6,7,8,9-tetrahydro-5h-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them   

Abstract: The present invention relates to compounds defined by formula (I), wherein the groups X, Y, W and R1 to R4 are defined as in claim 1, possessing valuable pharmacological activity. Particularly the compounds are agonists of the 5-HT2C receptor, and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this receptor, such as metabolic and CNS-related disorders.

FIELD OF THE INVENTION

The present invention relates to novel 6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives that are modulators of the 5-HT2C receptor, to processes for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful for treatment of 5-HT2C receptor-associated diseases, conditions or disorders, such as, obesity and related CNS-related disorders.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine which plays a prominent role in a variety of physiological functions in both the central nervous system (CNS) and the periphery of the body. These pleiotropic effects are mediated by at least 14 different receptors which are grouped into seven families (5-HT1-7) according to their primary structure and their intracellular signal transduction coupling systems (Hoyer, D., et al., Pharmacol Biochem Behav, 2002. 71(4): p. 533-54). With the exception of the 5-HT3 receptor, which is an ion channel, all serotonin receptors are G-protein coupled receptors (GPCRs).

The 5-HT2 receptor family consists of 5-HT2A, 5-HT2B, and 5-HT2C receptors. A number of studies suggest that the 5-HT2C receptor system is specifically involved in diseases or conditions such as the metabolic syndrome including obesity, type II diabetes, and dyslipidemia, as well as CNS-related disorders including depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as, but not limited to, type II diabetes, hypertension, stroke, certain forms of cancers and gallbladder disease. Obesity has become a major healthcare issue in the Western World and increasingly in some third world countries. The increase in the number of obese people is due largely to the increasing preference for high fat content foods but also, and this can be a more important factor, the decrease in activity in most people\'s lives. In the last 10 years there has been a 30% increase in the incidence of obesity in the USA and that about 30% of the population of the USA is now considered obese. In spite of the growing awareness of the health concerns linked to obesity the percentage of individuals that are overweight or obese continue to increase. In fact, the percentage of children and adolescents who are defined as overweight has more than doubled since the early 1970s and about 13 percent of children and adolescents are now seriously overweight. The most significant concern, from a public health perspective, is that children who are overweight grow up to be overweight or obese adults, and accordingly are at greater risk for major health problems. Therefore, it appears that the number of individuals that are overweight or obese will continue to increase. Whether someone is classified as overweight or obese is generally determined on the basis of his or her body mass index (BMI) which is more highly correlated with body fat than any other indicator of height and weight. A person is considered overweight when they have a BMI in the range of 25-30 kg/m2, whereas a person with a BMI over 30 kg/m2 is classified as obese. Obesity is further divided into three classes, Class I (BMI of about 30 to about 34.9 kg/m2), Class II (BMI of about 35 to 39.9 kg/m2) and Class III (about 40 kg/m2 or greater). There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.

It has been recognized that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, “Obesity: Trends and Treatments”, Scrip Reports, PJB Publications Ltd, 1996). As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (hypertension, coronary insufficiency, coronary heart disease, angina pectoris, congestive heart failure, atheromatous disease, cardiac insufficiency), high blood cholesterol, dyslipidemia, type II (non-insulin dependent) diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, stroke, gall bladder disease (particularly gallstones and cancer), cholescystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, some types of cancer (such as endometrial, breast, prostate, and colon), complications of pregnancy, poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation), diseases of reproduction (such as sexual dysfunction, both male and female, including male erectile dysfunction), bladder control problems (such as stress incontinence), uric acid nephrolithiasis, psychological disorders (such as depression, eating disorders, distorted body image, and low self esteem). Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

As the 5HT2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5HT2C receptor agonist can be an effective and safe pharmaceutical agent. Also, 5HT2C knockout mice are overweight with cognitive impairment and susceptibility to seizure thus establishing the clear use for a 5HT2C receptor agonist in 5HT2C receptor associated diseases or disorders. The 5HT2C receptor plays a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, 5HT2C receptor agonists can have anti-panic properties, and properties useful for the treatment of sexual dysfunction. In addition, 5HT2C receptor agonists are useful for the treatment of psychiatric symptoms and behaviors in individuals with eating disorders such as, but not limited to, anorexia nervosa and bulimia nervosa. Individuals with anorexia nervosa often demonstrate social isolation. Anorexic individuals often present symptoms of being depressed, anxious, obsession, perfectionistic traits, and rigid cognitive styles as well as sexual disinterest. Other eating disorders include, anorexia nervosa, bulimia nervosa, binge eating disorder (compulsive eating) and ED-NOS (i.e., eating disorders not otherwise specified-an official diagnosis). An individual diagnosed with ED-NOS possess atypical eating disorders including situations in which the individual meets all but a few of the criteria for a particular diagnosis. What the individual is doing with regard to food and weight is neither normal nor healthy.

