Aryl carbonyl derivatives as therapeutic agents

[0001] This application is a continuation of U.S. application Ser. No. 10/679,887, filed Oct. 6, 2003, which was a contiuation of the International Application No. PCT/DK03/00449, filed Jun. 27, 2003, which claimed priority under 35 U.S.C. 119 of Danish Application No. PA 2002 00999 filed Jun. 27, 2002, and Danish Application No. PA 2003 00286, filed Feb. 25, 2003, and U.S. Application No. 60/394,144, filed Jul. 3, 2002, and U.S. Application No. 60/452,228, filed Mar. 5, 2003, the contents of each of which are fully incorporated herein by reference.

[0002] This invention relates to compounds which are activators of glucokinase (GK), which may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

[0003] Diabetes is characterised by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: Type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack β-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which ocurs in patients with an impaired β-cell function besides a range of other abnormalities.

[0004] Type 1 diabetic patients are currently treated with insulin, while the majority of type 2 diabetic patients are treated either with sulphonylureas that stimulate β-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin. Among the agents applied to enhance tissue sensitivity towards insulin metformin is a representative example.

[0005] Even though sulphonylureas are widely used in the treatment of NIDDM this therapy is, in most instances, not satisfactory: In a large number of NIDDM patients sulphonylureas do not suffice to normalise blood sugar levels and the patients are, therefore, at high risk for acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulphonylureas and are thus gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the β-cells in NIDDM patients.

[0006] In normal subjects as well as in diabetic subjects, the liver produces glucose in order to avoid hypoglycaemia. This glucose production is derived either from the release of glucose from glycogen stores or from gluconeogenesis, which is a de novo intracellular synthesis of glucose. In type 2 diabetes, however, the regulation of hepatic glucose output is poorly controlled and is increased, and may be doubled after an overnight fast. Moreover, in these patients there exists a strong correlation between the increased fasting plasma glucose levels and the rate of hepatic glucose production. Similarly, hepatic glucose production will be increased in type 1 diabetes, if the disease is not properly controlled by insulin treatment.

[0007] Since existing forms of therapy of diabetes does not lead to sufficient glycaemic control and therefore are unsatisfactory, there is a great demand for novel therapeutic approaches.

[0008] Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and oclusive heart disease is well known. The earliest stage in this sequence is the formation of “fatty streaks” in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in colour due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of the “fibrous plaque”, which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the “complicated lesion” which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.

[0009] Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of “normal” are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particular high risk. Independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.

[0010] Hypertension (or high blood pressure) is a condition, which ocurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such “essential” hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder.

[0011] It is known that hypertension can directly lead to heart failure, renal failure, and stroke (brain haemorrhaging). These conditions are capable of causing short-term death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can lead to long-term death.

[0012] The exact cause of essential hypertension is unknown, though a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in constricted blood vessels and genetic factors.

[0013] The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure, and brain haemorrhaging. However, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being reduced, the underlying cause of essential hypertension is not responding to this treatment.

[0014] Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries, while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviates hypertension.

[0015] Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction, and congestive heart failure. Theses cardiac events are due, at least in part, to increased susceptibility to myocardial injury after ischemia and reperfusion, which can ocur in out-patient as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million patients undergoing non-cardiac surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to ocur in 5% and death in 1-2%. There is currently no drug therapy in this area, which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.

[0016] Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world. Except for exercise, diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably currently exist. However, due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity and/or means of appetite regulation.

[0017] The term obesity implies an excess of adipose tissue. In this context obesity is best viewed as any degree of excess adiposity that imparts a health risk. The cut off between normal and obese individuals can only be approximated, but the health risk imparted by the obesity is probably a continuum with increasing adiposity. The Framingham study demonstrated that a 20% excess over desirable weight clearly imparted a health risk (Mann G V N. Engl. J. Med 291:226, 1974). In the United States a National Institutes of Health consensus panel on obesity agreed that a 20% increase in relative weight or a body mass index (BMI=body weight in kilograms divided by the square of the height in meters) above the 85 th percentile for young adults constitutes a health risk. By the use of these criteria 20 to 30 percent of adult men and 30 to 40 percent of adult women in the United States are obese. (NIH, Ann Intern Med 103:147, 1985).

[0018] Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease, and certain types of cancer. In the industrialised western world the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority.

[0019] When energy intake exceeds expenditure, the excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity.

[0020] The regulation of eating behaviour is incompletely understood. To some extent appetite is controlled by discrete areas in the hypothalamus: a feeding centre in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety centre in the ventromedial hypothalamus (VMH). The cerebral cortex receives positive signals from the feeding centre that stimulate eating, and the satiety centre modulates this process by sending inhibitory impulses to the feeding centre. Several regulatory processes may influence these hypothalamic centres. The satiety centre may be activated by the increases in plasma glucose and/or insulin that follow a meal. Meal-induced gastric distension is another possible inhibitory factor. Additionally the hypothalamic centres are sensitive to catecholamines, and beta-adrenergic stimulation inhibits eating behaviour. Ultimately, the cerebral cortex controls eating behaviour, and impulses from the feeding centre to the cerebral cortex are only one input. Psychological, social, and genetic factors also influence food intake.

[0021] At present a variety of techniques are available to effect initial weight loss. Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients eventually regain their weight. An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.

[0022] WO 00/58293, WO 01/44216, WO/0183465, WO/0183478, WO/0185706, WO 01/85707, and WO02/08209, to Hoffman-La Roche, discloses compounds as glucokinase activators.

[0023] This invention provides amide derivatives of the general formula (I), as described below, as activators of glucokinase. The compounds of the present invention are useful as activators of glucokinase and thus are useful for the management, treatment, control and adjunct treatment of diseases where increasing the activity of glucokinase is beneficial. Such diseases include type I diabetes and type II diabetes. The present invention provides compounds as described below, pharmaceutical compositions comprising the compounds, their use for increasing the activity of glucokinase, their use in preparation of a medicament for treating said diseases and conditions and the use of compounds or pharmaceutical preparations of the present invention for treating said diseases and conditions as well as methods for treating said diseases and conditions, which methods comprise administering to a subject in need thereof an effective amount of a compound according to the present invention.

[0024] The present invention also provides glucokinase activators, for instance of the general formula (I), which are glucose sensitive glucokinase activators, that is, glucokinase activators, the activity of which decreases with increasing glucose concentrations.

