more slowly for the heavy isotope molecule due to the "kinetic isotopic effect". A reaction involving the breakdown of a C-D bond can be made up to 700 percent slower than a similar reaction involving a link C - H. If the C-D bond is not involved in any of these steps leading to the metabolite, there may be no effect that alters the behavior of the drug. If a deuterium is placed in a site involved in the metabolism of a drug, one will observe the isotopic effect only if the breakdown of the C-D bond is the limiting stage of the velocity. There is evidence suggesting that at any time that an aliphatic C - H bond occurs, usually catalyzed by oxidation by a mixed oxidase function, the replacement of hydrogen by deuterium will produce an observable isotopic effect. It is also important to understand that the incorporation of deuterium into the metabolism site slows down to the point where another metabolite produced by attack on a carbon atom not replaced by deuterium becomes the main pathway, a process called "metabolic change".

Deuterium markers such as drugs and doses marked with deuterium, in some cases repeatedly, thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without incident reported (eg Pons). G and King E, Pediatrics 1999 104: 633, Coward WA et al, Lancet 1979 7: 13, Schwarcz HP, Control Clinical Triais 1984 5 (4 Supl): 573, Rodewald LE et al, J. Pediatr. 1989 114 : 885; Butte NF et al Br, J. Nutr 1991, 65: 3, AcLennan AH et al Am. J. Obstet Gynecol, 1981 139: 948). Therefore, it is clear that any Deuterium released, for example, during the metabolism of compounds of this invention does not pose any risk.

The percentage by weight of hydrogen in a mammal (approximately 9%) and the natural abundance of deuterium (approximately 0.015%) indicates that a human 70 kg normally contains about one gram of deuterium. In addition, the replacement of up to about 15% of normal hydrogen with deuterium has been performed and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal adverse effects observed (Czajka DM and Finkel AJ, Ann. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al, Am. J. Physiol. 1961 201: 357). Higher concentrations of deuterium, usually in excess of 20%, can be toxic in animals. However, acute replacement of up to as high as 15% to 23% of hydrogen in deuterium human fluids has been found to produce no toxicity (Blagojevic N et al in "Dosimetry &Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. Pp. 125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound over its natural abundance is called enrichment or deuterium enrichment. Examples of the amount of enrichment include about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to approximately 100 mol%.

The hydrogens present in a particular organic compound have different capacities for exchange with deuterium. Certain hydrogen atoms are easily interchangeable under physiological conditions and, if replaced by deuterium atoms, they are expected to be readily exchanged by protons after administration to a patient. Certain hydrogen atoms can be exchanged for deuterium atoms by the action of a deuterated acid such as D2S04 / D20. Alternatively, the deuterium atoms can be incorporated in different combinations during the synthesis of compounds of the invention. Certain hydrogen atoms are not easily interchangeable by deuterium atoms. However, deuterium atoms in the remaining positions can be incorporated by the use of raw material or deuterated intermediates during the construction of compounds of the invention.

The deuterated or enuterated deuterium compounds of the invention can be prepared using known methods described in the literature. Such methods can be carried out using the corresponding reagents and / or intermediates deuterated and optionally, others containing isotopes to synthesize the compounds described herein, or invoking standard synthetic protocols known in the art for introduce isotopic atoms to a chemical structure. Relevant procedures and intermediates are described, for example in Lizondo, J et al, Drugs Fut, 21 (11), 1116 (1996); Brickner, S J et al, J Med Chem, 39 (3), 673 (1996); Mallesham, B et al, Org Letf, 5 (7), 963 (2003); PCT Publications WO1997010223, WO2005099353, W01995007271, WO2006008754; U.S. Patent Nos. 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; .and US Patent Application Publication No. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; 20090082471, whose methods are incorporated by reference herein.

The organic portions mentioned in the above definitions of the variables are -as the term halogen- collective terms for individual lists of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.

"Unless indicated otherwise, the term" substituted "means that a radical is substituted with 1, 2 or 3, especially 1, substituents which are selected in particular from the group consisting of halogen, 1 to 4 carbon atoms, hydroxy-alkyl of 1 to 4 carbon atoms, heterocyclyl-alkyl of 3 to 12 carbon atoms, alkoxy-alkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, OH, SH, CN, CF3, 0-CF3 > COOH, 0-CH2-COOH, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, COO-alkyl of 1 to 6 carbon atoms, CONH2, CONH- alkyl of 1 to 6 carbon atoms, S02NH-alkyl of 1 to 6 carbon atoms, CON- (alkyl of 1 to 6 carbon atoms) 2, S02N- (alkyl of 1 to 6 carbon atoms) 2, NH2, NH-alkyl of 1 to 6 carbon atoms, N- (alkyl of 1 to 6 carbon atoms) 2, NH- (alkyl of 1 to 4 carbon atoms-aryl of 6 to 12 carbon atoms), NH-CO -alkyl of 1 to 6 carbon atoms, NH-S02-alkyl of 1 to 6 carbon atoms, S02-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, O-aryio of 6 to 12 carbon atoms, 0-CH-2-aryl of 6 to 12 carbon atoms, CONH-aryl of 6 to 12 carbon atoms, S02NH-aryl of 6 to 12 carbon atoms, CONH-heterocyclyl of 3 to 12 carbon atoms carbon, S02NH-heterocyclyl 3 to 12 carbon atoms, S02-aryl of 6 to 12 carbon atoms, NH-S02-aryl of 6 to 12 carbon atoms, NH-CO-aryl of 6 to 12 carbon atoms, NH-S02-heterocyclyl of 3 to 12 carbon atoms, NH-CO-heterocyclyl of 3 to 12 carbon atoms and heterocyclyl of 3 to 12 carbon atoms, wherein aryl and heterocyclyl in turn may not be substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and haloalkoxy of 1 to 4 carbon atoms.

The term halogen in each case denotes fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine.

The alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of an alkyl group are methyl, alkyl of 2 to 4 carbon atoms such as ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl or tere-butyl. Alkyl of 1 to 2 carbon atoms is methyl or ethyl, alkyl of 1 to 3 carbon atoms is additional allyl, n-propyl or isopropyl.

Alkyl of 1 to 6 carbon atoms is a straight or branched chain alkyl group having between 1 and 6 carbon atoms. Examples include methyl, alkyl of 2 to 4 carbon atoms as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1, 1 -dimetilpropilo, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2-dimetilbutilb, 2 , 3-dimethylbutyl, 3,3-dimethylbutyl, 1 -etilbutilo, 2-eti I buty I, 1,1,2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1 -ethyl-1 and 1 -ethyl- -metilpropilo 2-methylpropyl.

Alkyl of 1 to 4 halogenated carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, where at least one, for example 1, 2, 3, 4 or all hydrogen atoms are replaced with 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as one in halogenomethyl, dihalogenomethyl, trihalogenomethyl, (R) -1-halogenoethyl, (S) -1 -halogenoetilo, 2-halogenoethyl, 1,1-dihalogenoetilo, 2,2-dihalogenoetilo, 2, 2,2-trihalogenoetilo, (R) -1-halogenopropilo, (S) -1 -halogen-propyl, 2-halogenopropilo, 3-halogenopropilo, 1, 1 -dihalogenopropilo, 2,2-dihalogenopropilo, 3,3-dihalogenopropilo, 3,3,3-trihalogenopropilo, (R) -2-h alógeno- 1-Methylethyl, (S) -2-halogeno-1-methylethyl, (R) -2,2-d halo-1-methylethyl, (S) -2,2-dihalogeno-1-methylethyl, (R) -1,2-dihalogeno-1-methylethyl, (S) -1,2-dih alogono-1-methylethyl, (R) -2,2,2-trihalogeno-1-methylethyl, (S) -2,2, 2-trihalogeno-1-methylethyl, 2-halogeno-1 - (halogenomethyl) ethyl, 1- (dihalogenometil) -2,2-dihalogenoetilo, (R) -1 -halogenobutilo, (S) -1 -halogenobutilo, 2-halobutyl , 3-halogenobutyl, 4-halogeno-butyl , 1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl, 4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, etc. Some particular examples include alkyl groups of 1 to 4 fluorinated carbon atoms, such as trifluoromethyl.

Aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms of carbon, in particular 1 or two carbon atoms, where a Hydrogen atom is replaced with aryl of 6 to 12 carbon atoms, such as in benzyl.

Hydroxy-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, where one or two Hydrogen atoms are replaced with one or two hydroxy groups, such as hydroxymethyl, (R) -1-hydroxyethyl, (S) -1-h idroxyethyl, 2-hydroxyethyl, (R) - -hydroxypropyl, (S) -1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, (R) -2-hydroxy-1-methylethyl, (S) -2-hydroxy-1-methylethyl, 2-hydroxy-1- (hydroxy-methyl) ethyl, (R) -1-hydroxybutyl, (S) -1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.

C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl is a straight or branched chain alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms carbon, wherein one or two hydrogen atoms are replaced with one or two alkoxy groups having between 1 and 6, preferably 1 to 4, in particular 1 or 2 carbon atoms, such as in methoxymethyl, (R) -1 - methoxyethyl, (S) -1-methoxyethyl, 2-methoxyethyl, (R) -1-methoxypropyl, (S) -1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, (R) -2-methoxy-1-methylethyl, (S) -2-methoxy-1-methylethyl, 2-methoxy-1- (methoxymethyl) ethyl, (R) -1-methoxybutyl, (S) -1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4- methoxybutyl, ethoxymethyl, (R) -1-ethoxyethyl, (S) -1-ethoxyethyl, 2-ethoxyethyl, (R) -1-ethoxypropyl, (S) -1-ethoxypropyl, 2-ethoxypropyl, 3-ethoxypropyl, (R) ) -2-ethoxy-1-methylethyl, (S) -2-ethoxy-1-methylethyl, 2-ethoxy-1 - (ethoxymethyl) ethyl, (R) -1-ethoxybutyl, (S) -1-ethoxybutyl, 2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl.

Amino-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, where a hydrogen atom is replaced with an amino group, such as in anrwnomethyl, 2-aminoethyl.

Alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms of carbon, in particular 1 or 2 carbon atoms, wherein a hydrogen atom is replaced with an alkylamino group of 1 to 6 carbon atoms, in particular with an alkylamino group of 1 to 4 carbon atoms, such as in methylaminomethyl, ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl, n-butylaminomethyl, 2-butylaminomethyl, iso-butylamino-methyl or fer-butylaminomethyl.

Di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or 2 carbon atoms, where a hydrogen atom is replaced with a d, -alkylamino group of 1 to 6 carbon atoms, in particular with a di-alkylamino group of 1 to 4 carbon atoms, such as in dimethylaminomethyl.

Alkylcarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms of carbon, in particular 1 or 2 carbon atoms, wherein a hydrogen atom is replaced with an alkylcarbonylamino group of 1 to 6 carbon atoms, in particular with an alkylcarbonylamino group of 1 to 4 carbon atoms, such as in methylcarbonylaminomethyl, ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl, iso-pr'ophenylcarbonylaminomethyl, n-butylcarbonylamino-methyl, 2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl or re-butylcarbonylamomethyl.

Alkylaminocarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms of carbon, in particular 1 or 2 carbon atoms, wherein a hydrogen atom is replaced with an alkylaminocarbonylamino group of 1 to 6 carbon atoms, in in particular with an alkylaminocarbonylamino group having 1 to 4 carbon atoms, such as in methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl, n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl, n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl, iso-butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

Di-alkylaminocarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight-chain or branched alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or 2 carbon atoms, wherein a hydrogen atom is replaced with a di-alkylaminocarbonylamino group of 1 to 6 carbon atoms, in particular with a di-alkylaminocarbonylamino group of 1 to 4 carbon atoms carbon, such as in dimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl, dimethylaminocarbonylamino-n-propyl.

Alkylsulfonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms of carbon, in particular 1 or 2 carbon atoms, wherein a hydrogen atom is replaced with an alkylsulfonylamino group of 1 to 6 carbon atoms, in particular with an alkylsulfonylamino group having 1 to 4 carbon atoms, such as in methylsulfonylaminomethyl, ethylsulfonylaminomethyl, n-propylsulphonylaminomethyl, iso-propylsulphonylaminomethyl, n-butylsulphonylamino-methyl, 2-butylsulphonylaminomethyl, iso-butylsulphonylaminomethyl or fer-butylsulphonylaminomethyl.

(Aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or 2 carbon atoms, where a hydrogen atom is replaced with a group (aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 atoms) carbon) amino, in particular a group (aryl of 6 to 12 carbon atoms-alkyl of 1 to 2 carbon atoms) amino, such as in benzylaminomethyl.

Heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl group having between 1 and 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 atoms of carbon, in particular 1 or 2 carbon atoms, wherein a hydrogen atom is replaced with heterocyclyl of 3 to 12 carbon atoms, such as in N-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl.

Cycloalkyl of 3 to 12 carbon atoms is a cycloaliphatic radical having between 3 and 12 carbon atoms. In in particular, between 3 and 6 carbon atoms in the form of a cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclic structure can be unsubstituted or carry 1, 2, 3 or 4 alkyl radicals of 1 to 4 carbon atoms, preferably one or more methyl radicals.

Carbonyl is > C = 0 C 1 -C 6 -alkylcarbonyl is a radical of formula RC (O) -, where R is an alkyl radical having between 1 and 6, preferably between 1 and 4, in particular 1 or 2 carbon atoms as defined in the present. Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.

C 1 -C 6 haloalkylcarbonyl is alkylcarbonyl of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms. Examples include fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl. Additional examples are 1,1,1-trifluoroethyl-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

Arylcarbonyl of 6 to 12 carbon atoms is a radical of formula R-C (O) -, where R is an aryl radical having between 6 and 12 carbon atoms as defined herein. Examples include benzoyl.

Alkoxycarbonyl of 1 to 6 carbon atoms is a radical of formula R-O-C (O) -, where R is an alkyl radical having between 1 and 6, preferably between 1 and 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methoxycarbonyl and re-butyloxycarbonyl.

C 1 -C 6 alkoxycarbonyl halogenated is an alkoxycarbonyl of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are replaced with 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.

Aryloxycarbonyl of 6 to 12 carbon atoms is a radical of formula R-O-C (O) -, where R is an aryl radical having between 6 and 12 carbon atoms as defined herein. Examples include phenoxycarbonyl.

Ciano is -C = N.

Aminocarbonyl is NH2C (0) -.

Alkylaminocarbonyl of 1 to 6 carbon atoms is a radical of the formula R-NH-C (O) -, where R is an alkyl radical having between 1 and 6, preferably between 1 and 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methylaminocarbonyl.

(Alkyl of 1 to 4 halogenated carbon atoms) aminocarbonyl is an alkylaminocarbonyl of 1 to 4 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are replace with 1, 2, 3, 4 or a number corresponding to identical or different halogen atoms.

Arylaminocarbonyl of 6 to 12 carbon atoms is a radical of the formula R-NH-C (O) -, where R is an aryl radical having between 6 and 12 carbon atoms as defined herein. Examples include phenylaminocarbonyl.

Alkenyl of 2 to 6 carbon atoms is a monounsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, for example vinyl, allyl (2-propen-1-yl), 1-propene-1-yl ,. 2-propen-2-yl, metalyl (2-methylprop-2-en-1-yl) and the like. Alkenyl of 3 to 5 carbon atoms is, in particular, allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1 -yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl 02-ethylprop-2-en-1-yl.

Alkynyl of 2 to 6 carbon atoms is a monounsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, for example ethinyl, 2-propin-1-yl, 1-propin-1-yl, 2- propin-2-yl and the like. Alkynyl of 3 to 5 carbon atoms is, in particular, 2-propin-1-yl, 2-butin-1-yl, 3-butin-1-yl, 2-pentanyl-1-yl, 3-pentin-1 -yl, 4-pentin-1 -yl.

Alkylene of 1 to 4 carbon atoms is a straight or branched chain alkylene group having between 1 and 4 carbon atoms. Examples include methylene and ethylene. An additional example is propylene.

Alkenylene of 2 to 4 carbon atoms is a straight or branched chain alkenylene group having between 2 and 4 carbon atoms.

Alkynylene of 2 to 4 carbon atoms is a straight or branched chain alkynylene group having between 2 and 4 carbon atoms. Examples include propynylene.

Aryl of 6 to 12 carbon atoms is an aromatic cyclic radical of 6 to 12 members, in particular of 6 to 10 members. Examples include phenyl and naphthyl.

Arylene of 3 to 12 carbon atoms is a diradical aryl. Examples include phen-1,4-ylene and phen-1,3-olene.

Hydroxy is -OH.

Alkoxy of 1 to 6 carbon atoms is a radical of formula R-O-, where R is a straight or branched chain alkyl group having between 1 and 6, in particular between 1 and 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy), tert-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2.2 -dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 2,3-dirriethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1, 1, 2-trimethylpropoxy, 1, 2,2-trimethylpropoxy, 1 - ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.

Alkoxy of 1 to 6 halogen atoms is a straight or branched chain alkoxy group having between 1 and 6, preferably between 1 and 4, in particular 1 or 2 carbon atoms. carbon, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are replaced with 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethoxy, dihalogenomethoxy , trihalogenomethoxy, (R) -1-halogenoethoxy, (S) -1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy, 2,2-dihalogeno-ethoxy, 2,2,2-trihalogenoethoxy, (R) -1 haloalpropoxy, (S) -1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy, 1, 1-dihalogenopropoxy, 2,2-dihalogeno-propoxy, 3, 3-dihalogenopropoxy, 3,3,3-trihalogenopropoxy, ( R) -2-halogeno-1-methylethoxy, (S) -2-halogeno-1-methylethoxy, (R) -2, 2-d halogeno-1-methylethoxy, (S) -2,2-dih allogen- 1-methylethoxy, (R) -1, 2-d halogen-1-methylethoxy, (S) -1, 2-di halogene-1-methylethoxy, (R) -2,2,2-trihalogen-1 - methyletoxy, (S) -2,2,2-tri-halogeno-1-methylethoxy, 2-halogeno-1- (halogenomethyl) ethoxy, 1 - (di halogenomethyl) -2, 2-d halogenoethoxy, (R) - 1-halogenobutoxy, (S) -1-halogenobutoxy, 2 halohalobutoxy, 3-halogenobutoxy, 4-halobutoxy, 1,1-dihalobutoxy, 2,2-dihalobutoxy, 3,3-dihalobutoxy, 4,4-dihalobutoxy, 4,4,4-trihalobutoxybutoxy, etc. Some particular examples include the alkoxy groups of 1 to 4 fluorinated carbon atoms as defined, such as trifluoromethoxy.