The first line of treatment for individuals that are overweight or obese is to offer diet and life style advice, such as, reducing the fat content of their diet and increasing their physical activity. However many patients find these difficult to maintain and need additional help from drug therapy to sustain results from these efforts.

Compounds marketed as anti-obesity agents include Orlistat and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhea. Sibutramine (a mixed 5-HT/noradrenalin reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine and dexfenfluramine have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.

The compounds of formula (I) are useful in the treatment and/or prevention of disorders involving elevated plasma blood glucose, particularly diabetes mellitus (including Type II or non-insulin dependent diabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus (IDDM); and Type III or malnutrition-related diabetes). The diabetes maybe diabetes secondary to pancreatic disease; or diabetes related to steroid use. The compounds of formula (I) are also useful in the treatment and/or prevention of the sequelae of hyperglycemia; in the treatment and/or prevention of diabetic complications; and in the treatment of insulin dependence. The invention is of particular use in the treatment or prevention of diabetes mellitus (including Type II or non-insulin dependent diabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus (IDDM); and Type III or malnutrition-related diabetes), and particularly in the treatment or prevention of Type II diabetes.

Diabetes has also been implicated in the development of severe sequelae such as kidney disease, eye diseases and nervous-system problems. Kidney disease, also called nephropathy, occurs when the kidney\'s “filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina and increases the risk of cataracts and glaucoma Finally, diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the leading causes of death.

It is an object of this invention to provide selective, directly acting 5-HT2 receptor ligands, hereinafter described as compounds of formula (I), for use in prevention and/or treatment of metabolic and CNS-related disorders, particularly diabetes, obesity, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy. It is a further object of this invention to provide selective, directly acting 5-HT2C receptor ligands, preferably 5-HT2C receptor agonists, for use in therapy and particularly for use as anti-obesity agents and diseases/disorders mentioned above.

SUMMARY

In one aspect the invention provides a compound of formula I:

as defined hereinafter, the isoforms, tautomers, stereoisomers, solvates, hydrates, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, or the combinations thereof.

The present invention further provides a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The present invention further provides a method of modulating a 5HT2C receptor comprising contacting the receptor with a compound of formula (I).

The present invention further provides a method of treating disorders of the central nervous system, damage to the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, sleep apnea or HDL-related condition comprising administering to a patient in need of the treating a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of decreasing food intake of a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of inducing satiety in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of controlling weight gain of a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of treating obesity comprising administering to a patient in need of such treating a therapeutically effective amount of a compound of formula (I).

The present invention further provides a compound of formula (I), as described herein, for use in a method of treatment of the human or animal body by therapy.

The present invention further provides compounds of formula (I) for treatment or prevention of diseases or conditions which can be influenced by modulating the 5-HT2C receptor, such as metabolic and CNS-related disorders, particularly Type II diabetes, obesity, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

The present invention further provides the use of a compound of formula (I) for preparing a pharmaceutical composition which is suitable for the treatment or prevention or diseases or conditions which can be influenced by modulating 5-HT2C receptor activity, such as metabolic and CNS-related disorders, particularly diabetes, obesity, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

In some embodiments, disorders of the central nervous system include, for example, depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, agressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension. In some embodiments, sexual dysfunction is male erectile dysfunction.

DETAILED DESCRIPTION

The present invention provides in its broadest/first embodiment E-0 a compound of formula (I):