[0025] The present invention also provides glucokinase activators, for instance of the general formula (I), which are liver specific glucokinase activators, that is, glucokinase activators which increase glucose utilization in the liver (i.e. increase glycogen deposition) without inducing any increase in insulin secretion in response to glucose.

[0026] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of metabolic disorders.

[0027] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for blood glucose lowering.

[0028] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for prevention of hyperglycemia.

[0029] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of impaired glucose tolerance IGT.

[0030] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of Syndrome X.

[0031] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for the treatment of impaired fasting glucose (IFG).

[0032] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of type 2 diabetes.

[0033] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of type 1 diabetes.

[0034] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes.

[0035] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

[0036] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of dyslipidemia or hyper-lipidemia.

[0037] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of hypertension.

[0038] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for the treatment of obesity.

[0039] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for lowering of food intake

[0040] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for appetite regulation.

[0041] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for regulating feeding behaviour.

[0042] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for enhancing the secretion of enteroincretins, such as GLP-1.

[0043] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for the adjuvant treatment of type 1 diabetes for preventing the onset of diabetic complications.

[0044] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for increasing the number and/or the size of beta cells in a mammalian subject.

[0045] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of beta cell degeneration, in particular apoptosis of beta cells.

[0046] The present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of functional dyspepsia, in particular irritable bowel syndrome.

[0047] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for treatment of metabolic disorders.

[0048] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for blood glucose lowering.

[0049] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of hyperglycemia.

[0050] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of IGT.

[0051] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of Syndrome X.

[0052] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of impaired fasting glucose (IFG).

[0053] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of type 2 diabetes.

[0054] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of type 1 diabetes.

[0055] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes.

[0056] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

[0057] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of dyslipidemia.

[0058] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of hyperlipidemia.

[0059] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of hypertension.

[0060] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for lowering of food intake.

[0061] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for appetite regulation.

[0062] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of obesity.

[0063] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for regulating feeding behaviour.

[0064] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for enhancing the secretion of enteroincretins, such as GLP-1.

[0065] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the adjuvant treatment of type 1 diabetes for preventing the onset of diabetic complications.

[0066] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for increasing the number and/or the size of beta cells in a mammalian subject.

[0067] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for treatment of beta cell degeneration, in particular apoptosis of beta cells.

[0068] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for treatment of functional dyspepsia, in particular irritable bowel syndrome.

The present invention provides a method of preventing hypoglycaemia comprising administration of a liver-specific glucokinas activator.

The present invention provides the use of a liver-specific glucokinas activator for the preparation of a medicament for the prevention of hypoglycaemia.

[0069] Other embodiments and aspects are as defined below and by the appended claims.

Definitions

[0070] In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning:

[0071] The term “optionally substituted” as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. When the group in question are substituted with more than one substituent the substituent may be the same or different.

[0072] The term “adjacent” as used herein regards the relative postions of two atoms or variables, these two atoms or variables sharing a bond or one variable preceding or succeeding the other in a variable specification. By way of example, “atom A adjacent to atom B” means that the two atoms A and B share a bond.

[0073] The term “halogen” or “halo” means fluorine, chlorine, bromine or iodine.

[0074] The term “perhalomethyl” means trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.

[0075] The use of prefixes of this structure: C_x-y-alkyl, C_x-y-alkenyl, C_x-y-alkynyl, C_x-y-cycloalyl or C_x-y-cycloalkyl-C_x-y-alkenyl- designates radical of the designated type having from x to y carbon atoms.

[0076] The term “alkyl” as used herein, alone or in combination, refers to a straight or branched chain saturated monovalent hydrocarbon radical having from one to ten carbon atoms, for example C_1-8-alkyl or C_1-6-alkyl. Typical C_1-8-alkyl groups and C_1-6-alkyl groups include, but are not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term “C_1-8-alkyl” as used herein also includes secondary C_3-8-alkyl and tertiary C_4-8-alkyl. The term “C_1-6-alkyl” as used herein also includes secondary C_3-6-alkyl and tertiary C_4-6-alkyl.

[0077] The term “alkylene” as used herein, alone or in combination, refers to a straight or branched chain saturated divalent hydrocarbon radical having from one to ten carbon atoms, for example C_1-8-alkylene or C_1-6-alkylene. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, and the like.

[0078] The term “alkenyl” as used herein, alone or in combination, refers to a straight or branched chain monovalent hydrocarbon radical containing from two to ten carbon atoms and at least one carbon-carbon double bond, for example C_2-8-alkenyl or C_2-6-alkenyl. Typical C_2-8-alkenyl groups and C_2-6-alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

[0079] The term “alkenylene” as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon double bond, for example C_2-8-alkenylene or C_2-6-alkenylene. Typical C_2-8-alkenylene groups and C_2-6-alkenylene groups include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.

[0080] The term “alkynyl” as used herein alone or in combination, refers to a straight or branched monovalent hydrocarbon radical containing from two to ten carbon atoms and at least one triple carbon-carbon bond, for example C_2-8-alkynyl or C_2-6-alkynyl. Typical C_2-8-alkynyl groups and C_2-6-alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.

[0081] The term “alkynylene” as used herein alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon triple bond, for example C_2-8-alkynylene or C_2-6-alkynylene. Typical C_2-8-alkynylene groups and C_2-6-alkynylene groups include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

[0082] The term “cycloalkyl” as used herein, alone or in combination, refers to a non-aromatic monovalent hydrocarbon radical having from three to twelve carbon atoms, and optionally with one or more degrees of unsaturation, for example C_3-8-cycloalkyl. Such a ring may be optionally fused to one or more benzene rings or to one or more of other cycloalkyl ring(s). Typical C_3-8-cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and the like.

[0083] The term “cycloalkylene” as used herein, alone or in combination, refers to a non-aromatic carbocyclic divalent hydrocarbon radical having from three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, for example C_3-8-cycloalkylene. Such a ring may be optionally fused to one or more benzene rings or to one or more of other cycloalkyl ring(s). Typical C_3-8-cycloalkylene groups include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.

[0084] The term “heterocyclic” or the term “heterocyclyl” as used herein, alone or in combination, refers to a three to twelve membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO₂, O, or N, for example C_3-8-heterocyclyl. Such a ring may be optionally fused to one or more of another “heterocyclic” ring(s) or cycloalkyl ring(s). Typical C_3-8-heterocyclyl groups include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.