Hydroxyalkoxy of 1 to 6 carbon atoms is an alkoxy radical having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced with hydroxy. Examples include 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy, 1- methyl-2-hydroxyethoxy and the like.

Alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4 carbon atoms, preferably 1 or 2 carbon atoms as defined herein, wherein one or two atoms of hydrogen are replaced with one or two alkoxy radicals having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy, 2-ethoxypropoxy, 1-methyl. -1-ethoxyethoxy and the like.

Amino-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an amino group. Examples include 2-aminoethoxy.

Alkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an alkylamino group having between 1 * and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include methylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy, iso-propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy, iso-butylaminomethoxy, re-tert-butylaminomethoxy, 2- (methylamino) ethoxy, 2- (ethylamino) ethoxy, 2- (n-propylamino) ethoxy, 2- (iso-propylamino) -ethoxy, 2- (n-butylamino) ethoxy, 2- (2-butylamino) ethoxy, 2- (iso-butyl) 'ylamino) ethoxy, 2- (re-tert-butylamino) ethoxy.

Di-alkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is it replaces with a dialkylamino group having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include dimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino) ethoxy, 2- (dimethylamino) ethoxy, 2- (diethylamino) ethoxy, 2- (N-methyl-N-ethylamino) ethoxy.

Alkylcarbonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an alkylcarbonylamino group where the alkyl group has between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein . Examples include methylcarbonylaminomethoxy, ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy, isopropylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy, 2-butylcarbonylaminomethoxy, iso-butylcarbonylamino-methoxy, tert-butylcarbonylaminomethoxy, 2- (methylcarbonylamino) ethoxy, 2- (ethylcarbonylamino) ethoxy, 2- ( n-pro pylcarbonylamino) ethoxy, 2- (iso-, propyl, carbonylamino) ethoxy, 2- (n-butylcarbonylamino) ethoxy, 2- (2- butylcarbonylamino) ethoxy, 2- (tert-butylcarbonylamino) ethoxy, 2- (tert-butylcarbonylamino) ethoxy.

Arylcarbonylamino of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an arylcarbonylamino group of 6 to 12 carbon atoms as defined herein. Examples include 2- (benzoylamino) ethoxy.

Alkoxycarbonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an alkoxycarbonylamino group wherein the alkoxy group has between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy, iso-propoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy, 2-butoxycarbonylaminomethoxy, isobutoxycarbonylaminomethoxy, tert-butoxycarbonylaminomethoxy, 2- (methoxycarbonylamino) ethoxy, 2- (ethoxycarbonylamino) ethoxy, 2- (n- propoxycarbonylamino) ethoxy, 2- (iso-propoxycarbonylamino) ethoxy, 2- (n-butoxycarbonylamino) ethoxy, 2- (2-butoxycarbonylamino) ethoxy, 2- (iso-butoxycarbonylamino) ethoxy, 2- (tert-bu toxic rbonilamino) ethoxy .

Alkenyloxy of 2 to 6 carbon atoms is a radical of formula R-0-, wherein R is a straight or branched chain alkenyl group having between 2 and 6, in particular between 2 and 4 carbon atoms. Examples include vinyloxy, allyloxy (2-propenyl-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methaloxy (2-methylprop-2-en-1-yloxy) and the like. Alkenyloxy of 3 to 5 carbon atoms is, in particular, allyloxy, 1-methylprop-2-en-1-yloxy-2-buten-1-yloxy, 3-buten-1-yloxy, methaloxy, 2- penten-1-yloxy, 3-penten-1-yloxy, 4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

Aryl of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an aryl group of 6 to 12 carbon atoms as defined herein. Examples include benzyloxy.

Alkylsulfonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an alkylsulfonylamino group having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include 2- (methylsulfonylamino) ethoxy, 2- (ethylsulphonylamino) ethoxy, 2 - [(2-methylpropyl) sulfonylamino] ethoxy.

(Alkyl of 1 to 6 carbon atoms halogenated) sulfonylamino-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an alkylsulfonylamino group having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein, wherein the alkyl group is halogenated. Examples include 2- (trifluoromethylsulfonylamino) ethoxy.

Aryl sulfonylamino of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with an arylsulfonylamino group of 6 to 12 carbon atoms as defined herein. Examples include 2- (phenylsulfonylamino) ethoxy, 2- (naphthylsulfonylamino) ethoxy.

(C 6 -C 12 -alkyl of 1 to 6 carbon atoms) C 1 -C 4 -alkylamino-alkoxy is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with a group (aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms) sulfonylamino, preferably with one group (aryl of 6 to 12 carbon atoms-alkyl) 1 to 2 carbon atoms) sulfonylamino. Examples include 2- (benzylsulfonylamino) ethoxy.

Heterocyclylsulfonylamino of 3 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined in present, wherein a hydrogen atom is replaced with a heterocyclisulfonylamino group * of 3 to 12 carbon atoms as defined herein. Examples include 2- (pyridin-3-ylsulfonylamino) ethoxy.

Heterocyclyl of 3 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms is an alkoxy radical having between 1 and 4, preferably 1 or 2 carbon atoms as defined herein, wherein a hydrogen atom is replaced with a heterocyclyl group of 3 to 12 carbon atoms as defined herein. Examples include 2- (N-pyrrolidinyl) ethoxy, 2- (N-morpholinyl) ethoxy and 2- (N -amidazolyl) ethoxy.

Alkylene dioxide of 1 to 2 carbon atoms is a radical of formula -O-R-O-, where R is a straight or branched chain alkylene group having 1 or 2 carbon atoms as defined herein. Examples include methylenedioxo.

Aryloxy of 6 to 12 carbon atoms is a radical of formula R-O-, where R is an aryl group having between 6 and 12, in particular 6 carbon atoms as defined herein. Examples include phenoxy.

Heterocyclyloxy of 3 to 12 carbon atoms is a radical of formula RO-, where R is a heterocyclyl group of 3 to 12 carbon atoms having between 3 and 12, in particular between 3 and 7 carbon atoms as defined in the present. Examples include pyridin-2-yloxy.

Alkylthio of 1 to 6 carbon atoms is a radical of formula R-S-, where R is an alkyl radical having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1 -methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-di methylbutoyl, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethyl Ibutylthio, 2,2-ethyl-b utilthio, 1,1,2-trimethylthiopropyl, 1, 2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and 1-ethyl -2-methylpropyl.

Alkylthio of 1 to 6 halogenated carbon atoms is a radical of formula R-S-, where R is a halogenated alkyl radical having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include halogenomethylthio, dihalogenomethylthio, trihalogenomethylthio, (R) -1-halogenoethylthio, (S) -1 -halogen-ethylthio, 2-halogen-ethylthio, 1,1-dihalogen-ethylthio, 2,2-di-halogen-ethylthio, 2,2,2- trihalogen-ethylthio, (R) -1-halogenopropylthio, (S) -1-halogenopropylthio, 2-halogeno-propylthio, 3-halopropylthio, 1,1-dihalopropylthio, 2,2-dihalogeno-propylthio, 3,3-diol halogenopropylthio, 3,3,3-trihalogenopropylthio, (R) -2-halogeno-1-methylethylthio, (S) -2-halogeno-1-methylethylthio, (R) -2,2-dihalogeno-1-methyl ethylthio, (S) ) -2,2-dihalogen-1-methylethylthio, (R) -1,2-dihalogen or-1-methylethylthio, (S) -1, 2-di halogen-1-methylethylthio, (R) -2, 2, 2-trihalogen-1 - methylethylthio, (S) -2,2,2-trihalogen-1-methyl ethylthio, 2-halogeno-1 - (halogenomethyl) ethylthio, 1- (dihalo-methyl) -2,2-dihalogenoethylthio ,. (R) -l-halogenobutylthio, (S) -l-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio, 4-halogenobutylthio, 1,1-dihalogeno-butylthio, 2,2-dihalogenobutylthio, 3,3-dihalogenobutylthio, 4, 4-dihalogeno-butylthio, 4,4,4-trihalogenobutylthio, etc. Some particular examples include alkylthio groups of 1 to 4 fluorinated carbon atoms as defined, such as trifluoromethylthio.

C 1 -C 6 -alkylsulfinyl is a radical of formula RS (O) -, where R is an alkyl radical having between 1 and 6, preferably between 1 and 4 carbophenyl atoms as defined in the present. include methylsulfinyl, ethylsulfinyl, pro pi Isu Ifi ni lo, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3- dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.; C 1-6 alkylsulfonyl is a radical of formula R-S (0) 2-, where R is an alkyl radical having between 1 and 6, preferably between 1 and 4 carbon atoms as define in the present. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, -methyl pentylsulfonyl, 2-methyl pentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3 dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1, 2, 2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl; (Alkyl of 1 to 6 halogenated carbon atoms) Sulfonyl is an alkylsulfonyl of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are they replace with 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.

Aryl sulfonyl of 6 to 12 carbon atoms is a radical of formula R-S (0) 2-, where R is an aryl radical having between 6 and 12 carbon atoms as defined herein. Examples include phenylsulfonyl.

(Aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms) sulfonyl is a radical of formula RS (0) 2-, where R is an aryl radical of 6 to 12 carbon atoms-alkyl 1 to 4 carbon atoms, in particular an aryl radical of 6 to 12 carbon atoms-alkyl of 1 to 2 carbon atoms as defined herein. Examples include benzylsulfonyl.

Heterocyclylsulfonyl of 3 to 12 carbon atoms is a radical of formula R-S (0) 2-, where R is heterocyclyl of 3 to 12 carbon atoms as defined herein.

Aminosulfonyl is NH 2 -S (0) 2-.

Alkylaminosulfonyl of 1 to 6 atoms, carbon is a radical of formula R-NH-S (0) 2- where R is an alkyl radical having between 1 and 6, preferably between 1 and 4 carbon atoms as defined in the present. Examples include methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, iso-propylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl, tert-butylaminosulfonyl.

Di-alkylaminosulfonyl of 1 to 6 carbon atoms is a radical of formula RR'NS (0) 2- where R and R 'are independently of one another an alkyl radical having between 1 and 6, preferably between 1 and 4 carbon atoms as defined herein. Examples include dimethylaminosulfonyl, diethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl.

Arylaminosulfonyl of 6 to 12 carbon atoms is a radical of formula R-NH-S (0) 2- where R is an aryl radical having between 6 and 12, preferably 6 carbon atoms as defined herein.

Amino is NH2.

Alkylamino of 1 to 6 carbon atoms is a radical of formula R-NH- where R is an alkyl radical having between 1 and 6, in particular between 1 and 4 carbon atoms as defined herein. Examples include methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino, re-tert-butylamino.

(Alkyl of 1 to 6 halogenated carbon atoms) amino is an alkylamino of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are they replace with 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.

Di-alkylamino of 1 to 6 carbon atoms is a radical of formula RR'N- where R and R 'are independently of each other an alkyl radical having between 1 and 6, in particular between 1 and 4 carbon atoms how is defined at the moment. Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino.

Di- (alkyl of 1 to 6 carbon atoms halogenated) amino is a di-alkylamino of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all Hydrogen atoms are replaced with 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.

Alkylcarbonylamino of 1 to 6 carbon atoms is a radical of formula R-C (0) -NH-, where R is an alkyl radical which it has between 1 and 6, in particular between 1 and 4 carbon atoms as defined herein. Examples include acetamido (methylcarbonylamino), propionamido, n-butyramido, 2-methylpropionamido (isopropylcarbonylamino), 2,2-dimethylpropionamido and the like.

(Alkyl of 1 to 6 halogenated carbon atoms) carbonylamino is an alkylcarbonylamino of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are they replace with?, 2, 3, 4 or a corresponding number of identical or different halogen atoms.

Arylcarbonylamino of 6 to 12 carbon atoms is a radical of formula R-C (0) -NH-, where R is an aryl radical having between 6 and 12 carbon atoms as defined herein. Examples include phenylcarbonylamino.

Alkenylamino of 2 to 6 carbon atoms is a radical of formula R-NH-, where R is a straight or branched chain alkenyl group having between 2 and 6, in particular 2 to 4, carbon atoms. Examples include vinylamino, allylamino (2-propen-1-ylamino), 1 -propene -lamino, 2-propene-2-ylamino, methallylamino (2-methylprop-2-en-1-ylamino) and the like. Alkenylamino of 3 to 5 carbon atoms is, in particular, allylamino, 1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino, methallylamino, 2-penten-1 -ylamino, 3-penten-1-ylamino, 4-penten--ylamino, 1-methylbut-2-en-1-ylamino or 2-ethylprop-2-en-ylamino.

Alkylsulfonylamino of 1 to 6 carbon atoms is a radical of formula RS (0) 2-NH-, where R is an alkyl radical having between 1 and 6, in particular between 1 and 4 carbon atoms as defined herein . Examples include methylsulfonylamino, ethylsulphonylamino, n-propylsulphonylamino, iso-propylsulphonylamino, n-butylsulphonylamino, 2-butylsulphonylamino, iso-butylsulphonylamino, ferc-b or ti Isulfoni lamino.

(C 1 -C 6 halogenated alkyl) Sulfonylamino is an alkylsulfonylamino of 1 to 6 carbon atoms as defined herein, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms are they replace with 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.

Aryl-sulfonylamino of 6 to 12 carbon atoms is a radical of formula R-S (0) 2-NH-, where R - is an aryl radical having between 6 and 12 carbon atoms as defined herein. Examples include phenylsulfonylamino.

Nitro is -N02.

Heterocyclyl of 3 to 12 carbon atoms is a heterocyclic radical of 3 to 12 members that includes a heterocyclic radical, which generally has 3, 4, 5, 6, or 7 atoms that form the ring (ring members), a radical unsaturated non-aromatic heterocyclic, which generally has 5, 6 or 7 atoms that form the ring, and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7 atoms that form the ring. The heterocyclic radicals can be linked by means of a carbon atom (Bind via C) or a nitrogen atom (Bind by means of N). Preferred heterocyclic radicals comprise 1 nitrogen atom as a ring member atom and optionally 1, 2 or 3 additional heteroatoms as ring members, which are independently selected from O, S and N. Similarly preferred heterocyclic radicals they comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1, 2 or 3 additional nitrogen atoms as ring members.