wherein: X denotes a divalent 4- to 10-membered monocylic, 7- to 12-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a carbocycle, a monoaza-heterocycle and a diaza-heterocycle, which is linked to the adjacent groups via carbon atoms or, if present, via nitrogen atoms, e.g. via one carbon and one nitrogen atom or via two nitrogen atoms,  wherein 1 or 2 —CH2— groups optionally are replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or  1 —CH2— group optionally is replaced by the divalent group >C═C(Rx)2, wherein Rx independently denotes H or C1-3-alkyl, and/or  wherein in an unsaturated group 1 double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or  wherein in any of the resulting groups one or two carbon atoms optionally and independently are substituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-C1-6-alkyl, thiohydroxy, C1-6-alkylthio, C3-6-alkenylthio, C3-6-alkynylthio, amino, C1-6-alkyl-amino, C3-6-alkenyl-amino, C3-6-alkynyl-amino, di-(C1-6-alkyl)-amino, di-(C3-6-alkenyl)-amino, di-(C3-6-alkynyl)-amino, amino-C1-6-alkyl, C1-3-alkyl-amino-C1-6-alkyl, di-(C1-3-alkyl)-amino-C1-6-alkyl, amino-C3-6-alkenyl, C1-3-alkyl-amino-C3-6-alkenyl, di-(C1-3-alkyl)-amino-C3-6-alkenyl, amino-C3-6-alkynyl, C1-3-alkyl-amino-C3-6-alkynyl, di-(C1-3-alkyl)amino-C3-6-alkynyl, hydroxycarbonyl, C1-6-alkyl-carbonyl, C2-6-alkenyl-carbonyl, C2-6-alkynyl-carbonyl, formyl, C1-6-alkoxy-carbonyl, C3-6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino, C2-6-alkenyl-carbonylamino, C2-6-alkynyl-carbonylamino, C1-6-alkyl-sulphonyl, C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-sulphinyl, C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, C1-6-alkyl-sulphonylamino, C2-6-alkenyl-sulphonylamino, C2-6-alkynyl-sulphonylamino, aminosulphonyl, C1-6-alkylaminosulphonyl, di-(C1-6-alkyl)-aminosulphonyl, C3-6-alkenylaminosulphonyl, di-(C3-6-alkenyl)-aminosulphonyl, C3-6-alkynylaminosulphonyl, or di-(C3-6-alkynyl)-amino sulphonyl groups, while the substituents may be identical or different, and/or  wherein one ring member nitrogen atom optionally is substituted by a C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, hydroxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-C1-6-alkyl, C1-6-alkyl-carbonyl, C2-6-alkenyl-carbonyl, C2-6-alkynyl-carbonyl, formyl, C1-6-alkoxy-carbonyl, C3-6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, C1-6-alkyl-sulphonyl, C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-sulphinyl, C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, aminosulphonyl, phenyl or phenyl-C1-3-alkyl group, Y is absent or denotes a —(CH2)n— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 or 2 —CH2— groups optionally are replaced independently by O, S, carbonyl, sulfonyl, or —NH—, with the proviso that two heteroatoms are not directly linked together, or  wherein 1 —CH2— group is replaced by O, S, carbonyl, sulfonyl, or —NH—, and additionally a —CH2—CH2— subgroup is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, or —NH—C(O)—, with the proviso that two heteroatoms are not directly linked together, and  wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C3-6-cycloalkyl or phenyl group, or by a straight-chained or branched C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, phenyl-C1-6-alkyl, C1-6-alkyl-carbonyl, or C1-6-alkyl-sulphonyl group, and/or  wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are replaced by halogen atoms, trifluoromethyl, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, phenyl, phenyl-C1-6-alkyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkyl-carbonyl, C1-6-alkoxy-carbonyl, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C1-6-alkyl-sulphonyl groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH2)m— bridge, wherein m is 2, 3, 4, or 5, W denotes H or an optionally substituted straight-chained or branched C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group, wherein 1 or 2 methyl groups optionally are replaced by optionally substituted phenyl groups or  an optionally substituted cyclo-C3-9-alkyl group, wherein independently in a cyclo-C4-9-alkyl group 2 hydrogen atoms attached to adjacent carbon atoms optionally are replaced to form a double bond within the ring, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and the resulting group is bound via a saturated or unsaturated carbon atom, or in a cyclo-C4-9-alkyl group 2 hydrogen atoms attached to the same carbon atom (relative 1,1-position) optionally are replaced by a C2-5-alkylenyl bridge or 2 hydrogen atoms attached to carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally are replaced by a C1-5-alkylenyl bridge, wherein any of the resulting polycyclic groups one or two —CH2— groups optionally are replaced by —NH— (or N-atoms for replacement of —CH< members), >N—(C1-6-alkyl), O, S, carbonyl, or sulfonyl, and/or two —CH2— groups in relative 1,3-position within a C4-5-alkylenyl bridge optionally are replaced by O atoms, and/or 2 hydrogen atoms attached to adjacent carbon atoms within a C4-5-alkylenyl bridge optionally are replaced to form a double bond, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and/or in a cyclo-C4-8-alkyl group one, two or three ring members optionally are replaced independently of each other by —NH—, >N—(C1-6-alkyl) (or N-atoms for replacement of —CH< members), O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and additionally but optionally 2 or 4 hydrogen atoms attached to adjacent ring carbon atoms are replaced to form a double bond or two conjugated double bonds within the ring, either of the double bonds optionally being condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and any of the resulting groups is bound via a saturated or unsaturated carbon atom or a nitrogen atom,  and wherein any of the resulting open-chained or cyclic groups independently 1 to 4 hydrogen atoms optionally are replaced by C1-6-alkyl or C1-6-alkoxy groups, and/or  any 1 to 6 hydrogen atoms attached to carbon atoms optionally are replaced by fluorine atoms, or W denotes an optionally substituted aryl or hetaryl group,  an optionally substituted cyclo-C3-8-alkyl-aryl or cyclo-C3-8-alkyl-hetaryl group, wherein the cyclo-C5-8-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or N-atoms for replacement of —CH< members), >N(C1-3-alkyl), O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, or if Y is absent W additionally denotes  a divalent —(CH2)p— group, wherein p is 2, 3, 4, 5, 6 or 7, attached in relative 1,1-position (geminal) to a carbon atom of group X, including the options: if p is 3, 4, 5, 6 or 7 it follows that 1 —CH2— group optionally is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C1-6-alkyl), or if p is 4, 5, 6 or 7 it follows that a —CH2—CH2— group optionally is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—N(C1-6-alkyl), —N(C1-6-alkyl)-C(O)—, or —CH═CH—, wherein the double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group,  a divalent —(CH2)q— group, wherein q is 3, 4, or 5, attached in relative 1,2-position (vicinal) to carbon atoms of group X, including the options: that 1 —CH2— group optionally is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C1-6-alkyl)-, or a —CH2—CH2— group optionally is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—N(C1-6-alkyl), —N(C1-6-alkyl)-C(O)—, or that in the resulting 5-, 6- and 7-membered carbocyclic ring 2, 4 or 6 hydrogen atoms optionally are replaced by 1, 2 or 3 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, wherein 1 —CH2— group optionally is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C1-6-alkyl), and/or one —CH═ unit is replaced by —N═,  a divalent —(CH2)r— group, wherein r is 5, 6 or 7, attached in relative 1,3-position to carbon atoms as binding sites of group X, including the options: that in the resulting 8-, 9- or 10-membered carbocyclic ring 2, 4, 6, 8 or 10 hydrogen atoms optionally are replaced by 1, 2, 3, 4 or 5 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, and/or that in the resulting 8-, 9- or 10-membered carbocyclic ring 1 hydrogen atom attached to the carbon atom in position 2 relative to the binding sites of group X and 1 hydrogen atom attached to a carbon atom of the —(CH2)r— group in position 6 or 7 relative to the binding sites of group X optionally are replaced by a bond (C0-bridge) to form a bicyclic ring system condensed with the group X, R1 denotes H, C1-6-alkyl, C3-6-alkenyl or C3-6-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, hydroxy, C1-3-alkoxy or cyclo-C3-7-alkyl-group, R2 and R3 independently denote H, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, hydroxy or C1-6-alkoxy, any of those C1-6-alkyl, C2-6-alkenyl or C3-6-alkynyl groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano or cyclo-C3-7-alkyl-group, R4 and R5 independently denote H, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, hydroxy or C1-3-alkoxy, any of those C1-6-alkyl, C2-6-alkenyl or C3-6-alkynyl groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, by a cyano, hydroxy, C1-3-alkoxy, or cyclo-C3-5-alkyl-group, or by a phenyl or pyridyl group both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C1-6-alkyl, cyclo-C3-7-alkyl, cyano, hydroxy, C1-6-alkoxy, amino, C1-6-alkyl-amino, or di-(C1-6-alkyl)-amino groups, wherein, if not specified otherwise, any alkyl groups or subgroups mentioned hereinbefore are straight-chained or branched, and the isoforms, tautomers, stereoisomers, solvates, hydrates, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, or the combinations thereof.