[0085] The term “heterocyclylene” as used herein, alone or in combination, refers to a three to twelve-membered heterocyclic ring diradical optionally having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO₂, O, or N. Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-dyil, and the like.

[0086] The term “alkoxy” as used herein, alone or in combination, refers to the monovalent radical R^aO—, where R^a is alkyl as defined above, for example C_1-8-alkyl giving C_1-8-alkoxy. Typical C_1-8-alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

[0087] The term “alkylthio” as used herein, alone or in combination, refers to a straight or branched monovalent radical comprising an alkyl group as described above linked through a divalent sulphur atom having its free valence bond from the sulphur atom, for example C_1-8-alkylthio. Typical C_1-8-alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

[0088] The term “alkoxycarbonyl” as used herein refers to the monovalent radical R^aOC(O)—, where R^a is alkyl as described above, for example C_1-8-alkoxycarbonyl. Typical C_1-8-alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tertbutoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.

[0089] The term “carbamoyl” as used herein refers to NH₂C(O)—.

[0090] The term “aryl” as used herein refers to a carbocyclic aromatic ring radical or to a aromatic ring system radical. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems.

[0091] The term “heteroaryl”, as used herein, alone or in combination, refers to an aromatic ring radical with for instance 5 to 7 member atoms, or to a aromatic ring system radical with for instance from 7 to 18 member atoms, containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms, wherein N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions; such as e.g. furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and indazolyl, and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.

[0092] Examples of “aryl” and “heteroaryl” includes, but are not limited to phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl, isooxaz-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl, isothiaz-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), 2,3-dihydro-benzo[b]thiophenyl (2,3-dihydro-benzo[b]thiophen-2-yl, 2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl, 2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiophen-6-yl, 2,3-dihydro-benzo[b]thiophen-7-yl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole (2-benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole, 6-benzo[1,3]dioxole, 7-benzo[1,3]dioxole), purinyl, and tetrazolyl (5-tetrazolyl, N-tetrazolyl).

[0093] The present invention also relates to partly or fully saturated analogues of the ring systems mentioned above.

[0094] When two such terms are used in combination, such as in aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl-C_1-6alkyl- and the like, it is to be understood that the first mentioned radical is a substituent on the latter mentioned radical, where the point of substitution is on the latter of the radicals, for example

[0095]

[0096] The term “arylene”, as used herein, alone or in combination, refers to carbocyclic aromatic ring diradical or to a aromatic ring system diradical. Examples of “arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like. The term “arylene” alone or in combination also include other divalent radicals of the monovalent radicals mentioned in the definition of aryl.

[0097] The term “heteroarylene”, as used herein, alone or in combination, refers to a five to seven membered aromatic ring diradical, or to a aromatic ring system diradical, containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms, wherein N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions. Examples of “heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like. The term “heteroarylene” alone or in combination also include other divalent radicals of the monovalent radicals mentioned in the definition of heteroaryl.

[0098] As used herein, the term “fused cycloalkylaryl” refers to a cycloalkyl group fused to an aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused cycloalkylaryl” used herein include 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl,

[0099]

[0100] As used herein, the term “fused cycloalkylarylene” refers to a fused cycloalkylaryl, wherein the aryl group is divalent. Examples include

[0101]

[0102] As used herein, the term “fused arylcycloalkyl” refers to an aryl group fused to a cycloalkyl group, the two having two atoms in common, and wherein the cycloalkyl group is the point of substitution Examples of “fused arylcycloalkyl” used herein include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),

[0103]

[0104] As used herein, the term “fused arylcycloalkylene” refers to a fused arylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include

[0105]

[0106] As used herein, the term “fused heterocyclylaryl” refers to a heterocyclyl group fused to an aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused heterocyclylaryl” used herein include 3,4-methylenedioxy-1-phenyl,

[0107]

[0108] As used herein, the term “fused heterocyclylarylene” refers to a fused heterocyclylaryl, wherein the aryl group is divalent. Examples include

[0109]

[0110] As used herein, the term “fused arylheterocyclyl” refers to an aryl group fused to a heterocyclyl group, the two having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused arylheterocyclyl” used herein include 2-(1,3-benzodioxolyl),

[0111]

[0112] As used herein, the term “fused arylheterocyclylene” refers to a fused arylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include

[0113]

[0114] As used herein, the term “fused cycloalkylheteroaryl” refers to a cycloalkyl group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused cycloalkylheteroaryl” used herein include 5-aza-6-indanyl,

[0115]

[0116] As used herein, the term “fused heteroarylcycloalkylene” refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include

[0117]

[0118] As used herein, the term “fused heterocyclylheteroaryl” refers to a heterocyclyl group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused heterocyclylheteroaryl” used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,

[0119]

[0120] As used herein, the term “fused heterocyclylheteroarylene” refers to a fused heterocyclylheteroaryl, wherein the heteroaryl group is divalent. Examples include

[0121]

[0122] As used herein, the term “fused heteroarylheterocyclyl” refers to a heteroaryl group fused to a heterocyclyl group, the two having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused heteroarylheterocyclyl” used herein include 5-aza-2,3-dihydrobenzofuran-2-yl,

[0123]

[0124] As used herein, the term “fused heteroarylheterocyclylene” refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include

[0125]

[0126] The term “alkylsulfanyl”, as used herein, refers to the group R^aS—, where R^a is alkyl as described above.

[0127] The term “alkylsulfenyl”, as used herein, refers to the group R^aS(O)—, where R^a is alkyl as described above.

[0128] The term “alkylsulfonyl”, as used herein, refers to the group R^aSO₂—, where R^a is alkyl as described above.

[0129] The term “acyl”, as used herein, refers to the group R^aC(O)—, where R^a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl as described above.

[0130] The term “aroyl”, as used herein, refers to the group R^aC(O)—, where R^a is aryl as described above.

[0131] The term “heteroaroyl”, as used herein, refers to the group R_aC(O)—, where R^a is heteroaryl as described above.

[0132] The term “aryloxycarbonyl”, as used herein, refers to the group R^a—O—C(O)—, where R^a is aryl as described above.

[0133] The term “acyloxy”, as used herein, refers to the group R^aC(O)O—, where R^a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl as described above.

[0134] The term “aryloxy”, as used herein refers to the group R^a—O—, where R^a is aryl as described above.