Examples of heterocyclyl of 3 to 12 carbon atoms include: Saturated rings of 3 or 4 members linked by means of C or N, such as; 2-oxiranyl, 2-oxethanyl, 3-oxethanyl, 2-aziridinyl, 3-thietanyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl; Saturated rings of 5 members linked by means of C, such as; tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydro-thien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazole- 4-yl, tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl, 1,2-oxa-thiolan- 5-yl, tetrahydroisothiazol-3-yl, t-trahydroisothiazole-4- ilo, tetrahydro-isothiazol-5-yl, 1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl, tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazole- 4-yl, tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, 1 , 3-oxathiolan-2-yl, 1,3-oxa-thiolan-4-yl, 1,3-oxathiolan-5-yl, 1,3-dithiolane-2-yl, 1,3-dithiolan 4-yl, 1, 3,2-dioxathiolan-4-yl; 6-member saturated rings linked by means of C, such as tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahyr 3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4- dioxan-2-yl, 1,3-d-itian-2-yl, 1,3-dithia? -4-yl, 1,3-d-itian-5-yl, 1,4-dithian-2-yl, 1,3-oxatiane-2-yl, 1,3-oxatiane-4-yl, 1,3-oxatiane-5-yl, 1,3-oxatiane-6-yl, 1,4-oxatiane-2-yl, 1,4-oxathian-3-yl, 1,2-dithia n-3-yl,, 2-di-thian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl , hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl, tetrahydro-1,3-oxazin-4-yl, tetrahydro-1, 3-oxaz in -5-yl, tetrahydro-1, 3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl, tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin - 5- i lo, tetra h id ro-, 3-thiazin-6-yl, tetrahydro-1, 4-thiazin-2-yl, tetrahydro-1,4-ti azi n -3-yl, tetrah idro-1, 4-oxazin-2-yl, tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl, tetrahydro-1,2-oxazin-4-yl, tetrah id ro- 1,2-oxazin-5-yl, tetrahydro-1,2-oxazin-6-yl; Saturated rings of 5 members linked by means of N, such as tetra h id ropyrrole-1-i lo (pyrro lidin-1-yl), tetrahydropyrazol-1-ylo, tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-ylo, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl; 6-member saturated rings linked by means of N, such as piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl (piperazin-1-yl), hexahydro-pyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl, tetrahydro-1, 3-ti azi n -3- i lo, tetrahydro-1, 4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl (morpholin-1-yl), tetrahydro-1,2-oxazin- 2-yl; Partially unsaturated rings of 5 members bonded by means of C, such as 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2- ilo, 4,5-dihydrofuran-3-yl, 2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5- dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3-dihydro-1 H -pyrrol-2-yl, 2,3-dihydro-1 H- pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1 H -pyrrol-3-yl, 4,5-dihydro-1 H -pyrrol-2-yl, 4,5-dihydro-1 H -pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H -pyrrol-2-yl, 3,4-di-hydro-5 H -pyrrol-3-yl, 4,5-dihydro-1 H -pyrazol-3-yl, 4,5- dihydro-1 H -pyrazol-4-yl, 4,5-dihydro-1 H -pyrazol-5-yl, 2,5-dihydro-1 H -pyrazol-3-yl, 2,5-dihydro-1 H- pyrazol-4-yl, 2,5-dihydro-1 H -pyrazol-5-yl, 4,5-dihydro-isoxazol-3-yl, 4,5-dihydroisoxazol-4-yl, 4,5-dihydroxisoxazol-5-yl, 2,5-dihydro-isoxazol-3-yl, 2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl, 2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl , 4,5-dihydroisothiazol-4-yl, 4,5-dihydro-isothiazol-5-yl, 2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5- dihydroisothiazol-5-yl, 2,3-dihydro-thiazol-3-yl, 2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2 -yl, 4,5-dihydro-1 H-imidazol-4-yl, 4,5-dihydro-1 H-imidazol-5-yl, 2,5-dihydro-1 H-imidazole-2 -yl, 2,5-dihydro-1 H-imidazol-4-yl, 2,5-dihydro-1 H-imidazol-5-yl, 2,3-dihydro-1 H-imidazole-2- ilo, 2, 3-dih id ro- 1 H-imidazol-4-yl, 4,5-dihydro-oxazol-2-yl, 4,5-dihydro-oxazol-4-yl, 4,5-dihydrooxazole -5-yl, 2,5-dihydrooxazol-2-yl, 2,5-dihydro-oxazol-4-yl, 2,5-dihydrooxazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3 -dihydro-oxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydro-thiazol-4-yl, 4,5-dihydrothiazol-5-yl , 2,5-dihydrothiazol-2-yl, 2,5-dihydro-thiazol-4-yl, 2,5-dihyd otiazol-5-yl, 2,3-dihydrothiazol-2-yl, 2,3-dihydro-thiazol-4-yl, 2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1, 3-dioxol-4-yl, 1,3-dithylo-2-yl, 1,3-dithi or (-4-11), 1,3-oxathiol-2-yl, 1,3-oxathiol- 4-yl, 1,3-oxa-thiol-5-yl; Partially unsaturated rings of 6 linked members by means of C, such as 2H-3,4-d-Hydropyran-6-yl, 2H-3,4-d-hydropyran-5-yl, 2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl , 2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl, 2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl , 2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl, 1, 2,3,4-tetrahydropyridin-6-yl, 1, 2,3,4-tetrahydrobromide ? -5-i, lo, 1, 2,3,4-tetrahydropyridin-4-yl, 1, 2,3,4-tetra-hydropyridin-3-yl, 1, 2,3,4-tetrabidropyridin-2-yl , 2H-5,6-dihydropyran-2-yl, 2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl, 2H-5,6-dihydropyran-5-yl, 2H-5 , 6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran -5-yl, 2H-5,6-dihydrothiopyran-6-yl, 1, 2,5,6-tetrahydropyridin-2-yl, 1, 2,5,6-tetra-hydropyridin-3-yl, 1, 2.5 , 6-tetrahydropyridin-4-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1, 2,5,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl , 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetr ahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, 2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl- , 4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3 -yl, 1, 4-dih id ro pir id in -4-i I, 2H-piran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5- ilo, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2 H -thi opi ra n -3- i lo, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran 6-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1, 2 -dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-di- hydropyridin-3-yl, 3,4-dihydro-pyridin-4-yl, 3,4-dihydropyridin-5-yl, 3,4-dihydro-pyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydro-pyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 2,3-dihydro-pyridin -2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydro-pyridin-5-yl, 2,3-d hydropyridin-6-yl, 2H- 5,6-dihydro-1,2-oxazin-3-Mo, 2H-5,6-d hydro-1, 2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5 -yl, 2H-5,6-d hydro-1, 2-oxazin-6-yl, 2H-5,6-dihydro-1, 2-thiazin-3-yl, 2H-5,6-d hydro-1 , 2-thiazin-4-yl, 2H-5,6-dihydro-1, 2-thiazin-5-yl, 2H-5,6-d hydro-1, 2-thiazin-6-yl, 4H-5, 6-dihydro-1,2-oxazin-3-yl, 4H-5,6-d hydro-1, 2-oxazin-4-yl, 4H-5,6-di-hydro-1,2-oxazin-5 -yl, 4H-5,6-d hydro-1, 2-oxazin-6-yl, 4H-5,6-dihydro-1, 2-thiazin-3-yl, 4H-5,6-d hydro-1 , 2-thiazin-4-yl, 4H-5,6-dihydro-1, 2-thiazin-5-yl, 4H-5,6-d hydro-1, 2-thiazin-6-yl, 2H-3, 6-dihydro-1,2-oxazin-3-yl, 2H-3,6-di-hydro-1,2-oxazin-4-yl, 2H-3,6- dihydro-1,2-oxazin-5-yl, 2H -3,6-d hydro-1, 2-oxazin-6-Mo, 2H-3,6-dihydro-1,2-thiazin-3-yl, 2H -3,6-d hydro-1, 2-thiazyl-4-yl, 2 H -3,6-dihydro-1,2-thiazin-5-yl, 2 H -3,6-d hydro-1, 2- thiazin-6-yl, 2H-3,4-dihydro-1, 2-oxazin-3-yl, 2 H -3,4-d hydro-1, 2-oxazin-4-yl, 2H-3,4-dihydro -1, 2-oxazin-5-yl, 2H -3,4-d hydro-1, 2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-Mo, 2H- 3,4-d hydro-1, 2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-Mo, 2H -3,4-d hydro-1, 2-thiazin- 6-yl, 2,3,4,5-tetra-idropyridazin-3-yl, 2,3,4,5-tetra-hydropyridazin-4-yl, 2,3,4,5-tetrahydropyridazin-5-yl, 2 , 3,4,5-tetrahydro-pyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl, 1, 2,5,6 -tetrahydropyridazin-3-yl, 1,2,5,6- tetrahydropyridazin-4-yl, 1, 2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl, 1, 2,3,6-tetra idro-pyridazin-3 -yl, 1,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1, 3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4 -yl, 4H-5,6-dihydro-1, 3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl, 4H-5,6-dihydro-1,3-thiazin -2-yl, 4H-5,6-dihydro-, 3-thiazin-4-yl, 4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1, 3- thiazin-6-yl, 3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl, 3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrathydropyrimidin-6-yl, 1, 2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl, 1, 2,3,4 -tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl , 2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl, 2 , 3-dihydro-1,4-thiazin-6-yl, 2H-1, 3-oxazin-2-yl, 2H-1, 3-oxazin-4-yl, 2H-1, 3-oxazin-5 -yl, 2H-1, 3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl , 2H-1, 3-thiazyl-6-i lo, 4H-1, 3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, 4H-, 3-oxazin-5-yl, 4H- 1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1, 3-thiazin-6-yl, 6H-1, 3-oxazin-2-yl, 6H-1, 3-oxazin-4-yl, 6H-1, 3-oxazin-5-yl, 6H-1, 3- oxazin-6-yl, 6H-1, 3-thiazin-2-yl, 6H-1, 3-oxazin-4-yl, 6H-1, 3-oxazin-5-yl, 6H-1, 3-thiazin- 6-yl, 2H-1, 4-oxazin-2-yl, 2H-1,4-oxazin-3-Mo, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl , 2H-1.4-t Izin-2-yl, 2H-1, 4-thiazin-3-yl, 2H-1, 4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin- 2-yl, 4H-1, 4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl, 1,4-dihydropyridazin-3-yl, 1, 4-dihydropyridazine- 4-yl, 1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl, 1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl, 1,2-dihydropyrazin -3-yl, 1,2-dihydropyrazin-5-yl, 1,2-dihydropyrazin-6-yl, 1,4-dihydr, opyrimidin-2-yl, 1,4-dihydropyrimidin-4-yl, 1.4 -dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl, 3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or 3,4 -dihydropyrimidin-6-yl; Partially unsaturated rings of 5 members bonded by means of N, such as 2,3-dihydro-1 H-pyrrol-1-yl, 2,5-dihydro-1 H-pyrrol-1-yl, 4,5-dihydro-1 H-pyrazol-1-yl, 2,5- dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazole- 2-yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1 H-imidazol-1-yl, 2,5-dihydro-1 H-imidazol-1-yl, 2,3-dihydro- 1 H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl; Partially unsaturated rings of 6 members bonded by means of N, such as 1,2,3,4-tetrahydropyridin-1-yl, 1, 2,5,6-tetrahydropyridin-1-yl, 1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl, 2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin- 2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1, 2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl, 1, 2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6- tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyro zin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl, 1, 2,3,4-tetrahydropyrimidin-3 -yl, 2,3-dihydro-1,4-thiazin-4-yl, 2H-1, 2-oxazin-2-yl, 2H-1,2-thiazin-2-Mo, 4H-1,4-oxaz N-4-yl, 4H-1,4-thiazin-4-yl, 1,4-d-hydropyridazin-1-yl,, 4-dihydropy-1-yl, 1, 2-dih id- p-raz in-1-yl, 1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl.

Heteroaromatic rings of 5 members linked by means of C, such as -. 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrro I-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl , isoxazol-4-yl, isoxazol-5-yl, siathiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,3-oxadiazol-4-yl, 1,2,3-oxadiazole- 5-yl, 1,2,4-oxadiazol-3-yl, 1,4-oxadiazol-5-yl, 1,4-oxadiazol-2-yl, 2,3-thiadiazole-4- ilo, 1, 2,3-thiadiazol-5-yl, 1, 2,4-thiadiazol-3-yl, 1, 2,4-thiadiazol-5-yl, 1, 3, 4-thiad iazo li l-2 -i lo, 1, 2,3-triazol-4-yl, 1, 2,4-triazol-3-yl, tetrazol-5-yl. 6-member heteroaromatic rings linked by means of C, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl (4-pyridyl), pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin -5-yl, pyrazin-2-yl, 1, 3, 5-tri azi n -2- i I, 1, 2, 4-triazi? -3-? 1, 2,4-triazin-5-yl, 1, 2,4-triazin-6-yl, 1, 2,4,5-tetrazin-3-yl. 5-member heteroaromatic rings linked by means of N, such as pyrrol-1-yl, pyrazole-1-N, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,4-triazol-1-yl, tetrazol-1-yl.

Heterocyclyl also includes bicyclic heterocycles, which comprise one of the 5 or 6 membered heterocyclic rings described and an additional desired, saturated, unsaturated or aromatic carbocycle, such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a heterocyclic ring of 5 or 6 additional desired members, this heterocyclic ring being saturated, unsaturated or aromatic. These include quinol.inyl, isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl, benzthienyl, benzo [b] thiazolyl, benzoxazolyl, benzthiazolyl and benzimidazolyl. Examples of 5- or 6-membered heteroaromatic compounds comprising a desired cycloalkylene ring include dihydroindolyl, dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, chromenyl and chromanyl.

Heteroarylene of 3 to 12 carbon atoms is a diradical heteroaryl. Examples include pyrid-2,5-ylene and pyrid-2,4-ylene.

With respect to the ability of the compounds to inhibit glycine transporter 1, the variables A, R, R1, W, A1, Q, Y, A2, Y 1 p2 3 v1 D4a D4b Y 2? 3 D5 n6 D8 D9 D 10 p 11 D 12 R13, R14, R15, R16, R7,? preferably they have the following meanings which, when taken alone or in combination, represent particular embodiments of the tetralin and indane derivatives of formula (I) or any other formula described at the moment.

In such formula (I) or (II), there may be one or more than one substituent R, R2 and / or R3. More particularly, there may be up to 3 substituents R2, and up to 6 substituents R3. Preferably there is a substituent R and 1, 2 or 3 substituents R2. The formulas (I) and (II) can therefore be illustrated as follows: where a is 1, 2, or 3 and b is 1, 2, 3, 4, 5, 6 or 7 (in the formula (I) or 1, 2, 3, 4, 5 or 6 (in the formula (I) If there is more than one radical R2, these can be the same or different radicals.If there is more than one radical R6, these can be the same or different radicals.

R1 is hydrogen, alkyl of 1 to 6 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl or sec-butyl, with n-butyl or n-pentyl being additional examples), cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example cyclopentylmethyl or cyclohexylmethyl, cyclopropylmethyl being an additional example), alkyl from 1 to 6 carbon atoms halogenated (for example 3-fluoroprop-1 -yl, 3-cloroprop- 1-i I oo 3,3,3-trifluoroprop-1-yl), hydroxy-alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms (e.g. ethoxyethyl), amino-alkyl of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms carbon, alkylcarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, I alkyloxycarbonylamino 1 to 6 carbon atoms-alkyl having 1 to 4 carbon atoms, alkylaminocarbonylamino 1 to 6 carbon atoms alkyl of 1 to 4 carbon atoms, di-alkylaminocarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkylsulfoni lamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, (aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 4 carbon atoms optionally substituted, aryl of 6 to 12 carbon atoms-optionally substituted alkyl of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms-optionally substituted alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms ( for example cyclopropyl or cyclobutyl lo), alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms halogenated carbon, aryloxycarbonyl of 6 to 12 carbon atoms, aminocarbonyl, alkylaminocarbonyl of one to six carbon atoms, (alkyl of 1 to 4 carbon atoms) aminocarbonyl halogenated arylaminocarbonyl 6 to 12 carbon atoms, alkenyl of 2 to 6 carbon atoms (for example prop-1, 2-in-1 -yl) alkynyl of 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms carbon substituted, optionally (eg phenyl and 2-methylphenyl an additional example), hydroxy, alkoxy of 1 to 6 carbon atoms (eg FERC-butyloxy), C 1 -C 6 halogenated alkyl, hydroxyalkoxy 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, amino-alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 atoms of carbon, di-alkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, alky ylcarbonylamino of 1 to -6 carbon atoms alkoxy of 1 to 4 carbon atoms, arylcarbonylamino 6 to 12 carbon atoms alkoxy of 1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms alkoxy of 1 to 4 carbon atoms, aryl of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, (alkyl of 1 to 6 carbon atoms) halogenated carbon) sulfonylamino-alkoxy of 1 to 4 carbon atoms, arylsulfonylamino of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, (aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms) sulfonylamino-alkoxy of 1 to 4 carbon atoms, heterocyclylsulfonylamino of 3 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms carbon, heterocyclyl of 3 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, aryloxy of 6 to 12 carbon atoms, heterocyclyloxy of 3 to 12 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms halogenated, alkylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) amino, di-alkylamino of 1 to 6 carbon atoms (for example dimethylamino), di- 1 to 6 halogenated carbon atoms) amino, alkylcarbonylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) carbonylamino, arylcarbonylamino of 6 to 12 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) sulfonylamino, aryisulfonylamino from 6 to 12 carbon atoms or optionally substituted heterocyclyl of 3 to 12 carbon atoms (for example 3-pyridyl, 2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 5-chloro-2 -thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-ethyl-1,2-diazol-4-yl , 1-difluoromethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl, 1-methyl-1,3-diazol-4-yl, 2-methyl-1, 3- thiazol-5-yl, 2. 4- dimethyl-1,3-thiazol-5-yl, 3-pyrrolidinyl, 1-rhethyl-pyrrol-3-yl, 2-pyridyl, 1-methyl-1,2-diazol-3-yl, 1-methyl- 3-trifluoromethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 5-methylisoxazol-3-yl or 1-methyl- 1, 2,4-triazol-3-yl).

Preferably, R 1 is alkyl of 1 to 6 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl or sec-butyl, with n-butyl or n-pentyl examples being additional), cycloalkyl of from 3 to 12 carbon atoms. carbon-alkyl of 1 to 4 carbon atoms (for example cyclopentylmethyl or cyclohexylmethyl, wherein cyclopropylmethyl is an additional example), alkyl of 1 to 6 carbon atoms halogenated (for example 3-fluoroprop-1-yl, 3-chloroprop-1 - i I oo 3,3,3-trifluoroprop-1-yl), alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms (e.g., ethoxyethyl, amino-alkyl of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkyloxycarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkylaminocarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, aryl of 6 to 12 carbon atoms-alkyl 1 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms (for example cyclopropyl or cyclobutyl), alkenyl of 2 to 6 carbon atoms (for example prop-1, 2-en-1-yl), aryl from 6 to 12 carbon atoms optionally substituted (for example phenyl), hydroxy, alkylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) amino, di-alkylamino of 1 to 6 carbon atoms or optionally substituted heterocyclyl of 3 to 12 carbon atoms (for example 3-pyridyl I, 2-thienyl, 4-methyl- 2- thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol- 4-yl, 1-ethyl-1,2-diazol-4-yl, 1-difluoromethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl, 1-methyl- 1,3-diazol-4-yl, 2-methyl-1,3-thiazol-5-yl, 2,4-dimethyl-1,3-thiazol-5-yl or 3- pyrrolidinyl).

In particular, R 1 is alkyl of 1 to 6 carbon atoms (for example n-propyl), cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example cyclopentylmethyl), cycloalkyl of 3 to 12 atoms carbon (for example cyclobutyl), or optionally substituted heterocyclyl of 3 to 12 carbon atoms (for example 3-pyridyl I or, -methyl-1,2-diazol-4-yl, 1-methyl-1,3-thiazole 4-yl, 3-oxoethenyl, 1-methyl-pyrrol-3-yl).

In relation to R1, aryl of 6 to 12 carbon atoms substituted in particular includes aryl of 6 to 12 carbon atoms, such as phenyl or naphthyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms, carbon, haloalkoxy of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms, morpholino and piperidinyl. The same applies to aryl of 6 to 12 carbon atoms substituted on aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms substituted.

In relation to R, heterocyclyl of 3 to 12 atoms of substituted carbon in particular includes heterocyclyl of 3 to 12 carbon atoms, such as pyridyl, thienyl, diazolyl, quinolinyl, piperidinyl, piperazinyl or morpholinyl, with pyrrolyl, isoxazolyl and triazolyl being additional examples of such heterocyclyl of 3 to 12 carbon atoms, substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 atoms of carbon, haloalkoxy of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms, arylamino of 6 to 12 carbon atoms and heterocyclyl of 3 to 12 carbon atoms (for example, morpholino or piperidinyl). The same applies to heteroaryl of 3 to 12 carbon atoms substituted on heteroaryl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms substituted.