The term “aryl” as used herein, either alone or in combination (e.g. as a sub-moiety) with another substituent, if not otherwise specified means either an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms, for example a phenyl or a naphthyl group. Any of the aryl groups mentioned hereinbefore is optionally substituted, if not otherwise specified.

The term “hetaryl” as used herein, either alone or in combination (e.g. as a sub-moiety) with another substituent, if not otherwise specified denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic hetaryl rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, which contain sufficient conjugated double bonds that an aromatic system is formed. The ring may be linked to the molecule through a carbon atom or, if present, through a nitrogen atom. Any of the hetaryl groups mentioned hereinbefore is optionally substituted, if not otherwise specified, including substitution at carbon atoms and/or a nitrogen atom. The following are examples of five- or six-membered heterocyclic aromatic groups:

Examples of 5-10-membered bicyclic hetaryl rings include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyrane, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

The expression “substituted” or “optionally substituted” as used herein, if not otherwise specified, means that any one or more hydrogen atoms attached to the designated carbon or nitrogen atom is or optionally is replaced by a lower-molecular group, provided that the designated atom\'s normal valence is not exceeded and that the substitution results in a stable compound. In connection with aryl or hetaryl groups this expressions includes at least mono- di- and trisubstitution. Examples of lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds. For example the groups may comprise: straight-chain or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups; aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may in turn be substituted by functional groups; a number of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups.