[0135] The term “aroyloxy”, as used herein, refers to the group R^aC(O)O—, where R^a is aryl as described above.

[0136] The term “heteroaroyloxy”, as used herein, refers to the group R^aC(O)O—, where R^a is heteroaryl as described above.

[0137] Whenever the terms “alkyl”, “cycloalkyl”, “aryl”, “heteroaryl” or the like or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for “alkyl” and “aryl”.

[0138] As used herein, the term “oxo” shall refer to the substituent ═O.

[0139] As used herein, the term “mercapto” shall refer to the substituent —SH.

[0140] As used herein, the term “carboxy” shall refer to the substituent —COOH.

[0141] As used herein, the term “cyano” shall refer to the substituent —CN.

[0142] As used herein, the term “aminosulfonyl” shall refer to the substituent —SO₂NH₂.

[0143] As used herein, the term “sulfanyl” shall refer to the substituent —S—.

[0144] As used herein, the term “sulfenyl” shall refer to the substituent —S(O)—.

[0145] As used herein, the term “sulfonyl” shall refer to the substituent —S(O)₂—.

[0146] As used herein, the term “direct bond”, where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a “direct bond”.

[0147] The term “lower”, as used herein, refers to an group having between one and six carbons, and may be indicated with the prefix C_x-6-. Lower alkyl may thus be indicated as C_1-6-alkyl, while lower alkylene may be indicated as C_2-6-alkylene.

[0148] A radical such as C_x-y-cycloalkyl-C_a-b-alkenyl shall designate that the radical's point of attachment is in part of the radical mentioned last.

[0149] As used herein, the term “optionally” means that the subsequently described event(s) may or may not ocur, and includes both event(s) which ocur and events that do not ocur.

[0150] As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

[0151] As used herein, the terms “contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—, —CH₂—NH—CH₃ and so forth.

[0152] Certain of the above defined terms may ocur more than once in the structural formulae, and upon such ocurrence each term shall be defined independently of the other.

[0153] As used herein, the term “solvate” is a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I)) and a solvent. Such solvents for the purpose of the present invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.

[0154] As used herein, the term “biohydrolyzable ester” is an ester of a drug substance (in this invention, a compound of formula (I)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters (e.g., C_1-4), lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.

[0155] As used herein, the term “biohydrolyzable amide” is an amide of a drug substance (in this invention, a compound of general formula (I)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

[0156] As used herein, the term “prodrug” includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of formula (I) and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I). Examples of these functional groups include, but are not limited to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, and the like.

[0157] The term “pharmacologically effective amount” or shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, animal or human that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount. The term “therapeutically effective amount” shall mean that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an animal or human that is being sought.

[0158] The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the full spectrum of treatments for a given disorder from which the patient is suffering, such as the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, the prevention of the disease and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being.
The term “human insulin” as used herein refers to naturally produced insulin or recombinantly produced insulin. Recombinant human insulin may be produced in any suitable host cell, for example the host cells may be bacterial, fungal (including yeast), insect, animal or plant cells.

[0159] The expression “insulin derivative” as used herein (and related expressions) refers to human insulin or an analogue thereof in which at least one organic substituent is bound to one or more of the amino acids.

[0160] By “analogue of human insulin” as used herein (and related expressions) is meant human insulin in which one or more amino acids have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or human insulin comprising additional amino acids, i.e. more than 51 amino acids, such that the resulting analogue possesses insulin activity.

[0161] Glucokinase (GK) plays an essential role in blood glucose homeostasis. GK catalyses glucose phosphorylation, and is the rate-limiting reaction for glycolysis in hepatocytes and pancreatic β-cells. In liver GK determine the rates of both glucose uptake and glycogen synthesis, and it is also thought to be essential for the regulation of various glucose-responsive genes (Girard, J. et al., Annu Rev Nutr 17, 325-352 (1997)). In the β-cells, GK determines glucose utilization and thus is necessary for glucose-stimulated insulin secretion. GK is also expressed in a population of neurones in the hypothalamus where it might be involved in feeding behaviour, and in the gut where it might contribute to the secretion of enteroincretins.

[0162] GK has two main distinctive characteristics: its expression, which is limited to tissues that require glucose-sensing (mainly liver and pancreatic β-cells), and its S_0.5 for glucose, which is much higher (8-12 mM) than that of the other members of the hexokinase family. Due to these kinetic characteristics, changes in serum glucose levels are paralleled by changes in glucose metabolism in liver which in turn regulate the balance between hepatic glucose output and glucose consumption.

[0163] Activators of glucokinase may thus be useful for treating diseases where increasing the activity of glucokinase is beneficial. Thus, there is a need for agents which activate glucokinase and increase glucokinase enzymatic activity. Such agents would be useful for the treatment of type I diabetes and type II diabetes.

[0164] Activators of glucokinase may also play a role in sensing low glucose levels and generating neurohumoral responses to hypoglycemia and may thus be useful for treating those patients with type 1 diabetes, which have a higher tendency to suffer from hypoglycemia.

[0165] Type I diabetes mellitus is a complex disease characterized by an elevated blood glucose concentration and polyuria. Secondary to the persistent elevation in blood glucose, patients develop devastating complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease. A major goal to improve the diabetic phenotype is to reduce fasting and postprandial hyperglycemia and, thus, avoid or delay the onset of diabetic complications. The Diabetes Control and Complications Trial has indicated that tight glycemic control through administration of daily multiple insulin injections delays the onset of complications. However, such intensive therapy is associated with an increase in body weight and higher risk for development of hypoglycaemic events. Alternative treatments to achieve glucose control without these side effects are, therefore, being developed. The combination of GK overexpression in the liver and subcutaneous insulin injections provides better glycemic control in type 1 diabetic animals than treatment with insulin alone (Morral, N., et al. Human Gene Therapy 13, 1561-1570 (2002)). Moreover, overexpression of hepatic GK can compensate, in part, for the metabolic disorders developed by insulin receptor-deficient mice (Jackerott, M. et al. Diabetologia 45, 1292-1297 (2002)).