According to one modality, W is -NR8- and Y is a link. According to an alternative modality, W is a bond and Y is -NR9-. According to a further alternative embodiment, W is a bond and Y is a bond, especially if R1 is a nitrogen-bonded radical, for example nitrogen-linked heterocyclyl such as piperazinyl or morpholinyl.

According to one modality, Q is -S (0) 2-. According to an alternative embodiment, Q is -C (O) -.

According to a particular additional modality, -W-A1-Q- Y- is -W-A1-S (0) 2-NR9-, -NR8-S (0) 2-, -A1-S (0) 2- or -S (0) 2-. According to a further particular embodiment, -W-A -Q-Y- is -W-A -CO-NR9- or -NR8-CO-.

A1 is optionally substituted C 1 -C 4 -alkylene or a bond. In relation to A1, substituted alkylene of 1 to 4 carbon atoms in particular includes alkylene of 1 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms and cyano. Preferably, A1 is a bond. If A1 is alkylene of 1 to 4 carbon atoms, W is preferably -NR8-.

A2 is alkylene of 1 to 4 carbon atoms optionally substituted (for example 1,2-ethylene or 1,3-propylene), alkylene of 1 to 4 carbon atoms-CO-, -CO-alkylene of 1 to 4 carbon atoms carbon, alkylene of 1 to 4 carbon atoms-O-alkylene of 1 to 4 carbon atoms, alkylene of 1 to 4 carbon atoms-NR10-alkylene of 1 to 4 carbon atoms, arylene of 6 to 12 carbon atoms optionally substituted, optionally substituted 6 to 12 carbon atoms, heteroarylene or a bond. Additionally, A2 can be optionally substituted 2 to 4 carbon atoms alkenylene or optionally substituted 2 to 4 carbon alkynylene. Preferably, A2 is optionally substituted alkylene of 1 to 4 carbon atoms (for example 1,2-ethylene or 1,3-propylene). More preferably, A2 is alkylene of 1 to 4 carbon atoms (eg 1,2- ethylene). Alternatively, it is preferable when A2 is arylene of 6 to 12 carbon atoms optionally substituted, in particular arylene of 6 to 12 carbon atoms selected from the group consisting of phen-1,4-ylene and phen-1, 3- Ilene, or optionally substituted heteroarylene of 6 to 12 carbon atoms, in particular heteroarylene of 6 to 12 carbon atoms selected from the group consisting of pyrid-2,5-ylene and pyrid-2,4-ylene. If A2 is a bond, X 1 is in particular optionally substituted 2 to 4 carbon atoms or optionally substituted 2 to 4 carbon atoms alkynylene.

In relation to A2, substituted alkylene of 1 to 4 carbon atoms in particular includes alkylene of 1 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and cyano.

In relation to A2, substituted alkenylene of 2 to 4 carbon atoms or substituted alkynylene of 2 to 4 carbon atoms in particular includes alkenylene of 2 to 4 carbon atoms or alkynylene of 2 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and cyano.

In relation to A2, arylene of 6 to 12 carbon atoms substituted in particular includes arylene of 6 to 12 carbon atoms substituted with 1, 2 or 3 substituents selected from a group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms , alkylsulfonyl of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms, arylamino of 6 to 12 carbon atoms and heterocyclyl of 3 to 12 carbon atoms (for example , morpholino or piperidinyl).

In relation to A2, heteroarylene of 6 to 12 carbon atoms substituted in particular includes heteroarylene of 6 to 12 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms, arylamino of 6 to 12 carbon atoms and heterocyclyl of 3 to 12 carbon atoms (for example, morpholino or piperidinyl).

X1 is -O-, -NR11-, -S- or > CH2 Preferably, X1 is -O-, -NR11, or -S-. More preferably, X1 is -O-: Alternatively, X1 is > CH2 According to a particular embodiment, A2 is a link and X1 is > CH2 According to a particular modality, R1-W-A -Q-Y-A2- X1- is R1-S (0) 2-NH-A2-X1-, R1-NH-S (0) 2-A2-X-, R1-C (0) -NH-A2-X1- or R1-NH -C (0) -A2-X1-.

According to a particular embodiment, the structural element -Y-A2- comprises at least 1 or 2 atoms in the main chain. According to additional particular embodiments the structural element -Y-A2- possesses up to 2, 3 or 4 atoms in the main chain, such as 1 to 4, 1 to 3, or 1 to 2 atoms in the main chain, or especially 1 or 2 atoms in the main chain.

According to a further particular embodiment, -Y-A2-is -NR9-alkylene of 1 to 4 carbon atoms (for example -NH-CH2 -, * - NH- (CH2) 2- or -NH- (CH2 ) 3-), with -Y-A2- preferably having 1 to 4, or 1 to 3, or especially 1 or 2 atoms in the main chain. In this particular embodiment, R 9 is as defined herein and R 9 is preferably hydrogen, alkyl of 1 to 6 carbon atoms (for example methyl or ethyl) or cycloalkium of 3 to 12 carbon atoms (for example cyclopropyl).

According to a further particular embodiment, -Y-A2-is -alkylene of 1 to 4 carbon atoms (for example -CH2-), with -Y-A2 preferably having 1 to 4, or 1 to 3, or especially 1 or 2 atoms in the main chain.

According to a further particular embodiment, the structural motif -Y-A2- as described herein is linked to Q which is -S (0) 2- or -C (O) -. Particular examples for this embodiment include phenalkylamine derivatives of the invention wherein R is R1-S (0) 2-Y-A2- or R1-C (0) -Y-A2-.

X4 is -O-, -NR9-, -S-, or > CH2 According to a particular embodiment, X4 is -O- or -NR9-.

In the phenylalkylamine derivatives of formula (I), n is zero, 1 or 2. According to a particular embodiment, n is 1.

In the phenylalkylamine derivatives of formula (II), m is zero, 1 or 2. According to a particular embodiment, m is 1 or 2.

According to a particular embodiment, the phenalkylamine derivatives of formula (I) have one of the following formulas: In the formulas, R1, W, A1, Q, Y, A2, R6, R2, R3, X2, X3, R5, Y1, Y2, R a, R4 are as defined herein.

According to a further particular embodiment, the phenylalkylamine derivatives of formula (II) have one of the following formulas: In the formulas, R, W, A1, O, Y, A2, R6, R2, R3, X2, X3, R5, Y, Y2, R4a, R4, are as defined herein.

In the phenylalkylamine derivatives of formula (I) or (II), the alkylamine moiety can, in principle, be linked to the benzene moiety in any available position: In the formulas, R1, W, A1, Q, Y, A2, X1, X4, n, m, R6, R X2, X3, R5, Y1, Y2, R a, R4 are as defined herein Particularly preferred are the phenalkylamine derivatives having one of the following formulas: do R5, Y, Y2, R4a, R4b are as defined herein.

In the saturated ring, the phenalkylamine derivatives of the invention can be substituted with one or more than a radical R6. If there is more than one radical R6, these may be the same or different radicals. The phenylalkylamine derivatives of the invention can therefore be represented by the following formula: where R a, R, R, R independently has one of the meanings given for R6, and R1, W, A1, Q, Y, A2, X1, X4, n, m, R2, R3, X2, X3, R5, Y1, Y2, R a, R b are as defined herein.

R6 is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or two radicals R6 together with the carbon atom to which they are attached form a carbonyl group. * Preferably, R6 is hydrogen or alkyl of 1 to 6 atoms of carbon. In particular, R is hydrogen.

In addition to half of the aicylamine, the phenalkylamine derivatives of the invention may have one or more of an additional substituent linked to the benzene ring. In these positions, the skeleton of the phenylalkylamine derivatives can thus be substituted with one or more of a radical R2. If there is more than one R2 radical, these can be the same or different radicals. The phenylalkylamine derivatives of the invention can therefore be represented by one of the following formulas: where R2a, R2, R2c, R2d independently have one of the meanings given for R2, and R1, W, A1, Q, Y, A2, X1, X4, n, m, R6, R3, X2, X3, R5, Y1 , Y2, R4a, Rb are as defined herein.

R2 is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, hydroxy alkyl of 1 to 4 carbon atoms, -CN, alkenyl of 2 to 6 carbon atoms, alkynyl from 2 to 6 carbon atoms, optionally substituted aryl of 6 to 12 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms halogenated, alkoxycarbonyl of 1 to 6 carbon atoms, alkenyloxy from 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, aminosulfonyl, amino, alkylamino of 1 to 6 carbon atoms, alkenylamino of 2 to 6 carbon atoms, nitro or heterocyclyl of 3 to 12 carbon atoms optionally substituted, or two R2 radicals together with the ring atoms to which they join form an ani 5 or 6 members.

An optionally substituted 5 or 6 membered ring which is formed by two radicals R 2 together with the ring atoms of the benzene ring to which they are attached is, for example, a benzene ring.

In relation to R2, the aryl of 6 to 12 carbon atoms substituted in particular include aryl of 6 to 12 carbon atoms, such as phenyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halogen and alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms , cyano, alkoxy of 1 to 4 carbon atoms and haloalkoxy of 1 to 4 carbon atoms.

In relation to R 2, the substituted heterocyclyl of 3 to 12 carbon atoms in particular includes heterocyclyl of 3 to 12 carbon atoms, such as morpholinyl, pyrrolidinyl and piperidinyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halogen , alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms and haloalkoxy of 1 to 4 carbon atoms.

Preferably, R 2 is hydrogen, halogen or alkoxy of 1 to 4 carbon atoms. In particular, R2 is hydrogen or halogen.

According to a particular embodiment, the phenalkylamine derivatives of the invention have one of the following formulas: where R1, W, A1, Q, Y, A2, X1, X4, n, m, R6, R2, R3, X2, X3, R5, Y, Y2, R4a, R4 are as defined herein.

R3 is hydrogen or alkyl of 1 to 6 carbon atoms. In particular, R3 is hydrogen, X2 is -O-, -NR7-, -S-, > CR 2aR 2b or a link.

Preferably, X2 is > CR12aR12b.

X3 is -O-, -NR7-, -S-, > CR13aR 3b or a link. Preferably, X3 is a bond.

Thus, it is preferred if X2 is > CR12aR12b and X3 is a link. , R 2a is hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted or hydroxy. Preferably, R 2a is hydrogen or alkyl of 1 to 6 carbon atoms.

R13a is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, alkylamino of 1 to 6 carbon atoms carbon-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl from 6 to 12 carbon atoms optionally substituted or hydroxy. Preferably, R13a is hydrogen or alkyl of 1 to 6 carbon atoms.

In relation to R 12a and R 3a, the alkyl of 1 to 6 carbon atoms substituted in particular includes alkyl of 1 to 6 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, alkoxy of 1 to 4 carbon atoms and amino.

In relation to R 2a and R 13a, aryl of 6 to 12 carbon atoms substituted in particular includes aryl of 6 to 12 carbon atoms, such as phenyl, substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms and haloalkoxy of 1 to 4 carbon atoms.

R12 is hydrogen or alkyl of 1 to 6 carbon atoms. According to a particular embodiment, R2 is hydrogen.

R 3 is hydrogen or alkyl of 1 to 6 carbon atoms. According to a particular embodiment, R 3b is hydrogen.

Alternatively, R12a and R12b, or R1 a and R13b, together are carbonyl or, preferably, alkylene of 1 to 4 carbon atoms optionally substituted (e.g. 1,3-propylene), where an alkylene -CH2- of 1 to 4 carbon atoms can be replaced by an oxygen atom or -NR17- or NR8.

In relation to R12a and R12b, or R13a and R3b, the substituted alkylene of 1 to 4 carbon atoms in particular includes alkylene of 1 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms and haloalkoxy of 1 to 4 carbon atoms.

According to a particular embodiment, R 2a is alkyl of 1 to 6 carbon atoms and R 12b is hydrogen or alkyl of 1 to 6 carbon atoms, or R 13a is alkyl of 1 to 6 carbon atoms and R 13b is hydrogen or alkyl of 1 to 6 carbon atoms.

According to a further particular embodiment, R 2a is hydrogen and R 1 is hydrogen, or R 13a is hydrogen and R 13 is hydrogen.

According to a further particular embodiment, R1 a and R12b together are optionally substituted 1,3-propylene, or R 3a and R 13b together are 1,3-propylene optionally substituted.

R5 is aryl of 6 to 12 carbon atoms optionally substituted (for example phenyl, 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, -fluorophenyl, 4-chlorophenyl, 4- methoxyphenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4-dichlorophenyl or 3,4-dichlorophenyl), cycloalkyl of 3 to 12 carbon atoms carbon optionally substituted (for example cyclohexyl) or heterocyclyl of 3 to 12 carbon atoms optionally substituted.

In relation to R 5, the substituted cycloalkyl of 3 to 12 carbon atoms in particular includes cycloalkyl of 3 to 12 carbon atoms, such as cyclopropyl or cyclohexyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl from 1 to 6 carbon atoms optionally substituted, alkyl of 1 to 6 carbon atoms halogenated, CN, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms halogenated, amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms and heterocyclyl of 3 to 12 carbon atoms.

In relation to R 5, aryl of 6 to 12 carbon atoms substituted in particular includes aryl of 6 to 12 carbon atoms, such as phenyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halogen (for example F, Cl, Br), alkyl of 1 to 6 carbon atoms optionally substituted (for example methyl), alkyl of 1 to 6 carbon atoms halogenated (for example trifluoromethyl), CN, hydroxy, alkoxy of 1 to 6 carbon atoms (by example methoxy), alkoxy of 1 to 4 carbon atoms halogenated, amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms and heterocyclyl of 3 to 12 carbon atoms.

In relation to R5, the heterocyclyl of 3 to 12 carbon atoms. substituted carbon in particular includes heterocyclyl of 3 to 12 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, optionally substituted alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 halogenated carbon atoms, CN, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogenated, amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms and heterocyclyl of 3 to 12 carbon atoms.

In relation to R 5, the heterocyclyl of 3 to 12 carbon atoms in particular is heteroaryl of 3 to 12 carbon atoms.

Preferably, R 5 is aryl of 6 to 12 carbon atoms optionally substituted, in particular as in the phenylalkylamine derivatives of the formula: where R1, W, A1, Q, Y, A2, X1, X4, n, m, R2, R3, X2, X3, Y, Y2, R4a R4b are as defined herein, and R 2a R 2 R 2 R 2 R 2 R 2 independently are hydrogen, halogen (for example F, Cl or Br), alkyl of 1 to 6 carbon atoms optionally substituted (for example methyl), alkyl of 1 to 6 carbon atoms halogenated (for example trifluoromethyl) , CN, hydroxy, alkoxy of 1 to 6 carbon atoms (for example methoxy), amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms or heterocyclyl of 3 to 12 carbon atoms.

It is also preferred if R 5 is heteroarylated from 6 to 12 carbon atoms optionally substituted, in particular as in the phenylalkylamine derivatives of the formula: where R1, W, A1, Q, Y, A2, X1, X4, n, m, R2, R3, X2, X3, Y1, Y2, R4a, R4b are as defined herein, and R2 b, R21c, R21d, R21e independently are hydrogen, halogen (for example F, Cl or Br), alkyl of 1 to 6 carbon atoms optionally substituted (for example methyl), alkyl of 1 to 6 carbon atoms halogenated (by example trifluoromethyl), CN, hydroxy, alkoxy of 1 to 4 carbon atoms (for example methoxy), amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms or heterocyclyl of 3 to 12 atoms of carbon.

According to a particular embodiment, the invention relates to phenylalkylamine derivatives of the formula: where R, W, A1, Q, Y, A2, X1, X4, n, m ,. R2, R3, Y, Y2, R a, R b are as defined herein, R5 being preferably optionally substituted aryl and in particular phenyl optionally substituted as described herein.

In relation to R5 or R21a, R21, R2 c, R21d, R21e, the alkyl of 1 to 6 carbon atoms substituted in particular includes alkyl of 1 to 6 carbon atoms, especially alkyl of 1 to 4 carbon atoms, substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms and heterocyclyl of 3 to 12 carbon atoms (for example morpholinyl or piperidinyl).

According to a particular embodiment, R21a, R21b, R21d, R2 e are hydrogen and R2 c is different from hydrogen (para-mono-substitution).

According to a further particular embodiment, R21a, R2ic R2I U p2ie are n¡c! Rerogen V it is different from hydrogen (meta-mono-substitution).

In relation to R21a, R21b, R21c, R2 d, R2 e, the heterocyclyl of 3 to 12 carbon atoms in particular includes morpholinyl, imidazolyl and pyrazolyl.

And it's a link or > CR aR 4. According to one modality, Y is a link.

Y2 is > CR15aR 5b.

Thus, according to a modality -Y-Y2- it is > CR15aR 5b. R14a is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted or hydroxyl.

R b is hydrogen or alkyl of 1 to 6 carbon atoms.

Alternatively, R14a, R4b together are optionally substituted carbonyl or alkylene of 1 to 4 carbon atoms, where one or two -CH2- of the alkylene of 1 to 4 carbon atoms can be replaced by an oxygen atom or -NR20-.

R 5a is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted or hydroxyl.

R15b is hydrogen or alkyl of 1 to 6 carbon atoms.

According to a particular embodiment, R 5a is hydrogen and R 15b is hydrogen.

Alternatively, R15a, R15b together are optionally substituted carbonyl or alkylene of 1 to 4 carbon atoms, wherein one or two -CH2- of alkylene of 1 to 4 atoms; carbon can be replaced by an oxygen atom or -NR20-.

In relation to R14a and R1b, or R15a and R15b, the substituted alkylene of 1 to 4 carbon atoms in particular includes alkylene of 1 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cyano, alkoxy of 1 to 4 carbon atoms and haloalkoxy of 1 to 4 carbon atoms.