More specifically, the expression “substituted” or “optionally substituted” as used herein means substitution with a group selected from the indicated substituents or, if not otherwise specified, with one, two, three, four or more substituents attached to carbon atoms selected from the group consisting of halogen atoms (fluorine, chlorine, bromine or iodine atoms), C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-8-alkyl, cyclo-C3-7-alkenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-C1-6-alkyl, C3-6-alkenoxy-C3-6-alkenyl, C3-6-alkenoxy-C3-6-alkynyl, C3-6-alkynoxy-C1-6-alkyl, C3-6-alkynoxy-C3-6-alkenyl, C3-6-alkynoxy-C3-6-alkynyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidino, piperidino, thiohydroxy, C1-6-alkylthio, C3-6-alkenylthio, C3-6-alkynylthio, amino, C1-6-alkyl-amino, C3-6-alkenyl-amino, C3-6-alkynyl-amino, di-(C1-6-alkyl)-amino, di-(C3-6-alkenyl)-amino, di-(C3-6-alkynyl)-amino, amino-C1-6-alkyl, C1-3-alkyl-amino-C1-6-alkyl, di-(C1-3-alkyl)-amino-C1-6-alkyl, amino-C3-6-alkenyl, C1-3-alkyl-amino-C3-6-alkenyl, di-(C1-3-alkyl)-amino-C3-6-alkenyl, amino-C3-6-alkynyl, C1-3-alkyl-amino-C3-6-alkynyl, di-(C1-3-alkyl)amino-C3-6-alkynyl, hydroxycarbonyl, phenyl, phenyl-C1-3-alkyl, phenyloxy, phenyl-C1-3-alkoxy, phenyloxy-C1-3-alkyl, phenylcarbonyl, pyridyl, thiazolyl; pyridylcarbonyl, C1-6-alkyl-carbonyl, C2-6-alkenyl-carbonyl, C2-6-alkynyl-carbonyl, formyl, C1-6-alkoxy-carbonyl, C3-6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C2-6-alkenyl-carbonylamino, C2-6-alkynyl-carbonylamino, formyl-C1-6-alkyl-amino, formyl-C3-6-alkenyl-amino, formyl-C3-6-alkynyl-amino, C1-6-alkyl-carbonyl-C1-6-alkyl-amino, C2-6-alkenyl-carbonyl-C1-6-alkyl-amino, C2-6-alkynyl-carbonyl-C1-6-alkyl-amino, C1-6-alkyl-carbonyl-C3-6-alkenyl-amino, C2-6-alkenyl-carbonyl-C3-6-alkenyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkenyl-amino, C1-6-alkyl-carbonyl-C3-6-alkynyl-amino, C2-6-alkenyl-carbonyl-C3-6-alkynyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkynyl-amino, C1-6-alkyl-sulphonyl, C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-sulphinyl, C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, C1-6-alkyl-sulphonylamino, C2-6-alkenyl-sulphonylamino, C2-6-alkynyl-sulphonylamino, C1-6-alkyl-sulphonyl-C1-6-alkylamino, C1-6-alkyl-sulphonyl-C3-6-alkenylamino, C1-6-alkyl-sulphonyl-C3-6-alkynylamino, C2-6-alkenyl-sulphonyl-C1-6-alkylamino, C2-6-alkenyl-sulphonyl-C3-6-alkenyl amino, C2-6-alkenyl-sulphonyl-C3-6-alkynylamino, C2-6-alkynyl-sulphonyl-C1-6-alkylamino, C2-6-alkynyl-sulphonyl-C3-6-alkenylamino, C2-6-alkynyl-sulphonyl-C3-6-alkynylamino, aminosulphonyl, C1-6-alkylaminosulphonyl, di-(C1-6-alkyl)aminosulphonyl, C3-6-alkenylaminosulphonyl, di-(C3-6-alkenyl)-aminosulphonyl, C3-6-alkynylaminosulphonyl and di-(C3-6-alkynyl)-aminosulphonyl groups, while the substituents may be identical or different and wherein any alkyl groups or alkyl sub-moieties optionally are partially or fully fluorinated, e.g. a CH3-substituent or methyl sub-moiety within the substituents mentioned herein is meant to include the corresponding fluoro-analogs such as the CFH2—, CF2H— and CF3— group, and wherein any phenyl, pyridyl and thiazolyl groups or phenyl-, pyridyl and thiazolyl-submoieties optionally are substituted with 1 or 2 substituents independently of each other selected from fluorine, chlorine, bromine, iodine, C1-3-alkyl, C1-3-alkoxy, amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino C1-3-alkylcarbonyl-amino, C1-3-alkylcarbonyl-C1-3-alkyl-amino, cyano or hydroxy, and with substituents attached to a nitrogen atom selected from the group consisting of C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, cyclo-C3-7-alkyl-C1-6-alkyl, pyrrolidino, piperidino, morpholino, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyano, hydroxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-C1-6-alkyl, C3-6-alkenoxy-C3-6-alkenyl, C3-6-alkenoxy-C3-6-alkynyl, C3-6-alkynoxy-C1-6-alkyl, C3-6-alkynoxy-C3-6-alkenyl, C3-6-alkynoxy-C3-6-alkynyl, amino-C1-6-alkyl, C1-3-alkyl-amino-C1-6-alkyl, di-(C1-3-alkyl)-amino-C1-6-alkyl, amino-C3-6-alkenyl, C1-3-alkyl-amino-C3-6-alkenyl, di-(C1-3-alkyl)-amino-C3-6-alkenyl, amino-C3-6-alkynyl, C1-3-alkyl-amino-C3-6-alkynyl, di-(C1-3-alkyl)-amino-C3-6-alkynyl, hydroxycarbonyl, phenyl, phenyl-C1-6-alkyl, phenylcarbonyl, pyridyl, pyridylcarbonyl, C1-6-alkyl-carbonyl, C2-6-alkenyl-carbonyl, C2-6-alkynyl-carbonyl, C1-6-alkoxy-carbonyl, C3-6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, C1-6-alkyl-sulphonyl, C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-sulphinyl, C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, aminosulphonyl, C1-6-alkylaminosulphonyl, di-(C1-6-alkyl)-aminosulphonyl, C3-6-alkenylaminosulphonyl, di-(C3-6-alkenyl)aminosulphonyl, C3-6-alkynylaminosulphonyl and di-(C3-6-alkynyl)-aminosulphonyl groups, while the substituents may be identical or different and wherein any alkyl groups or alkyl sub-moieties optionally are partially or fully fluorinated, e.g. a CH3— substituent or methyl sub-moiety within the substituents mentioned herein is meant to include the corresponding fluoro-analogs such as the CFH2—, CF2H— and CF3— group, and wherein any of the di-(C1-3-alkyl)-amino or di-(C1-6-alkyl)-amino moieties may form optionally with the nitrogen atom a 4 to 8 membered ring system, and wherein any phenyl and pyridyl groups or phenyl- and pyridyl-submoieties optionally are substituted with 1 or 2 substituents independently of each other selected from fluorine, chlorine, bromine, iodine, C1-3-alkyl, C1-3-alkoxy, amino, C1-3-alkyl-amino, C1-3-alkylcarbonyl-amino, cyano or hydroxy.