[0166] The present invention also relates to the use of a GK activator for the combined treatment of diabetes and obesity. GK, the GK regulatory protein and the KATP channel are expressed in neurones of the hypothalamus, a region of the brain that is important in the regulation of energy balance and the control of food intake. These neurones have been shown to express orectic and anorectic neuropeptides and have been assumed to be the glucose-sensing neurones within the hypothalamus that are either inhibited or excited by changes in ambient glucose concentrations (Mobbs, C. V. et al, American Journal of Physiology, Endocrinology & Metabolism 281, E649-54 (2001)). The ability of these neurones to sense changes in glucose levels is defective in a variety of genetic and experimentally induced models of obesity (Spanswick, D. et al, Nature Neuroscience 3, 757-8 (2000), Levin, B. E. et al, Brain Research 808, 317-9 (1998)). Intracerebroventricular (icv) infusion of glucose analogues, which are competitive inhibitors of glucokinase, stimulate food intake in lean rats (Kurata, K. et al, Metabolism: Clinical & Experimental 38, 46-51 (1989)). In contrast, icv infusion of glucose suppresses feeding (Kurata, K. et al, Physiology & Behavior 37, 615-20 (1986)). Small molecule activators of GK may thus decrease food intake and weight gain through central effects on GK. Therefore, GK activators may be of therapeutic use in treating eating disorders, including obesity, in addition to diabetes. The hypothalamic effects will be additive or synergistic to the effects of the same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of type 2 diabetes. Thus the GK/GK regulatory protein system can be described as a potential target of benefit in both diabetes and obesity.

[0167] The amplitude of glucose-induce insulin release is highly dependent on the action of the gastrointestinal hormones GLP-1 (glucogen-like peptide 1) and GIP. Unlike sulfonylureas, which stimulate insulin release at low as well as high glucose levels, the action of GLP-1 on β-cells is glucose dependent (Gromada, J. et al., Pflügers Arch 435, 583-594 (1998)). GLP-1 receptor agonist and drugs that slow the degradation of active GLP-1 are therefore under development as a novel treatments for type 2 diabetes. An alternative strategy would be to enhance endogenous GLP-1 levels. Of potential interest is the possibility that the release of GLP-1 and GIP might be regulated by glucokinase-expressing endocrine cells (Jetton, T. L. et al., J. Biol. Chem. 269, 3641-3654 (1994)) and glucose-responsive neurons (Liu, M. et al., J. Neurosci. 19, 10305-10317 (1999)). It has been reported that the release of GIP by intestinal K-cells is directly controlled by glucose (Kieffer, T. J. et al., Am J Physiol 267, E489-E496 (1994)), and GLP-1 secretion from GLUTag cells is triggered by glucose through a mechanism similar to that found in β-cells for insulin secretion (Reimann, F. et al, Diabetes 51, 2757-2763 (2002)). Small molecule activators of glucokinase may thus be used to increase GLP-1 and/or GIP secretion and thus for treatment, modulation, inhibition, decreasion, reduction, arrest or prevention of beta cell degeneration, such as necrosis or apoptosis of β-cells.

[0168] The present invention provides ortho-substituted heteroaryl and aryl ureas or carboxamide or sulfonamide activators of glucokinase.

[0169] In a first embodiment, the present invention provides compounds of the general formula (I).

[0170]
wherein

• [0171] A¹ is selected from the group consisting of arylene, heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene, fused cycloalkylheteroarylene, or fused heterocyclylheteroarylene; optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷, wherein
  • [0172] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0173] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6-alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0174] R² and R³ independently of each other are hydrogen, C_1-6alkyl, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6alkyl-heteroarylene-, heteroaryl, or aryl;
    • [0175] or
    • [0176] R² and R³, when attached to the same nitrogen atom, together with said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
    • [0177] Z and W¹ independently of each other are a direct bond, —O—, —N(R⁷)—, —S—, —SO₂—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)CON(R⁸)—, —N(R⁷)SO₂—, —SO₂N(R⁷)—, —C(O)—O—, —N(R⁷)SO₂N(R⁸)—, or —O—C(O)—, wherein
      • [0178] R⁷ and R⁸ in each individual case independently of each other are hydrogen or alkyl; and
    • [0179] R⁴, R⁵, and R⁶ independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl-alkylene-, and aryl-alkylene-;
    • [0180] or
    • [0181] R⁴ and R⁵ may be taken together to form a ring having the formula —(CH₂)_j-Q-(CH₂)_k— bonded to the nitrogen atom to which R⁴ and R⁵ are attached, wherein
      • [0182] j and k independently of each other is 1, 2, 3, or 4; and
      • [0183] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0184]

• • • • [0185] wherein
        • [0186] R⁹ and R¹⁰ independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, and aryl-alkylene-;
• [0187] L¹ is -D-alkylene-E-, -D-alkenylene-E-, -D-alkynylene-E-, -D-cycloalkylene-E-, -D-heterocyclylene-E-, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —N(R¹¹)—, or —C(═N—OR¹²)—, wherein
  • [0188] D and E independently of each other are a direct bond, —O— or —S—;
  • [0189] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, heteroaryl-alkylene-, alkyl-O—C(O)—, aryl-alkylene-O—C(O)—, heteroaryl-alkylene-O—C(O)—, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, heteroaryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, heteroaryl-alkylene-SO₂—, aryl-SO₂—, heteroaryl-SO₂—, alkyl-NH—SO₂—, aryl-alkylene-NH—SO₂—, heteroaryl-alkylene-NH—SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, heteroaryl-alkylene-C(O)—, alkyl-Y—, aryl-Y—, heteroaryl-Y—, aryl-alkylene-Y—, heteroaryl-alkylene-Y—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0190] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0191] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, heteroaryl, C_1-6-alkyl, C_1-6-alkoxy, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkoxy-, heteroaryl-C_1-6-alkoxy-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6alkoxy-heteroarylene-, or C_1-6-alkoxy-arylene-;
    • [0192] or
    • [0193] R₁₃ and R₁₄ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R₁₃ and R₁₄ are attached, wherein
      • [0194] o and p are independently of each other are 1, 2, 3, or 4; and
      • [0195] X is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0196]