R a is hydrogen, alkyl of 1 to 6 carbon atoms (for example methyl, ethyl, n-propyl or isopropyl), cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example cyclopropylmethyl), alkyl of 1 to 4 carbon atoms halogenated (for example 2-fluoro-ethyl or 2,2,2-trifluoroethyl), hydroxy-alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, CH 2 CN, cycloalkyl of 3 to 12 carbon atoms (for example cyclopropyl), aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example benzyl example), -CHO, alkylcarbonyl of 1 to 4 carbon atoms (for example methylcarbonyl, ethylcarbonyl or isopropylcarbonyl), (halogenated C 1 -C 4 alkyl) carbonyl (for example fluoromethylcarbonyl, di fluoro methylcarbonyl, tri fluoromethylcarbonyl, , 1, 1 - trifluoroet-2-ylcarbonyl or 1,1,1-trifluoroprop-3-ylcarbonyl), arylcarboni from 6 to 12 carbon atoms (for example phenylcarbonyl), alkoxycarbonyl of 1 to 4 carbon atoms (for example ethoxycarbonyl or tert-butyloxycarbonyl), aryloxycarbonyl of 6 to 12 carbon atoms (for example phenoxycarbonyl), alkylaminocarbonyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, -C (= NH) NH2, -C (= NH) NHCN, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms carbon, amino, -NO or heterocyclyl of 3 to 12 carbon atoms (for example 3-oxetanyl.

Preferably, R 4a is hydrogen, alkyl of 1 to 6 carbon atoms (for example methyl, ethyl, n-propyl or isopropyl), cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example cyclopropylmethyl) alkyl of 1 to 4 carbon atoms halogenated (for example 2-fluoroethyl or 2,2,2-trifluoroethyl), amino-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms (for example cyclopropyl) , CH2CN, cycloalkyl of 3 to 12 carbon atoms (for example cyclopropyl), aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example benzyl), alkylcarbonyl of 1 to 4 carbon atoms (for example example methylcarbonyl or isopropylcarbonyl), (halogenated C 1 -C alkyl) carbonyl (for example fluoromethylcarbonyl, difluoromethylcarbonyl or trifluoromethylcarbonyl), arylcarbonyl of 6 to 12 carbon atoms (for example phenylcarbonyl), alkoxycarbonyl of 1 to 4 carbon atoms (for example, ethoxycarbon ilo or tert-butyloxycarbonyl), aryloxycarbonyl of 6 to 12 carbon atoms (for example phenoxycarbonyl), -C (= NH) NH2, -C (= NH) NHCN, alkylsulfonyl of 1 to 6 carbon atoms, amino, -NO or heterocyclyl of 3 to 12 carbon atoms (for example 3- oxetanyl).

In particular, R 4a is hydrogen.

Alternatively, R4a and R3 together are optionally substituted C 1 -C 4 -alkylene (for example methylene or 1,2-ethylene, with an additional example being 1, 3-propylene, 1 -oxo-1,2-ethylene, 1 - oxo-1, 3-propylene) so that R4a and R3 together with the half of -Y-Y2-N- and the C atom to which R3 is bonded forms a heterocyclic ring having, in particular, 4, 5, or 6 atoms of the ring member (including the nitrogen atom). With R.sub.4a and R.sub.3 being together optionally substituted alkylene of 1 to 4 carbon atoms, such phenalkylamine derivatives can be represented by the following partial structure: where A is alkylene of 1 to 4 carbon atoms optionally substituted and R, W, A1, Q, Y, A2, X1, X4, n ', m, R2, R3, X2, X3, R5, Y1, Y2, R4b they are as defined in the present.

In relation to R 4a and R 3, the substituted alkylene of 1 to 4 carbon atoms in particular includes alkylene of 1 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen (for example fluoro), alkyl of 1 to 4 carbon atoms or oxo.

Alternatively, Y is > CR 4a R 14b and R 4a and R a together are C 1 -C 4 -alkylene optionally substituted (eg methylene) so that R 4a and R 14a together with the half of -C (R) -Y 2 -N- are bonded form a ring heterocyclic having, in particular, ring atoms of 4, 5, or 6 members (including the nitrogen atom). With R.sub.4a and R.sub.1 being together alkylene of 1 to 4 carbon atoms, such a ring can be represented by the following partial structure: where A is from 1 to 4 carbon atoms optionally substituted by alkylene and R1, W, A1, Q, Y, A2, X1, X4, n, m, R2,.

R3, X2, X3, R5, Y1, Y2, R4b are as defined herein.

In relation to R a and R a, the substituted alkylene of 1 to 4 carbon atoms in particular includes alkylene of 1 to 4 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen (for example fluoro), alkyl of 1 to 4 carbon atoms and oxo.

R4b is hydrogen, alkyl of 1 to 6 carbon atoms (for example methyl, with an additional example being ethyl), alkyl of 1 to 4 carbon atoms halogenated, hydroxy-alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, CH2CN, -CHO, alkylcarbonyl of 1 to 4 carbon atoms, (alkyl of 1 to 4 carbon atoms) carbonyl, arylcarbonyl of 6 to 12 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aryloxycarbonyl of 6 to 12 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, -C ( = NH) NH2, C (= NH) NHCN, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, amino, -NO or heterocyclyl of 3 to 12 carbon atoms.

Preferably, R4 is hydrogen or alkyl of 1 to 6 carbon atoms (for example methyl) or, especially if R4a and R3 together are optionally substituted 1 to 4 carbon atoms, R4b is hydrogen, alkyl of 1 to 6 carbon atoms, carbon (for example methyl, ethyl, 2-propyl, 2,2,2-trimethylethyl), alkyl of 1 to 4 carbon atoms halogenated (for example 2-fluroethyl, 2,2-difluroethyl, 2,2,2-trifluroethyl), alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms ( for example 2-methoxyethyl), (halogenated C 1-4 alkyl) carbonyl (for example 2-fluroacetyl, 2,2-difluoroacetyl, 2,2,2-trifluoroacetyl) or alkoxycarbonyl of 1 to 4 carbon atoms ( for example ethoxycarbonyl). In particular, R4 is hydrogen.

Alternatively, R a, R b together are C 1 -C 6 -alkylene optionally substituted (e.g., 1,4-butylene, 1,3-propylene, 2-fluoro-but-1,4-ylene or 1 -oxo- but-1, 4-ylene), wherein a -CH2- of the alkyl of 1 to 6 carbon atoms can be replaced by an oxygen atom (for example -CH "2-CH2-0-CH2-CH2-) or -NR16 .

In relation to R a and R 4b, the substituted alkyl of 1 to 6 carbon atoms in particular includes alkyl of 1 to 6 carbon atoms substituted with 1, 2 or 3 substituents selected from the group consisting of halogen (for example fluoro or chloro) , alkyl of 1 to 4 carbon atoms, cyano, hydroxy and alkoxy of 1 to 4 carbon atoms.

R7 is hydrogen or alkyl of 1 to 6 carbon atoms. Preferably, R7 is hydrogen.

R8 is hydrogen or alkyl of 1 to 6 carbon atoms. Preferably, R8 is hydrogen.

R9 is hydrogen, alkyl of 1 to 6 carbon atoms (per example methyl or ethyl), cycloalkyl of 3 to 12 carbon atoms (for example cyclopropyl), amino-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms optionally substituted p Heterocyclyl of 3 to 12 carbon atoms (for example 3-azetidinyl). Preferably, R9 is hydrogen or alkyl of 1 to 6 carbon atoms (for example methyl or ethyl).

According to a particular embodiment, R9 and R together are alkylene of 1 to 4 carbon atoms (for example 1, 3-1, 2-ethylene-or propylene) so that R9 and R1 together with the atom in Q to which R1 is linked and the nitrogen atom to which R9 is bonded form a heterocyclic ring having, in particular, 4, 5 or 6 membered ring atoms (including the nitrogen atom and Q). With W and A1 both being a link, such a ring can be represented by the following partial structure: where Q, A2, X1, are as s'e defined in the present (for example S (0) 2) and n is 0, 1, 2, 3 or 4.

According to a further particular embodiment, R9 is alkylene of 1 to 4 carbon atoms (for example methylene or 1,3-propylene) which is bonded to a carbon atom in A2 and A2 is alkylene of 1 to 4 carbon atoms so that R9 and at least part of A2 together with the nitrogen atom to which R9 it is linked forms a heterocyclic ring containing N having, in particular, ring atoms of 4, 5, 6 or 7 members (including the nitrogen atom). Such ring can be represented by the following partial structure: where R1, W, A1 and Q are as defined herein, p is 1 or 2, r is 0, 1 or 2 and q is 0, 1 or 2. In this particular embodiment, X1 is preferably -O-. The particular combinations of p, r and q include p = 1, r = 0, q = 1; and p = 1, r = 0, q = 0. Alternatively, p is 0, r is 3 and q is 1, with X1 preferably being -O-.

R10 is hydrogen, alkyl of 1 to 6 carbon atoms or alkylsulfonyl of 1 to 6 carbon atoms. Preferably, R 0 is hydrogen.

R 1 is hydrogen or alkyl of 1 to 6 carbon atoms. Preferably, R 1 is hydrogen.

Alternatively, R9, R1 together are alkylene of 1 to 4 carbon atoms (for example ethylene).

R 6 is hydrogen or alkyl of 1 to 6 carbon atoms. Preferably, R16 is hydrogen.

R17 is hydrogen or alkyl of 1 to 6 carbon atoms. Preferably, R 4 is hydrogen.

R 8 is hydrogen or alkyl of 1 to 6 carbon atoms. Preferably, R15 is hydrogen.

R19 is hydrogen or alkyl of 1 to 6 carbon atoms (for example methyl).

The particular embodiments of the phenalkylamine derivatives of the invention result if in the formula (I) R1 is alkyl of 1 to 6 carbon atoms or heterocyclyl of 3 to 12 carbon atoms optionally substituted; W is a link; A1 is a link; Q is -S (0) 2-; And it's NR9; A2 is alkylene of 1 to 4 carbon atoms (for example methylene); X1 -O-; X4 -O- or NR19; n is 1; R6 is hydrogen; R2 is hydrogen; R is hydrogen; X2 is CR12aR12; X3 is a link; R5 is faith or lo; Y1 is a link; Y2 is > CR15aR15b; R a is hydrogen; R4b is hydrogen; R12a is hydrogen; R 2b is hydrogen; R15a is hydrogen; R15b is hydrogen; Y R19 is alkyl of 1 to 6 carbon atoms (for example methyl).

The particular embodiments of the phenalkylamine derivatives of the invention result if in the formula (II) R1 is cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms (for example cyclopropylmethyl), or heterocyclyl of 3 to 12 carbon atoms optionally substituted (for example 1-methyl-, 2-diazole-4-) ilo or 1-methyl-1,3-diazol-4-yl); W is a link; A1 is a link; Q is -S (0) 2- or -C (O) -; m is 2; R6 is hydrogen; R2 is hydrogen; R3 is hydrogen; X2 is > CR12aR1 b; X3 is a link; R5 is phenyl; Y1 is a link; Y2 is > CR15aR15b; R 4a is hydrogen or alkyl of 1 to 6 carbon atoms (by methyl example); R4b is hydrogen or alkyl of 1 to 6 carbon atoms (for example methyl); or R12a is hydrogen; R12b is hydrogen; R 5a is hydrogen; Y R15b is hydrogen.

The particular compounds of the present invention are the phenalkylamine derivatives described in the preparation examples and physiologically tolerated salts thereof. These include for each example of preparation the exemplified compound as well as the corresponding free base and any other physiologically tolerated salt of the free base (if the exemplified compound is a salt), or any physiologically tolerated salt of the free base (if the compound exemplified it is a free base). These also include enantiomers, diastereomers, tautomers and any other isomeric form of the compounds, are described explicitly or implicitly.

The particular compounds of the present invention are the rigid phenylalkylamine derivatives described in the preparation examples and physiologically tolerated acid addition salts thereof.

The compounds of formula (I) or (II) can be prepared by analogy to methods which are well known in the art. The right methods for the preparation of compounds of formula (I) or (II) are explained in the following. Reaction Schemes.

The compounds of formula (I) can be prepared by analogy to the methods which are well known in the art. A suitable method for the preparation of compounds of formula (I) is detailed in the following Reaction Schemes. The variables X1, X2, X3, X4, R2, R6 are as defined herein, L represents an alkyl substituent (for example Me, Et), L2 and L are suitable protecting groups (for example L2 = COOtBu and L = tBuMe2Si or Bn). The process, represented in Reaction Scheme 1, is useful for obtaining phenalkylamines of general formula 5, wherein X 1 is O and X 4 is N.

Reaction Scheme 1 The compounds of formula 2 can be obtained by the substitution reaction with derivatives, of 2,3-dibromopropionic acid to produce dihydrobenzoxazine type structures of formula 2 (J. Med. Chem. 2006, 49, 7095, Bioorg. &Med, Chem. Letters 2006, 16, 1338). The bromination ofe. the side chain (for example methyl) and protection of the aniline leads to the structure 4. The subsequent reduction of the ester leads to alcohols of formula 5, which can be protected by the appropriate protective group L (for example L = tBuMe2Si or Bn) . "'| *; The process represented in Reaction Scheme 2 is useful for obtaining rigid phenalkylamines, where the variables X1, X2, X3, X4, R5 are as defined herein, L is a suitable protective group (for example COOtBu), and L represents a free carboxylic acid or a corresponding ester (for example H, Me, Et, alkyl). The compounds of general formula 7 wherein X1 and X4 are O for example are well described in the literature and often commercially available.

Reaction Scheme 2 A'-SOzCI As shown in Reaction Scheme 2, the compound of general formula 7 can be easily reduced to give the compound of general formula 8 by common reducing agents (for example, borane complexes). Conversion to the corresponding bromide through a standard substitution protocol (for example PBr3 in the presence of a base such as Et3N) leads to formula 9. Nitrile 10 can be obtained by a subsequent substitution with a cyanide salt (for example NaCN) . A subsequent aldol-like condensation reaction in the presence of a base (for example NaOEt) and a suitable aldehyde (for example benzaldehyde) followed by the reduction of the initially formed double bond yields the rigid phenalkylamines of formula 11. The compounds 11 can further be converted to compounds of formula 12 by a deprotection step. As described above, a standard substitution protocol with a bromine source (for example PBr3 in the presence of a base such as Et3N) can provide bromides of formula 13, which can be easily transformed into the amines of formula 14 through a substitution of azide followed by reduction of PPh3 (Staudinger-protocol, Bioorg. & Med. Chem. Letters 2006, 16, 1338). Reaction with sulfonyl chlorides leads to the corresponding sulfonamides of formula 15. Compounds of general formula 16 can be obtained by reduction of nitrile (for example, borane complexes, Raney nickel).

The process depicted in Reaction Scheme 3 is useful for obtaining rigid phenalkylamines, where Y is a bond, A2 is CH2 and Q is S02 (Journal of Organic Chemistry 1985, 50, 5184).

Reaction Scheme 3: From the compound of formula '13 the corresponding thioethers 17 can be obtained by substitution of the bromide with a suitable sulfur nucleophile (for example sodium thiolates). Oxidation to the sulfones of formula 18 can be achieved by the state of the processes of the art (for example Nal04, oxone, KMn04, meta-chlorobenzoic acid). The compounds of general formula 19| can then be obtained through reduction methods as described above (Reaction Scheme 2).

The process represented in Reaction Scheme 4 is useful for obtaining rigid phenalkylamines, where Y and A1 are bonds, A2 is CH2, Q is S02 and W is N.

Reaction Scheme 4: From compounds of formula 13 the corresponding sulfonylchlorides can be obtained as described in the literature (Org. &Bioorg, Chem. 2007, 51, 1093). Sulfonamides can be obtained by the state of the reaction of the art with a suitable amine to give compound 21, which can be further transformed into compounds of formula 22 through reduction procedures as described above (Reaction Scheme 2). \ The compounds of formula (II) can be prepared by analogy to methods which are well known in the art. A suitable method for the preparation of compounds of formula (II) is detailed in the following Schemes of Reaction. The variables X2, X3, R5 are as defined herein and L is a suitable protecting group (for example L = COOtBu).

The process represented in Reaction Scheme 5 is useful for obtaining rigid phenalkylamines, where the variables X2, X3, R5 are as defined herein, L is a suitable protecting group (for example COOtBu), and l_i represents a carboxylic acid free or a suitable ester (for example H, Me, Et, alkyl).

Reaction Scheme 5 As shown in Reaction Scheme 5, the compound of general formula 23 can be easily reduced to give the compound of general formula 24 by common reducing agents (for example, borane complexes). Conversion to the corresponding bromide through the standard substitution protocol (for example PBr3 in the presence of a base such as Et3N) leads to formula 25. Nitrile 26 can be obtained from 25 by a subsequent substitution with a salt of cyanide (for example NaCN). A subsequent aldol-like condensation reaction in the presence of a low (for example NaOEt) and a suitable aldehyde (for example benzajdehyde) followed by the reduction of the double bond formed initially produces rigid phenalkylamines of formula 27. The compound 27 can be further converted to compounds of general formula 32 as shown in Reaction Scheme 6.

The process represented in Reaction Scheme 6 is useful to obtain the phenylalkylamines of formula II, where Q is -S (0) 2.

Reaction Scheme 6 In Reaction Scheme 6, the variables R1, W, A1, R2, R4a, R4, X2, X3 are as defined herein and L is a suitable protecting group (for example L = COOtBu) .: As shown in the above Reaction Scheme 6, the compound of general formula 28 easily undergoes the cleavage of the appropriate protecting group (for example COOtBu). The sulfonylation under basic conditions (e.g., DMAP, pyridine) yields compounds of general formula 30. The subsequent reduction of nitrile to the corresponding amines 31 can be achieved using standard protocols (e.g. borane complexes, Raney nickel, H2). The alkylation leads to rigid phenalkylamines of general formula 32.

Suitable amino protecting groups are well known in the art such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOMie, Plenum Press, 1973; and T. W. Greene & P. G. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The compounds of formula (I) have the ability to inhibit the activity of the glycine transporter, in particular the glycine transporter 1 (GlyTI).