The expressions “prevention”, “prophylaxis”, “prophylactic treatment” or “preventive treatment” used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or a CNS-related disorder mentioned herein. Thus the expression “prevention of a disease” as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.

The expression “treatment” or “therapy” means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression “treatment of a disease” as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

Further preferred embodiments of the invention are characterized by the following definitions:

a) Definitions (ai) for X in the order of preference, ascending from preferably (a1) to more preferably (a2) up to most preferably (a6): (a1): According to a first preferred embodiment, X is defined as mentioned hereinbefore under the broadest/first embodiment of the invention E-0. (a2): According to a second preferred embodiment, X denotes a divalent 4- to 8-membered monocylic, 7- to 10-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a carbocycle, a monoaza-heterocycle and a diaza-heterocycle, which is linked to the adjacent groups via carbon atoms or, if present, via nitrogen atoms, e.g. via one carbon and one nitrogen atom or via both nitrogen atoms,  wherein 1 to 2 —CH2— groups optionally are replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or  wherein 1 double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or  wherein in all groups falling under the above definition of X one or two carbon atoms optionally and independently are substituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkenyl, phenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl-carbonyl, formyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino C2-6-alkenyl-carbonylamino or C2-6-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or,  wherein one ring member nitrogen atom optionally is substituted by a C1-3-alkyl, cyclo-C3-6-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-3-alkoxy-carbonyl or C1-3-alkyl-sulphonyl group. (a3): According to a third preferred embodiment, X denotes a divalent phenyl group or a group selected from formulas (II) to (XIII),