• • • • [0197] wherein
        • [0198] R¹⁶ and R¹⁷ are selected from hydrogen, aryl, heteroaryl, C_1-6-alkyl, C_1-6-alkoxy, aryl-C_1-6alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6-alkoxy-arylene-, C_1-6-alkoxy-heteroarylene-, heteroarylaryl-C_1-6-alkoxy-, or aryl-alkoxy-; and
    • [0199] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, heteroaryl-alkylene-, or aryl-alkylene-; and
  • [0200] R¹² is selected from hydrogen, aryl, heteroaryl, alkyl, aryl-alkylene-, heteroaryl-alkylene-, alkyl-arylene-, alkyl-heteroarylene-, alkoxy-heteroarylene-, or alkoxy-arylene-;
• [0201] G¹ is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹, C_3-10-cycloalkyl and C_1-6-alkyl, wherein
  • [0202] R¹⁸ and R¹⁹ independently of each other are hydrogen, C_1-6-alkyl, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl;
  • [0203] or
  • [0204] R¹⁸ and R¹⁹, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
    or
• [0205] G¹ is aryl, heteroaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, or fused cycloalkylaryl,
  optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴²;
• [0206] L² is a direct bond, alkylene, alkenylene, alkynylene, —N(R²⁰)—, -alkylene-N(R²⁰)—, -alkenylene-N(R²⁰)—, -alkynylene-N(R²⁰)—, wherein
  • [0207] R²⁰ is hydrogen, or
  • [0208] R²⁰ is alkyl, alkenyl, alkynyl, cycloalkyl-W³—, heterocyclyl-W³—, aryl-W³—, heteroaryl-W³—, optionally substituted with one or more substituents R³⁰, R³¹, and R³², wherein
    • [0209] W³ is alkylene or a direct bond;
      wherein L¹ and L² are attached to adjacent atoms in A¹;
• [0210] L³ is —C(O)—, or —S(O)₂—;
• [0211] R¹ is hydrogen, or
• [0212] R¹ is alkyl, alkenyl, alkynyl, cycloalkyl-W⁴—, heterocyclyl-W⁴—, aryl-W⁴—, or heteroaryl-W⁴—, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵, wherein
  • [0213] W⁴ is alkylene or a direct bond;
• [0214] G² is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining said heteroaryl group to —N(R¹)—;
  or a group of the formula

[0215]
wherein

• • [0216] G³ and G⁵ independently of each other are alkyl, alkenyl, alkynyl, cycloalkyl-R²²—, heterocyclyl-R²²—, aryl-R²²—, heteroaryl-R²²-,
  • [0217] optionally substituted with one or more substituents R⁴⁶, R⁴⁷, and R⁴⁸, wherein
    • [0218] R²² is alkylene or a direct bond; and
  • [0219] R²¹ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl-W⁵—, or heterocyclyl-W⁵—, optionally substituted with one or more substituents R³⁶, R³⁷, and R³⁸, or R²¹ is aryl-W⁵—, or heteroaryl-W⁵—, optionally substituted with one or more substituents R⁴⁹, R⁵⁰, and R⁵¹, wherein
    • [0220] W⁵ is alkylene or a direct bond;
      wherein
• [0221] R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, and R³⁸ independently of each other are selected from —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵², —NR⁵²R⁵³, —SR₅₂, —NR⁵²S(O)₂R⁵³, —S(O)₂NR⁵²R⁵³, —S(O)NR⁵²R⁵³, —S(O)R⁵², —S(O)₂R⁵², —C(O)NR⁵²R⁵³, —OC(O)NR⁵²R⁵³, —NR⁵²C(O)R⁵³, —CH₂C(O)NR⁵²R⁵³, —OCH₂C(O)NR⁵²R⁵³, —CH₂OR⁵², —CH₂NR⁵²R⁵³, —OC(O)R⁵², —C(O)R⁵² and —C(O)OR⁵²; or
• [0222] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁵², —NR⁵²R⁵³ and C_1-6alkyl; or
• [0223] C_3-10-cycloalkyl, C_4-8-cycloalkenyl, heterocyclyl, C_3-10-cycloalkyl-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkoxy-, C_3-10-Cycloalkyloxy, C_3-10-cycloalkyl-C_1-6-alkylthio-, C_3-10-cycloalkylthio, C_3-10-cycloalkyl-C_2-6-alkenylene-, C_3-10-cycloalkyl-C_2-6-alkynylene-, C_4-8-cycloalkenyl-C_1-6-alkylene-, C_4-8-cycloalkenyl-C_2-6-alkenylene-, C_4-8-cycloalkenyl-C_2-6-alkynylene-, heterocyclyl-C_1-6-alkylene-, heterocyclyl-C_2-6-alkenylene-, heterocyclyl-C_2-6-alkynylene-, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C_1-6-alkoxy-, aryl-C_1-6-alkylene-, aryl-C_2-6-alkenylene-, aryl-C_2-6-alkynylene-, heteroaryl, heteroaryl-C_1-6-alkylene-, heteroaryl-C_2-6-alkenylene- and heteroaryl-C_2-6-alkynylene-, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR⁵², —CN, —CF₃, —OCF₃, —NO₂, —OR⁵², —NR⁵²R⁵³ and C_1-6alkyl, wherein
  • [0224] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6alkylene-heteroaryl-C_1-6-alkylene-heteroaryl, or aryl;
  • [0225] or
  • [0226] R⁵² and R⁵³, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
• [0227] R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰ and R⁵¹ independently of each other are halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, —OC(O)R⁵⁴, —C(O)R⁵⁴ and —C(O)OR⁵⁴; or
• [0228] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —R⁵⁴, —NR⁵⁴R⁵⁵ and C_1-6-alkyl; C_3-10-cycloalkyl, C_4-8-cycloalkenyl, heterocyclyl, C_3-10-cycloalkyl-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkoxy-, C_3-10-cycloalkyloxy, C_3-10-cycloalkyl-C_1-6-alkylthio-, C_3-10-cycloalkylthio, C_3-10-cycloalkyl-C_2-6-alkenylene-, C_3-10-cycloalkyl-C_2-6-alkynylene-, C_4-8-cycloalkenyl-C_1-6-alkylene-, C_4-8-cycloalkenyl-C_2-6-alkenylene-, C_4-8-cycloalkenyl-C_2-6-alkynylene-, heterocyclyl-C_1-6-alkylene-, heterocyclyl-C_2-6-alkenylene-, heterocyclyl-C_2-6-alkynylene-; or
• [0229] aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C_1-6-alkoxy-, aryl-C_1-6-alkylene-, aryl-C_2-6-alkenylene-, aryl-C_2-6-alkynylene-, heteroaryl, heteroaryl-C_1-6-alkylene-, heteroaryl-C_2-6-alkenylene- and heteroaryl-C_2-6-alkynylene-, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR⁵⁴, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁴, —NR⁵R⁵⁵ or C_1-6-alkyl wherein
  • [0230] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
  • [0231] or
  • [0232] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or —(CHR⁶³)_u—(CHR⁶⁴)_v-Z,
  • [0233] wherein
    • [0234] u is 1 or 2;
    • [0235] v is 0, 1 or 2;
    • [0236] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6-alkyl, C_1-6alkyl-arylene- aryl, hydroxy, hydroxyalkyl, amino, or aminoalkyl;
    • [0237] Z is hydrogen, —O—R⁶⁵, —C(O)O—R⁶⁵—CONR⁶⁵R⁶⁶, alkylamino, or dialkylamino, wherein
      • [0238] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6-alkyl;
    • [0239] or
    • [0240] Z is a five or six membered ring wherein at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen;
      or
  • [0241] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, and optionally substituted with one or more C_1-6alkyl groups;
    or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0242] Other embodiments of the present invention are clear from the following list of embodiments.