The utility of the compounds according to the present invention as inhibitors of the activity of the glycine transporter, in particular the activity of GlyTI, can be demonstrated by methodology known in the art. For example, hGlyTI c_5_CHO recombinant cells expressing human GlyTIc can be used to measure glycine capture and its inhibition (IC50) by a compound of formula (I) or (II).

Among the compounds of formula (I) or (II) those that are. they prefer those that achieve effective inhibition at low concentrations. In particular, compounds of formula (I) that inhibit glycine transporter 1 (GlyTI) to a IC5o level < 1 μ ??, more preferably at an IC50 level < 0.5 μ ???, particularly preferably at an IC50 level < 0.2 μ ??? and more preferably at an IC50 level < 0.1 μ ???.

The compounds of formula (I) or (II) according to the present invention are therefore useful as pharmaceuticals.

Accordingly, the present invention also relates to pharmaceutical compositions comprising an inert carrier and a compound of formula (I) or (II).

The present invention also relates to the use of the compounds of formula (I) or (II) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1, and the corresponding methods for inhibiting the GlyT1 glycine transporter.

The NMDA receptor is central in a wide range of CNS processes, and its role in a variety of diseases in humans or other species has been described. GlyT1 inhibitors delay glycine clearance from the synapses, causing the level of synaptic glycine to increase. This on the contrary increases the occupation of the glycine binding site at the NMDA receptor, which increases the activation of the NMDA receptor followed by the release of glutamate from the presynaptic terminal. Inhibitors of glycine transport and in particular glycine transporter inhibitors GlyT1 are therefore known to be useful in the treatment of a variety of neurological and psychiatric disorders. In addition, glycine A receptors play a role in a variety of diseases in humans or other species. Increasing the extracellular concentrations of glycine by inhibiting glycine transport can increase the activity of glycine A receptors. Thus, inhibitors of the glycine transporter and in particular glycine transporter inhibitors GlyT1, are useful for treating a variety of neurological and psychiatric disorders.

The present invention therefore further relates to the use of the compounds of formula (I) or (II) for the manufacture of a medicament for the treatment of a neurological or psychiatric disorder, and with the corresponding methods for the treatment of such disorders .

According to a particular embodiment, the disorder is associated with glycinergic or glutamatergic neurotransmission dysfunction.

According to another additional particular embodiment, the disorder is one or more of the following conditions or diseases: schizophrenia or a pysic disorder that includes schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophrenic disorder, schizoaffective disorder, illusory disorder , brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and psychotic disorder induced by substances, which includes both positive and negative symptoms of schizophrenia and other psychoses, cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or heart attack, HIV disease, Parkinson's disease, Huntington's disease , Pick's disease, Creutzfeldt-Jacob's disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or cognitive impairment that includes cognitive impairment related to age; Anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, disorder of anxiety induced by substances and anxiety due to a general medical condition; disorders related to addictive substances and behaviors (including substance-induced delirium, persistent dementia, persistent amnestic disorder, psychotic disorder or anxiety disorder, tolerance, dependence or abstinence from substances that include alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders that include depressive disorders; depression that includes depression unipolar, seasonal depression and postpartum depression, premenstrual syndrome (PEM), and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and mood disorders induced by substances; learning disorders, persuasive developmental disorder that includes autistic disorder, attention deficit disorders that include attention deficit hyperactivity disorder (ADHD) -and conduct disorder; movement disorders, which include akinesia and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supnanuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex, and basal ganglia calcification ), medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor), Gilles de la Tourette syndrome, epilepsy, muscle spasms, and disorders associated with muscle spasticity or weakness that includes tremors; dyskinesias [including tremor (such as tremor due to rest, postural tremor, and intentional tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, chorea symptomatic, drug-induced chorea and hemiballism), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics, and symptomatic tics), and dystonia (including generalized dystonia such as idiopathic dystonia, dystonia induced by drugs, symptomatic dystonia and paroximal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonia due to dystonic spasm of writer and hemiplegic)]; urinary incontinence; neuronal damage that includes eye damage, retinopathy or macular degeneration of the eye, tinnitus, deterioration and hearing loss, and cerebral edema; emesis; and sleep disorders that include insomnia and narcolepsy.

According to another particular additional modality, the disorder is pain, in particular of chronic pain and especially neuropathic pain.

Pain can be classified as acute and chronic pain. Acute pain and chronic pain differ in their etiology, pathophysiology, diagnosis and treatment.

Acute pain, which occurs after a tissue injury, is self-limiting, serves as an alert for the tissue that is being damaged and that after tissue repair usually decreases. There are minimal psychological symptoms associated with acute pain except for mild anxiety. Acute pain is nociceptive in nature and occurs after the chemical, mechanical and thermal stimulation of pain receptors A-delta and C- polymodal Chronic pain, on the other hand, has no protective biological function. Instead of being the symptom of tissue damage it is a disease in itself. Chronic pain is unstoppable and does not become self-limiting and may persist for years, perhaps decades after the initial injury. Chronic pain can be refractory to many treatment regimens. The psychological symptoms associated with chronic pain include chronic anxiety, fear, depression, insomnia and impairment of social interaction. Chronic non-malignant pain is predominantly neuropathic in nature and involves damage to the peripheral or central nervous system.

Acute pain and chronic pain are caused by different neurophysiological processes and therefore tend to respond to different types of treatment. Acute pain can be somatic or visceral in nature. Somatic pain tends to be well localized, constant pain and is described as throbbing, painful, pulsating or permanent. Visceral pain, on the other hand, tends to be vague in its distribution, paroxysmal in nature and is usually described as deep, painful, oppressive or colicky. Examples of acute pain include post-operative pain, pain associated with trauma and arthritis pain. Acute pain usually responds to treatment with opioids or non-spheroidal anti-inflammatory drugs.

Chronic pain, unlike acute pain, is described as burning, electrical, tingling and prickly in nature. It can be continuous presentation or paroxysmal. The characteristic of chronic pain are allodynia and hyperalgesia. Allodynia is pain that results from a stimulus that normally does not produce a painful response, such as a gentle touch. Hyperalgesia is an increased sensitivity to a normally painful stimulus. Hyperalgesia mainly occurs immediately in the area of the lesion. Secondarily, hyperalgesia occurs in the undamaged area surrounding the lesion. Examples of chronic pain include complex regional pain syndrome, pain originating from peripheral neuropathies, post-operative pain, chronic fatigue syndrome pain, tension type headache, pain originating in mechanical nerve injury and severe pain associated with diseases such as cancer, metabolic diseases, neurotropic viral disease, neurotoxicity, inflammation, multiple sclerosis or any pain originating as a consequence of or asiociated to stress or depressive illness.

Although opioids are cheap and effective, during their use there are side effects that potentially threaten life, most notably respiratory depression and muscular rigidity. Additionally, the doses of opioids that can be administered are limited by nausea, emesis, constipation, pruritus and urinary retention, which generally As a result, patients choose to receive suboptimal pain control instead of suffering from these distressing side effects. Additionally, these side effects generally result in patients requiring extended hospitalization. Opioids are highly addictive-and they are regulated drugs in many territories.

The compounds of formula (I) or (II) are particularly useful in the treatment of schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric (TDP), learning disorders, persuasive developmental disorder that includes autistic disorder, attention deficit disorders including attention deficit hyperactivity disorder, tic disorders that include Tourette's disorder, disorders of anxiety which include phobia and post-traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's disease, Parkinson's, Huntington's, spasticity, myoclonus, muscle spasm, tinnitus and deterioration and hearing loss are of particular importance.

The particular cognitive disorders are dementia, delirium, amnestic disorders and cognitive impairment that includes cognitive deterioration related to age.

The particular anxiety disorders are disorder of generalized anxiety, obsessive-compulsive disorder and panic attack.

Schizophrenia or particular psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance induced disorders.

Particular neurological disorders that can be treated with the compounds of formula (I) or (II) include in particular a cognitive disorder such as dementia, cognitive impairment, attention deficit hyperactivity disorder.

Particular psychiatric disorders that can be treated to the compounds of formula (I) or (II) include in particular an anxiety disorder, a mood disorder such as depression or a bipolar disorder, schizophrenia, a psychotic disorder.

In the context of the treatment, the use according to the invention of the compounds of formula (I) or (II) involves a method. In this method, an effective amount of one or more compounds of formula (I) or (II), generally formulated according to pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human. Whether such treatment is indicated, and how it is done, depends on the individual case and is a matter of medical evaluation (diagnosis) that takes into account the signs, symptoms and / or abnormalities that are present, the risks of developing signs, symptoms and / or particular anomalies, and other factors.

In general, the treatment is carried out by means of the single or repeated administration on a daily basis, when appropriate together, or alternating, with other drugs or preparations containing drugs.

The invention also relates to the manufacture of pharmaceutical compositions for the treatment of an individual, preferably a mammal, in particular a human. Therefore, the compounds of formula (I) or (II) are usually administered in the form of pharmaceutical compositions comprising an inert carrier (for example a pharmaceutically acceptable excipient) together with at least one compound according to the invention and, when appropriate, other drugs. These compositions can, for example, be administered orally, straightly, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular coated tablets, dragees, sachets, cache, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semi-solid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, preparations for injections and preparations for infusion, and drops for the eyes and eardrops. Implantable release devices can also be used for the administration of inhibitors according to the invention. Additionally, it is also possible to use liposomes or microspheres.

When the compositions are produced, the compounds according to the invention are optionally mixed or diluted with one or more carriers (excipients). The carriers (excipients) may be solid, semi-solid or liquid materials that serve as carriers, carriers or medium for the active compound.

Suitable transporters (excipients) are listed in specialist medical monographs. Additionally, the formulations may comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; conservatives; antioxidants; anti-irritants; chelating agents; coating auxiliaries; emulsion stabilizers; i trainers films; gel formers; odor masking agents; flavor correctors; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; agents that allow the skin to recover / preserve its fatty content; raw materials for ointments, creams and oils; derivatives of silicones; auxiliaries to spread; stabilizers; sterilizers; bases for suppositories; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation with respect to this is based on the specialized knowledge as described, for example, in Fiedler, HP, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.

The compounds of formula (I) or (II) may also be suitable for combination with other therapeutic agents.

Therefore, the present invention also provides: i) a combination comprising a compound of formula (I) with one or more additional therapeutic agents; ii) a pharmaceutical composition comprising a combined product as defined above in i) and at least one carrier, diluent or excipient; iii) the use of a combination as defined above in i) the manufacture of a medicament for treating or preventing a disorder, disease or condition as defined herein; iv) a combination as defined above in i) for use in the treatment or prevention of a disorder, disease or condition as defined herein; v) a set of elements for use in the treatment of a disorder, disease or condition as defined herein, comprising a first dosage form comprising a compound of formula (I) or (II) and one or more other forms of additional dosages, each of which comprises one or more additional therapeutic agents for simultaneous therapeutic administration, vi) a combination as defined above in i) for use in therapy; vii) a method for treating or preventing a disorder, disease or condition as defined herein which comprises administering an effective amount of a combination as defined above in i); viii) a combination as defined above in i) to treat or prevent a disorder, disease or condition as defined herein.

The combination therapies of the invention can be administered as adjuvants. "Administration as adjuvants" means the simultaneous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. In general, those of skill in the art and in the present are referred to this regimen of therapeutic administration of two or more therapeutic agents as one administration Therapeutic treatment of adjuvants; and it is also known as complementary therapeutic administration (add-on). Any of the treatment regimens in which a patient receives a separate but simultaneous or overlapping therapeutic administration of the compounds of formula (I) or (II) and at least one additional therapeutic agent, and all of them, are within the scope of the invention. scope of the present invention. In a form of therapeutic mode of adjuvant administration as described herein, typically a patient is stabilized with the therapeutic administration of one or more of the components over a period of time and then the latter receives an administration of another component.

The combination therapy of the infection can also be administered simultaneously. "Simultaneous administration" means a treatment regimen where the individual components are administered together, either in the form of a single pharmaceutical composition or a single device comprising or containing both components, or as separate compositions or devices, each of which comprises one of the components, administered simultaneously. Such combinations1 of separate individual components for the simultaneous administration of a combination can be provided in the form of a set of elements.

In a further aspect, the invention provides a method for treating a psychotic disorder by therapeutic administration of compounds of formula (I) or (II) as adjuvants to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) or (II) in the manufacture of a medicament for the therapeutic administration of adjuvants for treating a psychotic disorder in a patient receiving therapeutic administration of at least an antipsychotic agent. The invention also provides compounds of formula (I) or (II) for use in the therapeutic administration of adjuvants for treating a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.

In a further aspect, the invention provides a method for treating a psychotic disorder by therapeutic administration of adjuvants of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I) or (II). In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for the therapeutic administration of adjuvants for treating a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or (II). The invention also provides at least one antipsychotic agent for the therapeutic administration of adjuvants to treat a psychotic disorder in a patient who receives the therapeutic administration; of compounds of formula (I) or (II).

In a further aspect, the invention provides a method for treating a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or: (II) in combination with at least one antipsychotic agent. The invention also provides the use of a combination of compounds of formula (I) or (II) and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention also provides a combination of compounds of formula (I) or (II) and at least one antipsychotic agent for (simultaneous therapeutic administration in the treatment of a psychotic disorder.) The invention also provides the use of compounds of formula (I). ) or (II) in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder The invention also provides compounds of formula (I) or (II) for use in the administration therapy; simultaneous with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention also provides the use of at least one antipsychotic agent * in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or (II) in the treatment of a psychotic disorder. The invention also provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) or (II) in the treatment of a psychotic disorder. " In still other aspects, the invention provides a method for treating a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or (II) and at least one mood stabilizer or an antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or (II) and at least one mood stabilizer or an antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or (II) and at least one mood stabilizer or an antimanic agent in the manufacture of a medicament for treating a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or (II) and at least one stabilizer of the state of mood or an antimanic agent to use in the treatment of a psychotic disorder.

Antipsychotic agents include both typical and atypical antipsychotic drugs. Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as, for example, haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as, for example, thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazols; dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines; triazines such as lamotrigine, dibenzoxazepines, such as, for example, loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that possess antipsychotic activity.

The examples of trademarks and suppliers of the selected antipsychotic drugs are the following: clozapine (obtainable under the trademark CLOZARIL®, from Milan, Zenith Goldline, UDL, Novartis); olanzapine (obtainable under the trademark ZYPREX®, from Lilly); ziprasidone (obtainable under the trademark GEODON®, from Pfizer); risperidone (which can be obtained with the trademark RISPERDAL®, Janssen); quetiapine fumarate (obtainable under the trademark SEROQUEL®, from AstraZeneca); haloperidol (obtainable under the trademark HALDOL®, from Ortho-McNeil); chlorpromazine (obtainable with the trademark THORAZINE®, from SmithKine Beecham (GSK)); flufenazine (obtainable under the trademark PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (obtainable under the trademark NAVANE®, from Pfizer); trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl] -2- (trifluoromethyl) phenothiazine as dihydrochloride, that can be obtained with the trademark STELAZINA, from Smith Klein Beckman); perphenazine (obtainable under the trademark TRILAFON®, from Schering); thioridazine (obtainable under the trademark MELLARI L®, from Novartis, Roxane, HiTech, Teva, and Alfarma); Molindone (obtainable under the trademark MOBAN®, from Endo); and loxapine (which can be obtained under the brand name LOXITANE (D; from Watson).) In addition, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eenlazarpan®) can be used.Another antipsychotic drugs include promazine (which is can be obtained with the trademark SPARINE®), triflurpromazine (which can be obtained under the trademark VESPRI N®), chlorprothixene (which can be obtained under the trademark TARACTAN®), droperidol (which can be obtained under the trademark INAPSINE ®), acetophenazine (obtainable under the trademark TINDAL®), prochlorperazine (which can be obtained under the trademark COMPAZINE®), methotrimeprazine (obtainable under the trademark NOZINAN®), pipotiazine (which can be obtained obtain with the trademark PIPOTRIL®), ziprasidone, and hoperidone.

In a further aspect, the invention provides a method for treating a neurodegenerative disorder such as Alzheimer's disease by therapeutic administration of compounds of formula (I) or (II) as adjuvants to a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease. In a further aspect, the invention provides the use of compounds of formula (I) or (II) in the manufacture of a medicament for the therapeutic administration of adjuvants for the treatment of a neurodegenerative disorder such as Alzheimer's disease in a patient. which receives therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease. The invention also provides compounds of formula (I) or (II) for use in the therapeutic administration of adjuvants for the treatment of a neurodegenerative disorder such as Alzheimer's disease in a patient receiving therapeutic administration of at least one appropriate agent for the treatment of a neurodegenerative disorder such as Alzheimer's disease.

In a further aspect, the invention provides a method for treating a neurodegenerative disorder such as Alzheimer's disease by therapeutic administration of adjuvants of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease to a patient who receives therapeutic administration of compounds of formula (I) or (II). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of a disorder neurodegenerative such as Alzheimer's disease in the manufacture of a medicament for the therapeutic administration of adjuvants for the treatment of a neurodegenerative disorder such as Alzheimer's disease in a patient receiving therapeutic administration of compounds of formula (I) or (II) ). The invention also provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease for the therapeutic administration of adjuvants for the treatment of a neurodegenerative disorder such as Alzheimer's disease in a patient receiving the administration. Therapeutics of compounds of formula (I) or (II).

In a further aspect, the invention provides a method for treating a neurodegenerative disorder such as Alzheimer's disease by simultaneous therapeutic administration of compounds of formula (I) or (II) in combination with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease. The invention also provides the use of a combination of compounds of formula (I) or (II) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease in the manufacture of a medicament for therapeutic administration. in the treatment of a neurodegenerative disorder such as Alzheimer's disease. The invention also provides a combination of compounds of formula (I) or (II) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as the disease of Alzheimer's The invention also provides the use of compounds of formula (I) or (II) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease in the treatment of a neurodegenerative disorder such as Alzheimer's disease. The invention also provides compounds of formula (I) or (II) for use in the simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease in the treatment of a neurodegenerative disorder such as Alzheimer disease. The invention also provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or (II) in the treatment of a neurodegenerative disorder such as the disease; of Alzheimer's The invention also provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease for simultaneous therapeutic administration with compounds of formula (I) or (II) in the treatment of a neurodegenerative disorder such as Alzheimer's disease.