 wherein 1 —CH2— group optionally is replaced by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or  wherein a double bond, if present, optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or  wherein in all groups falling under the above definition of X one or two carbon atoms optionally and independently are substituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl-carbonyl, formyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino C2-6-alkenyl-carbonylamino or C2-6-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or,  wherein one ring member nitrogen atom, if present, optionally is substituted by a C1-3-alkyl, cyclo-C3-6-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-3-alkoxy-carbonyl or C1-3-alkyl-sulphonyl group. (a4): According to a fourth preferred embodiment, X denotes a divalent phenyl group or a group selected from formulas (II-XIII) mentioned under embodiment (a3),  which is linked to the adjacent groups of formula (I) via carbon atoms or, if present, via nitrogen atoms, e.g. via one carbon and one nitrogen atom or via both nitrogen atoms,  wherein 1 —CH2— group optionally is replaced by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or  wherein a double bond, if present, optionally is condensed with a phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl group, and/or  wherein in all groups falling under the above definition of X one or two carbon atoms optionally and independently are substituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl-carbonyl, formyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino C2-6-alkenyl-carbonylamino or C2-6-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or,  wherein one ring member nitrogen atom, if present, optionally is substituted by a C1-3-alkyl, cyclo-C3-6-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-3-alkoxy-carbonyl or C1-3-alkyl-sulphonyl group. (a5): According to a fifth preferred embodiment, X denotes a group selected from formulas (II), (III), (VI) or (XIII) mentioned under embodiment (a3),  wherein 1 —CH2— group optionally is replaced independently of each other by O or carbonyl,  wherein one or two carbon atoms optionally and independently are substituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl-carbonyl, formyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-amino-carbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino C2-6-alkenyl-carbonylamino or C2-6-alkynyl-carbonylamino groups, while the substituents may be identical or different. (a6): According to a sixth preferred embodiment, X denotes a group selected from formulas (II), (III), (VI), (VII) or (XIII) mentioned under embodiment (a3),  wherein 1 —CH2— group optionally is replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together,  wherein one or two carbon atoms optionally and independently are substituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl-carbonyl, formyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-amino-carbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino C2-6-alkenyl-carbonylamino or C2-6-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or one ring member nitrogen atom is substituted by C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, cyclo-C3-7-alkyl or cyclo-C3-7-alkenyl. b) Definitions (bi) for Y in the order of preference, ascending from preferably (b1) to more preferably (b2) up to most preferably (b7): (b1): According to a first preferred embodiment Y is defined as mentioned hereinbefore under the broadest/first embodiment of the invention E-0. (b2): According to a second preferred embodiment, Y is absent or denotes a —(CH2)n— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 —CH2— group optionally is replaced by O, S, carbonyl or —NH—, or  wherein 1 —CH2— group is replaced by O, S or —NH—, and additionally a second —CH2— group is replaced by carbonyl, or  wherein 1 —CH2— group is replaced by O, S or —NH—, and additionally a —CH2—CH2— subgroup is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, or —NH—C(O)—, and  wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C3-6-cycloalkyl or phenyl group, or by a straight-chained or branched C1-6-alkyl, phenyl-C1-6-alkyl, C1-6-alkyl-carbonyl, or C1-6-alkylsulphonyl group, and/or  wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are replaced by halogen atoms, trifluoromethyl, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, phenyl, phenyl-C1-3-alkyl, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-6-alkyl-carbonyl, C1-6-alkoxy-carbonyl, C1-6-alkyl-carbonylamino, C1-6-alkyl-carbonyl-(C1-3-alkyl)-amino, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C1-6-alkyl-sulphonyl groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH2)m— bridge, wherein m is 2, 3, 4, or 5. (b3): According to a third preferred embodiment, Y is absent or denotes a —(CH2)n— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 —CH2— group optionally is replaced by O, carbonyl or —NH—, or  wherein 1 —CH2— group is replaced by O or —NH—, and additionally a second —CH2— group is replaced by carbonyl, or  wherein 1 —CH2— group is replaced by O and additionally a —CH2—CH2— subgroup is replaced by —C(O)—NH—, or —NH—C(O)—, and  wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C3-6-cycloalkyl or phenyl group, or by a straight-chained or branched C1-4-alkyl, phenyl-C1-3-alkyl, C1-4-alkyl-carbonyl, or C1-4-alkylsulphonyl group, and/or  wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are replaced by