Embodiment 2: A compound according to embodiment 1, wherein

• [0243] A¹ is arylene or heteroarylene, optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷, wherein
  • [0244] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0245] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6-alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6alkylene-Z-, wherein
    • [0246] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined for embodiment 1.
      Embodiment 3: A compound according to embodiment 2, wherein
• [0247] A¹ is C_6-10-arylene or C_4-10-heteroarylene, optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷, wherein
  • [0248] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0249] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6-alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0250] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined for embodiment 1.
      Embodiment 4: A compound according to any of embodiments 1 to 3, wherein
  • [0251] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0252] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0253] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined for embodiment 1.
      Embodiment 5: A compound according to any of embodiments 1 to 7, wherein
  • [0254] R⁴, R⁵, and R⁶ independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl-alkylene-, and aryl-alkylene-.
    Embodiment 6: A compound according to embodiment 11, wherein
  • [0255] R⁴, R⁵, and R⁶ independently of each other are hydrogen or alkyl.
    Embodiment 7: A compound according to embodiment 12, wherein
  • [0256] R⁴, R⁵, and R⁶ are hydrogen.
    Embodiment 8: A compound according to any of embodiments 1 to 7, wherein
  • [0257] R⁴ and R⁵ is taken together to form a ring having the formula —(CH₂)_j-Q-(CH₂)_k-bonded to the nitrogen atom to which R⁴ and R⁵ are attached, wherein
    • [0258] j and k independently of each other is 1, 2, 3, or 4;
    • [0259] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0260]

• • • [0261] wherein
      • [0262] R⁹ and R¹⁰ independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, and arylalkyl-.
        Embodiment 9: A compound according to embodiment 14, wherein
  • [0263] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0264]

• • [0265] wherein
    • [0266] R⁹ and R¹⁰ independently of each other are hydrogen or alkyl.
      Embodiment 10: A compound according to embodiment 15, wherein
  • [0267] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0268]
Embodiment 11: A compound according to embodiment 16, wherein Q is a direct bond.
Embodiment 12: A compound according to any of embodiments 1 to 17, wherein

• • [0269] W¹ is a direct bond, —O—, —NH—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment 13: A compound according to embodiment 18, wherein W¹ is a direct bond, —O—, —S—, or —SO₂—.
    Embodiment 14: A compound according to embodiment 19, wherein W¹ is a direct bond.
    Embodiment 15: A compound according to embodiment 7, wherein
  • [0270] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
    • [0271] R², R³, and Z are as defined for embodiment 1.
      Embodiment 16: A compound according to embodiment 22, wherein
  • [0272] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —CF₃—OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0273] R², R³, and Z are as defined for embodiment 1.
      Embodiment 17: A compound according to embodiment 23, wherein
  • [0274] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0275] R², R³, and Z are as defined for embodiment 1.
      Embodiment 18: A compound according to embodiment 24, wherein
  • [0276] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —NO₂, —OR², or —NR²R³, wherein
    • [0277] R², R³, and Z are as defined for embodiment 1.
      Embodiment 19: A compound according to any of embodiments 1 to 26, wherein
  • [0278] R² and R³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment 20: A compound according to embodiment 27, wherein
  • [0279] R² and R³ independently of each other, are hydrogen, C_1-6alkyl, aryl-C_1-6-alkylene- or aryl.
    Embodiment 21: A compound according to embodiment 28, wherein
  • [0280] R² is hydrogen or C_1-6-alkyl.
    Embodiment 22: A compound according to embodiment 29, wherein
  • [0281] R² is hydrogen.
    Embodiment 23: A compound according to any of embodiments 1 to 30, wherein
  • [0282] R³ is hydrogen or C_1-6alkyl.
    Embodiment 24: A compound according to embodiment 31, wherein
  • [0283] R³ is hydrogen.
    Embodiment 25: A compound according to any of embodiments 1 to 22, wherein
  • [0284] R² and R³, when attached to the same nitrogen atom, together with said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 26: A compound according to any of embodiments 1 to 33, wherein
  • [0285] Z is a direct bond, —O—, —NH—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment 27: A compound according to embodiment 34, wherein
  • [0286] Z is a direct bond, —O—, —S—, or —SO₂—.
    Embodiment 28: A compound according to embodiment 35, wherein
  • [0287] Z is a direct bond.
    Embodiment 29: A compound according to embodiment 2, wherein
• [0288] A¹ is

[0289]

• [0290] R²³, R²⁴, R²⁵, and R²⁶, independently of each other, are hydrogen or as defined for embodiment 1.
  Embodiment 30: A compound according to embodiment 37, wherein
  • [0291] R²³, R²⁴, R²⁵, and R²⁶ independently of each other are selected from the group consisting of
  • [0292] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0293] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined for embodiment 1.
      Embodiment 31: A compound according to embodiment 37 or 38, wherein
  • [0294] R⁴, R⁵, and R⁶ independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl-alkylene-, and aryl-alkylene-.
    Embodiment 32: A compound according to embodiment 39, wherein
  • [0295] R⁴, R⁵, and R⁶ independently of each other are hydrogen or alkyl.
    Embodiment 33: A compound according to embodiment 40, wherein
  • [0296] R⁴, R⁵, and R⁶ are hydrogen.
    Embodiment 34: A compound according to embodiment 37 or 38, wherein
  • [0297] R⁴ and R⁵ is taken together to form a ring having the formula —(CH₂)_j-Q-(CH₂)_k— bonded to the nitrogen atom to which R⁴ and R⁵ are attached, wherein
    • [0298] j and k independently of each other is 1, 2, 3, or 4;
    • [0299] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0300]