Examples of agents suitable for the treatment of a neurodegenerative disorder such as Alzheimer's disease that are useful in the present invention include, but are not limited to: cholinesterase inhibitors, agents targeting nicotinic or acetylcholine muscarinic receptors, NMDA receptors , amyloid formation, mitochondrial dysfunction, calpain activity associated with disease, neurological inflammation, tumor necrosis factor receptors, NF-kappaB, peroxisome proliferator-activated gamma receptor, variant 4 of Apolipoprotein E (ApoE4), increased activity of the HPA axis associated with disease, epileptic discharges, vascular dysfunction, vascular risk factors, and oxidative stress.

The appropriate cholinesterase inhibitors that can be using in combination the compounds of the invention include for example tacrine, donepezil, galantamine and rivastigmine.

Agents directed towards suitable NMDA receptors that can be used in combination with the compounds of the invention include for example memantine.

The agents that affect the increase of activity of the HPA axis suitable that can be used in combination to the Compounds of the invention include for example CRF1 antagonists or V1b antagonists.

Therefore, in a further aspect the invention provides a method for treating pain by therapeutic administration of compounds of formula (I) or (II) as adjuvants to a patient receiving therapeutic administration of at least one agent appropriate for the treatment of pain. In a further aspect, the invention provides the use of compounds of formula (I) or (II) in the manufacture of a medicament for the therapeutic administration of adjuvants for the treatment of pain in a patient receiving therapeutic administration of at least an appropriate agent for the treatment of pain. The invention also provides compounds of formula (I) or (II) for use in the therapeutic administration of adjuvants for the treatment of pain in a patient receiving therapeutic administration of at least one agent appropriate for the treatment of pain.

In a further aspect, the invention provides a method of treating pain by therapeutic administration of adjuvants of at least one agent suitable for the treatment of pain to a patient receiving therapeutic administration of compounds of formula (I) or (II). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for the therapeutic administration of adjuvants. for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I) or (II). The invention also provides at least one agent suitable for the treatment of pain for the therapeutic administration of adjuvants for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I) or (II).

In a further aspect, the invention provides a method for treating pain by simultaneous therapeutic administration of compounds of formula (I) or (II) in combination with at least one agent suitable for the treatment of pain. The invention also provides the use of a combination of compounds of formula (I) or (II) and at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of pain. The invention also provides a combination of compounds of formula (I) or. (11). "and at least one agent appropriate for the treatment of pain for simultaneous therapeutic administration in the treatment of: pain. The invention also provides the use of compounds of formula (I) or (II) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention also provides compounds of formula (I) or (II) for use in the simultaneous therapeutic administration with at least one agent appropriate for the treatment of pain in the treatment of pain. The invention also provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or (II) in the treatment of pain. The invention also provides at least one agent suitable for the treatment of pain for simultaneous therapeutic administration with compounds of formula (I) or (II) in the treatment of pain.

Examples of agents suitable for the treatment of pain that are useful in the present invention include, but are not limited to: NSAIDs (nonsteroidal anti-inflammatory drugs), anticonvulsant drugs such as carbamazepine and gabapentin, sodium channel blockers, antidepressant drugs, cannabinoids and local anesthetics.

Suitable agents for use in combination with the compounds of the invention include for example celecoxib, etoricoxib, lumiracoxib, paracetamol, tramadol, methadone, venlafaxine, imipramine, duloxetine, buprppion, gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam, remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil, pethidine, diamorphine and butorphanol; Those skilled in the art will appreciate that the compounds according to the invention can be advantageously used in conjunction with one or more agents i ? Additional therapeutics, for example, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRIs), noradrenaline reuptake inhibitors (SNRIs), for its acronym in English), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5? -? antagonists, antagonists of I 5HT1 B, 5HT1 D antagonists, D1 agonists, agonists of 1 and / or anticonvulsant agents, as well as cognition enhancers.

Suitable 5HT3 antagonists which can be used in combination to the compounds of the invention include for example ondansetron, granisetron, metocloprajmide.

The right serotonin agonists that can be used using in combination the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.

Suitable SSRIs that can be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldin.

Suitable SNRIs that can be used in combination with the compounds of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants that can be used in combination with a compound of the invention i They include imipramine, amitriptyline, clomipramine and nortriptyline.

Suitable dopaminergic antidepressants that can be used in combination with a compound of the invention include bupropion and aminaptin.

Suitable anticonvulsant agents that can be used in combination to the compounds of the invention include for example divalproex, carbamazepine and diazepam.

The following examples serve to explain the invention without limiting it.

The compounds were characterized by mass spectroscopy, generally recorded by means of HPLC-MS in a rapid gradient on C18 material (electrospray ionization mode (ESI)).

Preparation Examples Example 1 : . { 2- (2- (1-methyl-1H-imidazol-4-ylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1-amine} 1. 1 7e "c-butyl-7- (hydroxymethyl) -3,4-dihydroisoquinolin-2 (1 H) -carboxylate To a solution of 0.245 mmol of 2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid in 2 ml of dry THF at room temperature 0.736 mmoles of dimethyl borane sulfide complex were added and stirred the mixture overnight. The mixture was diluted with EtOAc and washed with saturated Na 2 CO 3 solution and brine. The aqueous layer was extracted with EtOAc. The combined organic layers were washed, dried over MgSO4 and filtered. Evaporation of the solvent gave 60 mg of a pale yellow oil (93%).

ESI-MS [M + Na +] = 286 Calculated for G15H2iN03 = 263 1. 2 7-tert-butyl-7- (bromomethyl) -3,4-dihydroisoquinoline-2 (1 H) -i carboxylate To a solution of 0.380 mmoles of tert-butyl-7- (hydroxymethyl) -3,4-dihydroisoquinolin-2 (1 H) -arboxylate in 2.5 ml of CH2Cl2 at 0 ° C 1139 mmole of Et3N and 0.456 mmole of tribromophosphine were added. . The mixture was allowed to warm to room temperature and was stirred for 1 h. Saturated NaHCO3 solution and EtOAc were added to the reaction mixture.1 The aqueous layer was extracted with EtOAc. The combined organic layers were washed, dried over MgSO4 and filtered. The evaporation of the solvent gave 105 mg of the crude material which was purified by flash chromatography to yield 76 mg of colorless oil (61.3%).

ESI-MS [M + Na +] = 348/350 Calculated; for C15H20BrNO2 = 326 .3 7erc-butyl-7- (cyanomethyl) -3,4-dihydroisoquinolin-2 (1 H) -carbo'xylate To a solution of 21.76 mmoles of re-tert-butyl-7- (bromomethyl) -3,4-dihydroisoquinoline-2 (1 H) -carboxylate in 80 ml of DMF at 0 ° C was added 65.3 mmoles of sodium cyanide in small portions . The mixture was stirred at room temperature for 2 h. The brine solution was added to the mixture and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave 5.6 g of a brown oil. The material was purified by flash chromatography to yield 1.63 g of a yellow solid; (27.5%).

ESI-MS [M + Na +] = 295 Calculated for C 16 H 20 N 2 O 2 = 272 1.4 (Z) -ferc-butyl-7- (1-cyano-2-phenyl) inyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate To a solution of 0.231 mmoles of tert-butyl-7- (cyanomethyl) -3,4-dihydroisoquinoline-2 (1 H) -carboxylate in 2 ml of ethanol 0.278 mmoles of NaOEt solution (21%) and 0.254 mmoles were added. of benzaldehyde. The mixture was stirred at room temperature overnight. The mixture was diluted with ethanol and H20, and white precipitation was observed. The solid was filtered and washed with ethanol and H20. The white solid was dissolved in methanol. Evaporation of the solvent gave 64 mg (77%) of solid material.

ESI-MS [M + Na +] = 383 Calculated for C 23 H 24 2 O 2 = 360 1.5 7 ~ erc-butyl-7- (1-cyano-2-phenylethyl) -3,4-dihydroisoquinoline-2 (1 H) -carboxylate They were added to a suspension of 0.178 mmol of (Z) -tert-butyl-7- (1-cyano-2-phenylvinyl) -3,4-dihydroisoquinolin-2 (1 H) -carboxylate in 2 ml of ethanol at 0 °. C 0.178 mmoles of sodium borohydride. The mixture was allowed to warm to room temperature and stirred for 3 d. The mixture was poured into ice water and citric acid (5%) was added until acidity. The aqueous phase was eluted with EtOAc. The combined organic phase was washed with brine, dried over MgSO 4, and filtered. Evaporation of the solvent gave 61.2 mg (95%) of a slightly yellow crude oil, which appeared directly to the Boc deprotection. 1. 6 3-phenyl-2- (1, 2,3,4-tetrahydroisoquimolin-7-yl) propanenitrile 0.171 mmol of tert-butyl-7- (1-cyano-2-phenylethyl) -3,4-dihydroisoquinoline-2 (1 H) -carboxylate were dissolved in 1.3 ml of formic acid and stirred at room temperature for 1 h . i After the addition of saturated NaHCO 3 solution, the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4 and filtered. Evaporation of the solvent gave 38.5 mg of solid material (86%).

ESI-MS [M + H +] = 262 Calculated for Ci¿Hi8N2 = 263 1. 7 2- (2- (1-methyl-1 H-imidazol-4-ylsulphoryl) -1, 2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropanenitrile To a solution of 0.135 mmoies of 3-phenyl-2- (1, 2,3,4-tetrahydroisoquinolin-7-yl) propanenitrile in 2 ml of CH2Cl2 0.203 mmoies of DMAP and 0.162 mmoies of 1-methyl chloride were added. 1H-imidazole-4-sulfonyl. The mixture was stirred at room temperature for 3 h. An additional 0.162 mmoles of 1-methyl-1 H-imidazole-4-sulfonyl chloride was added and the mixture was stirred for 3 d. The mixture was diluted with CH2Cl2 and washed with 1 N HCl, saturated NaHCO3 and H20. The combined aqueous layers were extracted with CH2Cl2- The combined organic phase was dried over MgSO4 and filtered. Evaporation of the solvent gave 90 mg of the crude material. The material was purified by flash chromatography to yield 53 mg of a white solid (97%).

ESI-MS [M + H +] = 406 Calculated for C22H22N402S = 407 1.8 2- (1-methyl-1H-imidazol-4-ylsulfonyl) -1, 2,3,4-tetrah id roisoquinolin-7-yl -3-phenylpropan-1 -amine The synthesis was carried out from 0.123 mmoles of 2- (2- (1-methy1-1H-imidazol-4-ylsulfonyl) -1,2,3,4-tetrahydroquinoline-7-yl) -3- phenylpropanenitrile, which was dissolved in THF (1 ml), after which 0.37 mmoles of THF complex of BH3 (1 M in THF) were added at 0 ° C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with CH2Cl2 and washed with 1 N HCl, saturated NaHCO3 and H20. The aqueous phase was extracted with CH2Cl2. The combined organic phase was dried over MgSO4 and filtered. Evaporation of the solvent gave 50 mg of the crude material. The material was purified by flash chromatography to yield 11 mg of a white solid (22%).

ESI-MS [M + H +] = 41 1 Calculated for C22H26N402S = 410 Example 2. ¡ . { 2- (2- (1-methyl-1H-pyrazol-4-ylsulfonyl) -1, 2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1-amine} 2- (2- (1-Methyl-1 H -pyrazol-4-ylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1 -amine was prepared in analogy to Example 1 using 1-methyl-1 H-pyrazole-4-sulfonyl chloride in Place of 1-methyl-1 H-imidazole-4-sulfonyl chloride.

ESI-MS [M + H +] = 411 Calculated for C22H26N4O2S = 410. Example 3: 2- (2- (1-methyl-1 H -pyrazol-4-ylsulfonyl) -1, 2,3,4- i tetrahydroisoquinolin-7-yl) -3-phenylpropan-1-amine 3. 1 2- (2- (cyclopropylmethylsulfonyl) -1, 2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropanenitrile 2- (2- (Cyclopropylmethylsulfonyl) -1, 2,3,4- I was prepared tetrahydroisoquinolin-7-yl) -3-phenylpropanonitrile in analogy to example 1 using cyclopropylmethanesulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M + Na +] = 403 Calculated for C22H24N202S = 380 3. 2 2- (2- (1-methyl-1 H -pyrazol-4-ylsulfonyl) -1, 2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1-amine 2- (2- (Cyclopropylmethylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropanenitril in methanol was dissolved and hydrogenated using H-Cube technology (Raney-Ni cartridge, 1 bar, H2 complete). The reaction mixture was concentrated and 1N HCl was added. Then H20 and CH2Cl2 were added and extracted the aqueous phase by CH2Cl2. The aqueous phase was lyophilized and gave 2.8 mg (8.7%) of a hygroscopic solid.

ESI-MS [M + H +] = 385 Calculated for C22H28 2O2S = 384 Example 4: N, N-dimethyl-2- (2- (1-methyl-1 H-imidazol-4-ylsulfonyl) -1, 2,3,4-tet hydroisoquinolin-7-yl) -3-phenylpropan-1-amine 0.058 mmol of 2- (2- (1-methyl-1 H-imidazol-4-ylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1-amine was dissolved (Example 1 ) in 2 ml of methanol. A solution of formaldehyde (0.351 mmol, 37%) and 0.351 mmol of sodium cyanotrihydroborate were added and the mixture was stirred at room temperature overnight. H20 was added to the reaction mixture and the aqueous phase was extracted with CH2Cl2- The combined organic phases were dried over MgSO4 and filtered. The filtrate was concentrated to 6 mg of crude solid material. The solid was washed with diisopropyl ether and dissolved in methanol. An equimolar amount of 1 N HCl was added and the volatiles removed in vacuo. The residue was washed with diethyl ether, dissolved in H20, acidified with 1 N HCl and washed with additional diethyl ether. It was lyophilized the aqueous phase to give 4.6 mg of the desired product (16.5%). ESI-MS [M + H +] = 439 Calculated for C24H30N4O2S = 438 Example 5: N, N, N-trimethyl] -2- (2- (1-methy1-1 H -pyrazol-4-ylsulfonyl) -1,2,3,4-tetrahydro-psoquinolin-7-yl) iodide - 3-phenylpropan-1-amino 0.022 mmol of 2- (2- (1-methyl-1 H -pyrazol-4-ylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1-amine was dissolved (Example 2) ) in 1 ml of acetonitrile. To this solution were added 0.022 mmoles of iodomethane and 0.044 mols of cesium carbonate at room temperature and the mixture was stirred overnight. H20 and CH2Cl2 were added to the reaction mixture and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and filtered. The filtrate was concentrated to yield 4 mg of crude solid material. The solid was washed with diethyl ether and dried in vacuo. 0.5 mg of the desired product (4.6%) was obtained.

ESI-MS [M + H +] = 453 Calculated for C25H33N402S = 453 Biological test 1. [3 H] glycine absorption in recombinant CHO cells expressing human GlyT1: I Recombinant hGlyTI c_5_CH0 cells expressing human GlyTIc were plated at 20,000 cells per well in 96-well Cytostar-T scintillation microplates (Amersham Biosciences) and cultured under subconfluence for 24 h. For glycine absorption assays, the culture medium was aspirated and the cells were washed once with 100 μ? of HBSS (Gibco BRL, # 14025-050) with 5 nM L-allanine (Merck # 1007). 80 μ? of HBSS buffer, followed by 10 μ? of inhibitor or vehicle (10% of DIVISO) and ¡10 μ? of [3 H] -glycine (TRK71, Amersham Biosciences) at a final concentration of 200 nM for initiation of glycine uptake. Plates were placed in a Wallaca Microbeta (PerkinElmer) and counted continuously by solid phase scintillation spectrometry for up to 3 hours. The non-specific absorption was determined in the presence of 10 μ? of Org24598: Cl50 calculations were made by logistic non-linear regression analysis of four parameters (GraphPad Prism) using determinations within the linear increase range of the incorporation of [3H] - I glycine between 60 and 120 min. 2. Radioligand binding assay using recombinant CHO cell membranes expressing human GlyT1: The binding of the radioligand to membranes expressing the human GlyTIc transporter was determined as described in Mezler et al., Molecular Pharmacology 74: 1705-1715, 2008.