halogen atoms, trifluoromethyl, C1-4-alkyl, C2-4-alkenyl, C3-6-cycloalkyl, phenyl, phenyl-C1-3-alkyl, hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-4-alkyl-carbonyl, C1-4-alkoxy-carbonyl, C1-4-alkyl-carbonylamino, C1-4-alkyl-carbonyl-(C1-3-alkyl)-amino, C1-3-alkyl-aminocarbonyl, or di-(C1-3-alkyl)-aminocarbonyl groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH2)m— bridge, wherein m is 2, 3, 4, or 5. (b4): According to a fourth preferred embodiment, Y is absent. (b5): According to a fifth preferred embodiment, Y denotes a —(CH2)n— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 —CH2— group optionally is replaced by O, carbonyl or —NH—, or  wherein 1 —CH2— group is replaced by O or —NH—, and additionally a second —CH2— group is replaced by carbonyl, or  wherein 1 —CH2— group is replaced by O and additionally a —CH2—CH2— subgroup is replaced by —C(O)—NH—, or —NH—C(O)—, and  wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C3-6-cycloalkyl or phenyl group, or by a straight-chained or branched C1-4-alkyl, phenyl-C1-3-alkyl, or C1-3-alkyl-carbonyl, and/or  wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are independently replaced by F, Cl, C1-4-alkyl or trifluoromethyl, or 1 hydrogen atom attached to a carbon atom optionally is replaced by C3-6-cycloalkyl, phenyl, phenyl-C1-3-alkyl, hydroxy, or C1-3-alkoxy groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH2)m— bridge, wherein m is 2, 3, or 4. (b6): According to a sixth preferred embodiment, Y denotes a C1-2-alkyl-linker wherein 1 —CH2— group optionally is replaced by O. (b7): According to a seventh preferred embodiment, Y denotes a carbonyl group. c) Definitions (ci) for W in the order of preference, ascending from preferably (c1) to more preferably (c2) up to most preferably (c4): (c1): According to a first preferred embodiment W is defined as mentioned hereinbefore under the broadest/first embodiment of the invention E-0. (c2): According to a second preferred embodiment, W denotes H or an optionally substituted straight-chained or branched C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group, wherein 1 or 2 methyl groups optionally are replaced by optionally substituted phenyl groups or  an optionally substituted cyclo-C3-9-alkyl group, wherein independently in a cyclo-C4-7-alkyl group 2 hydrogen atoms attached to adjacent carbon atoms optionally are replaced to form a double bond within the ring, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and the resulting group is bound via a saturated or unsaturated carbon atom, or in a cyclo-C4-9-alkyl group 2 hydrogen atoms attached to the same carbon atom (relative 1,1-position) optionally are replaced by a C2-5-alkylenyl bridge, or 2 hydrogen atoms attached to carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally are replaced by a C1-5-alkylenyl bridge, wherein any of the resulting polycyclic groups one or two —CH2— groups optionally are replaced by —NH—, >N—(C1-6-alkyl), (or N-atoms for replacement of —CH< members), O, or carbonyl, and/or two —CH2— groups in relative 1,3-position of a C4-5-alkylenyl bridge optionally are replaced by O atoms, and/or 2 hydrogen atoms attached to adjacent carbon atoms within a C4-5-alkylenyl bridge optionally are replaced to form a double bond, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and/or in a cyclo-C4-8-alkyl group one, two or three ring members optionally are replaced independently of each other by —NH—, >N—(C1-6-alkyl), (or N-atoms for replacement of —CH< members), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, and additionally but optionally 2 or 4 hydrogen atoms attached to adjacent ring carbon atoms are replaced to form a double bond or two conjugated double bonds within the ring, either of the double bonds optionally being condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and any of the resulting groups is bound via a saturated or unsaturated carbon atom or a nitrogen atom,  and wherein any of the resulting open-chained or cyclic groups independently 1 to 3 hydrogen atoms optionally are replaced by C1-4-alkyl or C1-4-alkoxy groups, and/or  any 1 to 6 hydrogen atoms attached to carbon atoms optionally are replaced by fluorine atoms, or W denotes an optionally substituted aryl or hetaryl group,  an optionally substituted cyclo-C3-8-alkyl-aryl or cyclo-C3-8-alkyl-hetaryl group, wherein the cyclo-C5-8-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or N-atoms for replacement of —CH< members), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, or if Y is absent W additionally denotes  a divalent —(CH2)p— group, wherein p is 2, 3, 4, or 5, attached in relative 1,1-position (geminal) to a carbon atom of group X, including the options:

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20130123231 - Acc inhibitors and uses thereof - The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same. ...

20130123234 - Aryl- or heteroaryl-substituted benzene compounds - The present invention relates to aryl- or heteroaryl-substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for ...

20130123232 - Azetidinyl diamides as monoacylglycerol lipase inhibitors - wherein Y, Z, R1, and s are defined herein. Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: ...

20130123233 - Azetidinyl diamides as monoacylglycerol lipase inhibitors - wherein Y, Z, R1, and s are defined herein. Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: ...


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