The following results were obtained with the compounds described in the examples: i Table 1:

Claims (53)

CLAIMS i j Fenalkylamine Derivatives of Formula (I) R is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms halogenated, tri- (alkyl of 1 to 4 carbon atoms) -silyl-alkyl of 1 to 4 carbon atoms, hydroxy-alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkyloxycarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkylaminocarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylaminocarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms 1 to 4 carbon atoms, (aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms optionally substituted) amino-alkyl of 1 to 4 carbon atoms, aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms optionally substituted, heterocyclyl of 3 to 12 carbon atoms-optionally substituted alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms halogenad, aryloxycarbonyl of 6 to 12 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 1 to 6 carbon atoms, (alkyl of 1 to 4 carbon atoms halogenated) aminocarbonyl, arylaminocarbonyl from 6 to 12 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms halogenated, hydroxyalkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, amino-alkoxy of 1 i to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, arylcarbonylamino of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, aryl of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated ) sulfonylamino-alkoxy of 1 to 4 carbon atoms, aryisulfonylamino of 6 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, (aryl of 6 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms) sulfonylamino -alkoxy of 1 to 4 carbon atoms, heterocyclylsulfonylamino of 3 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms-alkoxy of 1 to 4 carbon atoms, aryloxy of 6 to 12 carbon atoms, heterocyclyloxy of 3 to 12 carbon atoms, alkylthio of 1 to 6 carbon atoms , alkylthio of 1 to 6 carbon atoms halogenated, alkylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) amino, di-alkylamino of 1 to 6 carbon atoms, di- (a Iq ui) I or 1 to 6 carbon atoms halogenated) amino, alkylcarbonylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) carbonylamino, arylcarbonylamino of 6 to 12 carbon atoms, alkylsulfonylamino of 1 to 6 atoms of carbon, (alkyl of 1 to 6 carbon atoms halogenated) sulfonylamino, aryisulfonylamino of 6 to 12 carbon atoms or heterocyclyl of 3 I at 12 carbon atoms optionally substituted; W is -NR8- or a bond; ! A1 is optionally substituted C 1 -C 4 -alkylene or a bond; Q is -S (0) 2- or -C (O) -; 1 And it is -NR9- or a link; A2 is C 1 -C 4 -alkylene optionally substituted, C 1 -C 4 -alkylene, C 1 -C 4 -alkylene, C 1 -C 4 -alkyl, C 1 -C 4 -alkylene 1 to 4 carbon atoms, alkylene of 1 to 4 carbon atoms-NR10-alkylene of 1 to 4 carbon atoms, alkenylene of 2 to 4 carbon atoms optionally substituted, alkynylene of 2 to 4 carbon atoms optionally substituted. arylene of 6 to 12 carbon atoms optionally substituted, heteroarylene of 6 to 12 carbon atoms optionally substituted or a bond; X1 is -O-, -NR11-, -S-, or > CH2; X4 is -O-, -NR19-, -S-, or > CH2; i n is 0, 1, or 2; m is 0, 1, or 2; R6 is hydrogen, halogen, alkyl of 1 to 6 atoms of i carbon or alkoxy of 1 to 6 carbon atoms, or two R6 radicals together with the carbon atom to which they are attached form a carbonyl group; R2 is hydrogen, halogen, alkyl of 1 to 6 atoms I í carbon, alkyl of 1 to 4 carbon atoms! halogenated, hydroxy-alkyl of 1 to 4 carbon atoms, -CN, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms halogenated, alkoxycarbonyl of 1 to 6 carbon atoms, alkennioxy of 2 to 6 carbon atoms, arylated of 6 to 12 carbon atoms-alkoxy of 1 to 4 atoms of carbon, alkylcarbonyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 6 to 12 carbon atoms, aminosulfonyl, amino, alkylamino of 1 to 6 carbon atoms carbon, alkenylamino of 2 to 6 carbon atoms, nitro or heterocyclyl of 3 to 12 carbon atoms optionally substituted, or two radicals R 2 together with the ring atoms to which they are attached form a 5 or 6 membered ring; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; X2 is -O-, -NR7-, -S-, > CR12aR12b or a link; X3 is -O-, -NR7-, -S-, > CR13aR13b or a link; R5 is aryl of 6 to 12 carbon atoms optionally substituted, cycloalkyl of 3 to 12 carbon atoms optionally substituted or heterocyclyl of 3 to 12 carbon atoms optionally substituted; Y1 is > CR 4aR14b or a link; Y2 is > CR15aR15b; R a is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 halogenated carbon atoms, hydroxy-alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, CH 2 CN, aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, -CHO , alkylcarbonyl of 1 to 4 carbon atoms, (alkyl of 1 to 4 carbon atoms halogenated) carbonyl, arylcarbonyl of 6 to 12 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aryloxycarbonyl of 6 to 12 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, -C (= NH) NH2, -C (= NH) NHCN, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms carbon; amino, -NO or heterocyclyl of 3 to 12 carbon atoms; or: R a, R3 i together they are optionally substituted alkylene of 1 to 6 carbon atoms; or R4a R14a i together they are optionally substituted alkylene of 1 to 6 carbon atoms; R 4b is hydrogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, hydroxy-alkyl of 1 to 4 carbon atoms, alkoxy-alkyl of 1 to 6 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, CH2CN, -CHO, i alkylcarbonyl of 1 to 4 carbon atoms, (alkyl of 1 to 4 carbon atoms halogenated) carbonyl, arylcarbonyl of 6 to 12 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aryloxycarbonyl of 6 to 12 carbon atoms, alkylaminocarbonyl from 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, -C (= NH) NH2, -C (= NH), NHCN, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms carbon, amino, -NO or heterocyclyl of 3 to 12 carbon atoms; or R4a, R4b! together they are optionally substituted alkylene of 1 to 6 carbon atoms, wherein an alkylene -CH2- of 1 to 6 carbon atoms can be substituted by an oxygen atom or -NR16; or R7 is hydrogen or alkyl of 1 to 6 carbon atoms; R8 is hydrogen or alkyl of 1 to 6 carbon atoms; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, amino-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms. optionally substituted carbon or heterocyclyl of 3 to 12 carbon atoms; or R9, R1 together they are alkylene of 1 to 4 carbon atoms; or R9 is alkylene which is linked to carbon atom in A2 and A2 is alkylene of 1 to 4 carbon atoms; R10 is hydrogen, alkyl of 1 to 6 carbon atoms or alkylsulfonyl of 1 to 6 carbon atoms; R1 is hydrogen or alkyl of 1 to 6 carbon atoms, or R9, R11 together they are alkylene of 1 to 4 carbon atoms, R12 is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms-alkyl of 1 to 4 atoms carbon, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, optionally substituted aryl of 6 to 12 carbon atoms or hydroxy; R12 is hydrogen or alkyl of 1 to 6 carbon atoms, or together they are optionally substituted carbonyl or alkylene of 1 to 4 carbon atoms, where an alkylene -CH2- of 1 to 4 carbon atoms can be replaced by an oxygen atom or -NR17-; R13a is hydrogen, alkyl of 1 to 6 carbon atoms I optionally substituted, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, heterocyclyl of 3 to 12 carbon atoms- alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted or hydroxy; i R13b is hydrogen or alkyl, or 13a 13b together they are carbonyl or alkylene of 1 to 4 carbon atoms optionally substituted, wherein an alkylene -CH2- of 1 to 4 carbon atoms can be replaced by an oxygen atom or -NR18-; R14a is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 atoms carbon, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted or hydroxy; R1 d is hydrogen or alkyl of 1 to 6 carbon atoms, or p14a Rl4b together they are optionally substituted carbonyl or alkylene of 1 to 4 carbon atoms, wherein one or two -CH2- of alkylene of 1 to 4 carbon atoms can be replaced by an oxygen atom or -NR20-; R15a is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, di-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 atoms carbon, heterocyclyl of 3 to 12 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms optionally substituted or hydroxy; R 5d is hydrogen or alkyl of 1 to 6 carbon atoms, or p 15 to p 15 b together they are optionally substituted carbonyl or alkylene of 1 to 4 carbon atoms, wherein one or two alkylene -CH2- of

1 to 4 carbon atoms can be replaced by an oxygen atom or -NR20-; R16 is hydrogen or alkyl of 1 to 6 carbon atoms; R17 is hydrogen or alkyl of 1 to 6 carbon atoms; R18 is hydrogen or alkyl of 1 to 6 carbon atoms; R 9 is hydrogen or alkyl of 1 to 6 carbon atoms, Y R20 is hydrogen or alkyl of 1 to 6 carbon atoms, or a physiologically tolerated salt thereof.

2. Compound as claimed in claim 1, wherein -Y-A2- comprises at least 1 or 2 atoms in the main chain.

3. Compound as claimed in claim 1 or 2, wherein R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms halogenated , alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, C 1-6 alkylamino-C 1-4 -alkyl, C 1-6 -alkyloxycarbonylamino-C 1-6 -alkyl, C 1-6 -alkylaminocarbonylamino-C 1-4 alkyl carbon atoms, aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 6 carbon atoms, optionally substituted aryl of 6 to 12 carbon atoms, hydroxy, alkylamino of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms halogenated) amino, di-alkylamino of 1 to 6 carbon atoms or optionally substituted 3 to 12 carbon atoms with heterocyclyl

4. Compound as claimed in any of claims 1 to 3, wherein W is -N 8- and Y is a bond, or W is a bond and Y is -NR 9-. j

5. Compound as claimed in any of claims 1 to 4, wherein A1 is a link.

6. Compound as claimed in any of claims 1 to 4, wherein A1 is alkylene of 1 to 6 carbon atoms and W is -NR8-.

7. Compound as claimed in any of the where R, W, A1, Q, Y, A2, X1, X4, n, R6, R2, R3, X2, X3, R5, Y1, Y 'R 4a R 4b they are as defined in any of claims 1 to 6.!

8. Compound as claimed in claim 7, which has the formula! where R1, W, A1, Q, Y, A2, X1; X4, n, R6, R2, R3, X2, X3, R5, Y1, Y2, R4a, R4b are as defined in any of claims 1 to 6.

9. Compound as claimed in any of claims 1 to 8, wherein A2 is alkylene of 1 to 4 carbon atoms.

10. Compound as claimed in any of claims 1 to 8, wherein A2 is arylene of 6 to 12 carbon atoms selected from the group consisting of phen-1,4-ylene and phen-1,3-ylene, or heteroarylene of 6 to 12: carbon atoms selected from the group consisting of pyrid-2,5-ylene and pyrid-2,4-ylene.

11. Compound as claimed in any of claims 1 to 8, wherein X1 is -O- or -NR11, or X1 is > CH2 and A2 is a link.

12. Compound as claimed in any of claims 1 to 11, wherein R1-WA-QY-A2 is R1-S (0) 2-NH-A2, R1-NH-S (0) 2-A2, R-C ( 0) -NH-A2- or R1-NH-C (0) -A2-.

13. Compound as claimed in any of claims 1 to 12, wherein n is 1.

14. Compound as claimed in any of the claims 1 to 13, wherein X4 is -O- or -NR19-.

15. Compound as claimed in any of claims 1 to 6, which has the formula where R1, W, A1, Q, m, R6, FL2, R3, X2, X3, R5, Y1, Y2, R4a, R4b are as defined in any of claims 1 to 6.

16. Compound as claimed in claim 15, having the formula i where R1, W, A1, Q, m, R6, R2, R3, X ?, X3, R5, Y1, Y2, R4a, R4 are as defined in any of claims 1 to 6.

17. Compound as claimed in any of claims 1 to 6, 15 or 16, wherein R1-W-A1-Q- is R1-S (0) 2-NH-, R1-NH-S (0) 2-, R1-C (0) -NH- or R -NH-C (0) -.

18. Compound as claimed in any of the I claims 1 to 6, or 15 to 17, where m is 1 or 2. i

19. Compound as claimed in any of claims 1 to 18, wherein R6 is hydrogen.

20. Compound as claimed in any of claims 1 to 19, wherein R2 is hydrogen or i halogen

21. Compound as claimed in any of claims 1 to 20, wherein R3 is hydrogen.

22. Compound as claimed in any of claims 1 to 21, wherein X2 is CR aR12.

23. Compound as claimed in any of claims 1 to 22, wherein X3 is a bond.

24. Compound as claimed in any one of claims 1 to 23, wherein R12a is hydrogen or alkyl of 1 to 6 carbon atoms and R12 is hydrogen or alkyl of 1 to 6 carbon atoms. ,

25. Compound as claimed in any of claims 1 to 23, wherein R12a, R12b together are alkylene of 1 to 4 carbon atoms optionally substituted.

26. Compound as claimed in any of claims 1 to 25, wherein R5 is optionally substituted aryl or cycloalkyl of 3 to 12 carbon atoms i optionally substituted.

27. Compound as claimed in claim 26, which has the formula I 64 where R1, W, A1, Q, Y, A2, X1, X4, n, m, R6, R2, R3, X2, X3, Y1, Y2, R4a, R4b are as defined in any of claims 1 to 26; and R21a, 'R21b, R2 c, R2 d, R2 e are independently hydrogen, halogen, optionally substituted alkyl of 1 to 6 carbon atoms, alkylated of 1 to 6 halogenated carbon atoms, CN, hydroxy, alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms or heterocyclyl of 3 to 12 carbon atoms.

28. Compound as claimed in any of the claims 1 to 27, where Y1 is a bond.

29. Compound as claimed in any of claims 1 to 28, wherein Y2 is > CR 5aR 5b.

30. Compound as claimed in claim 1 to 29, wherein R 4a is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms halogenated carbon, amino-alkyl of 1 to 4 carbon atoms, CH2CN, aryl of 6 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, -CHO, alkylcarbonyl of 1 to 4 carbon atoms, (alkyl of 1) to 4 carbon atoms halogenated) carbonyl, arylcarbonyl of 6 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aryloxycarbonyl of 6 to 12 carbon atoms, -C (= NH ) NH2, -C (= NH) NHCN, alkylsulfonyl of 1 to 6 carbon atoms, amino, -NO or heterocyclyl of 3 to 12 carbon atoms.

31. Compound as claimed in any of claims 1 to 29, wherein R 4a, R 3 together are optionally substituted by alkylene of 1 to 4 carbon atoms.

32. Compound as claimed in any of claims 1 to 29, wherein R 4a, R 1 a together are alkylene of 1 to 4 carbon atoms optionally substituted.

33. Compound as claimed in claim 32, wherein R is hydrogen.

34. Compound as claimed in any of the i claims 1 to 33, wherein R4 is hydrogen or alkyl of 1 to 6 i carbon atoms.

35. Compound as claimed in any one of claims 1 to 29, wherein R4a, R4b together are optionally substituted C 1 -C 6 -alkylene, wherein an -CH 2 -alkylene of 1 to 4 carbon atoms can be replaced by a oxygen.

36. Compound as claimed in any of claims 1 to 35, wherein R15a is hydrogen and R15b is hydrogen.

37. Compound as claimed in any of claims 1 to 35, wherein R15a and R15b together are carbonyl.

38. Compound as claimed in any of claims 1 to 37, wherein R9 is hydrogen or alkyl of 1 to 6 carbon atoms. '

39. Compound as claimed in any of claims 1 to 38, wherein R19 is hydrogen or alkyl of 1 to 6 carbon atoms.

40. Compound as claimed in claim 1, which is a compound of formula (I) wherein R1 is alkyl of 1 to 6 carbon atoms or heterocyclyl of 3 to 12 carbon atoms optionally substituted; W is a link; A1 is a link; Q is -S (0) 2-; i i And it's NR9; ' A2 is alkylene of 1 to 4 carbon atoms - X1 -O- I X4 -O- or NR19; n is 1; R6 is hydrogen; R2 is hydrogen; i R3 is hydrogen;; X2 is CR12aR b; X3 is a link; R5 is phenyl; Y1 is a link; Y2 is > CR 5aR15b; i R4a is hydrogen;; R4b is hydrogen; R1 a is hydrogen; R12 is hydrogen; R 5a is hydrogen; R15 is hydrogen; Y R19 is alkyl of 1 to 6 carbon atoms.

41. Compound as claimed in claim 1, i which is a compound of formula (II) where R1 is cycloalkyl of 3 to 12 carbon atoms-alkyl of 1 to 4 carbon atoms, or heterocyclyl of 3 to 12 optionally substituted carbon atoms; W is a link; A1 is a link; Q is -S (0) 2- or -C (O) -; m is 1 or 2; R6 is hydrogen; R2 is hydrogen; R3 is hydrogen; Y1 is a link; Y2 is > CR15aR15; 1 R a is hydrogen, or alkyl of 1 to 6 carbon atoms; R4b is hydrogen or alkyl of 1 to 6 carbon atoms; X2 is CR12aR12; ! X3 is a link; , R5 is phenyl; R12a is hydrogen; R12b is hydrogen; R15a is hydrogen; Y R 5b is hydrogen.

The compound as claimed in the claim 1, which is: 2- (2- (1-methyl-1 H-imidazol-4-ylsulfonyl) -1,2,3,4-tetrahydroquinquinolin-7-yl) -3-phenylpropan-1-amine; 2- (2- (1-methyl-1 H-pi) -l-4-ylsulphonyl) -1, 2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1 -amine; 2- (2- (1-methyl-1 H -pyrazol-4-ylsulfonyl) -1, 2,3,4- tetra h id roisoquinolin-7-yl) -3-phenylpropan-1 -amine; N, N-dimethyl-2- (2- (1-methyl-1 H-imidazol-4-ylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-phenylpropan-1 -amine; N, N, N-trimethyl-2- (2- (1-methyl-1 H -pyrazol-4-ylsulfonyl) -1, 2,3,4-tetrahydroquinoline-7-yl) -3-phenylpropan -1-amino; or a salt physiologically tolerated thereof.

43. The compound as claimed in any of claims 1 to 42, for use in therapy.

44. The pharmaceutical composition comprising an i carrier and a compound of any of claims 1 to 42.

45. A method for inhibiting the glycine transporter GlyT1 in a mammal in need of the drug which comprises the administration of an effective amount of a compound of any of claims 1 to 42.

46. The use of a compound of any of claims 1 to 42, in the manufacture of a medicament for inhibiting the GLyT1 glycine transporter. i

47. A method for treating a neurological or psychiatric disorder or pain in a mammalian patient in need of miso comprising administering to the patient a therapeutically effective amount of a compound of any of claims 1 to 42. i

48. The use of a compound of any of claims 1 to 42, in the manufacture of a medicament for I 170 treat a neurological or psychiatric disorder or pain.

49. The compound of any of claims 1 to 42, for use in a method for treating a neurological or psychiatric disorder or pain.

50. The method, use or compound as claimed in I any of claims 43 to 49, wherein the disorder is associated with glycinergic or glutamatergic neurotransmission dysfunction.

51. The method, use or compound as claimed in any of claims 43 to 50, wherein the neurological disorder is a cognitive disorder such as dementia, cognitive impairment, or attention deficit disorder. I

52. The method, use or compound as claimed in claim 51, wherein the attention deficit disorder is an attention deficit hyperactivity disorder.

53. The method, use or compound as claimed in any of any of claims 43 to 50, wherein the psychiatric disorder is an anxiety disorder, a mood disorder such as depression, biplar disorder, schizophrenia, or a psychotic disorder.