• • • [0301] wherein
      • [0302] R⁹ and R¹⁰ independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, and arylalkyl-.
        Embodiment 35: A compound according to embodiment 42, wherein
  • [0303] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0304]

• • [0305] wherein
    • [0306] R⁹ and R¹⁰ independently of each other are hydrogen or alkyl.
      Embodiment 36: A compound according to embodiment 43, wherein
  • [0307] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0308]
Embodiment 37: A compound according to embodiment 44, wherein

• • [0309] Q is a direct bond.
    Embodiment 38: A compound according to any of embodiments 37 to 45, wherein
  • [0310] W¹ is a direct bond, —O—, —NH—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment 39: A compound according to embodiment 46, wherein
  • [0311] W¹ is a direct bond, —O—, —S—, or —SO₂—.
    Embodiment 40: A compound according to embodiment 48, wherein
  • [0312] W¹ is a direct bond.
    Embodiment 41: A compound according to embodiment 37, wherein
  • [0313] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
    • [0314] R², R³, and Z are as defined for embodiment 37.
      Embodiment 42: A compound according to embodiment 50, wherein
  • [0315] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0316] R², R³, and Z are as defined for embodiment 37.
      Embodiment 43: A compound according to embodiment 51, wherein
  • [0317] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR², —CN, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0318] R², R³, and Z are as defined for embodiment 37.
      Embodiment 44: A compound according to any of embodiments 37 to 52, wherein
  • [0319] Z is a direct bond, —O—, —NH—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment 45: A compound according to embodiment 53, wherein
  • [0320] Z is a direct bond, —O—, —S—, or —SO₂—.
    Embodiment 46: A compound according to embodiment 54, wherein
  • [0321] Z is a direct bond.
    Embodiment 47: A compound according to embodiment 52, wherein
  • [0322] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR, —CN, —NO₂, —OR², —NR²R³, or C_1-6alkyl, wherein
    • [0323] R², and R³ are as defined for embodiment 37.
      Embodiment 48: A compound according to any of embodiments 37 to 56, wherein
  • [0324] R² and R³ independently of each other are hydrogen, C_1-6alkyl, aryl-C_1-6alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment 49: A compound according to embodiment 57, wherein
  • [0325] R² and R³ independently of each other, are hydrogen, C_1-6alkyl, aryl-C_1-6-alkylene- or aryl.
    Embodiment 50: A compound according to embodiment 58, wherein
  • [0326] R² is hydrogen or C_1-6-alkyl.
    Embodiment 51: A compound according to embodiment 59, wherein
  • [0327] R² is hydrogen.
    Embodiment 52: A compound according to any of embodiments 37 to 60, wherein
  • [0328] R³ is hydrogen or C_1-6-alkyl.
    Embodiment 53: A compound according to embodiment 61, wherein
  • [0329] R³ is hydrogen.
    Embodiment 54: A compound according to any of embodiments 37 to 50, wherein
  • [0330] R² and R³, when attached to the same nitrogen atom, together with said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 55: A compound according to any of embodiments 37 to 55, wherein
  • [0331] at least one of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment 56: A compound according to embodiment 64, wherein
  • [0332] at least two of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment 57. A compound according to embodiment 65, wherein
  • [0333] R²³ and R²⁶ are hydrogen.
    Embodiment 58: A compound according to embodiment 65 or embodiment 66, wherein
  • [0334] at least three of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment 59: A compound according to any of embodiments 37 to 67, wherein R²⁴ or R²⁵ is halogen.
    Embodiment 60: A compound according to embodiment 68, wherein R²⁴ or R²⁵ is fluoro.
    Embodiment 61: A compound according to any of embodiments 37 to 67, wherein R²⁴ or R²⁵ is C_1-6-alkyl.
    Embodiment 62: A compound according to embodiment 68, wherein R²⁴ or R²⁵ is methyl.
    Embodiment 63: A compound according to any of embodiments 37 to 67, wherein
  • [0335] R²⁴ is hydrogen.
    Embodiment 64: A compound according to any of embodiments 37 to 72, wherein
  • [0336] R²⁵ is hydrogen.
    Embodiment 65: A compound according to embodiment 37, wherein
  • [0337] R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment 66: A compound according to any of embodiments 1 to 74, wherein
  • [0338] L¹ is -D-alkylene-E-, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —N(R¹¹)—, or —C(═N—OR¹²), wherein
    • [0339] D, E, R¹¹ and R¹² are as defined for embodiment 1.
      Embodiment 67: A compound according to embodiment 75, wherein
  • [0340] L¹ is -D-alkylene-E-, —O—, —C(O)—, —N(R¹¹)—, or —C(═N—OR¹²)—, wherein
    • [0341] D, E, R¹¹ and R¹² are as defined for embodiment 1.
      Embodiment 68: A compound according to embodiment 75, wherein
  • [0342] L¹ is —O—.
    Embodiment 69: A compound according to embodiment 75, wherein
  • [0343] L¹ is —S—.
    Embodiment 70: A compound according to embodiment 75, wherein
  • [0344] L¹ is —C(O)—.
    Embodiment 71: A compound according to any of embodiments 1 to 76, wherein
  • [0345] D is a direct bond or —O—;
  • [0346] E is a direct bond or —O—; and
  • [0347] R¹¹ and R¹² are as defined for embodiment 1.
    Embodiment 72: A compound according to embodiment 81, wherein
  • [0348] D is a direct bond.
    Embodiment 73: A compound according to embodiment 81, wherein
  • [0349] D is —O—.
    Embodiment 74: A compound according to any of embodiments 81 to 83, wherein
  • [0350] E is a direct bond.
    Embodiment 75: A compound according to any of embodiments 81 to 83, wherein
  • [0351] E is —O—.
    Embodiment 76: A compound according to any of embodiments 1 to 85, wherein
  • [0352] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0353] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0354] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6alkyl, or aryl-C_1-6alkylene-;
    • [0355] or
    • [0356] R¹³ and R¹⁴ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R¹³ and R¹⁴ are attached, wherein
      • [0357] o and p are independently of each other are 1, 2, 3, or 4; and
      • [0358] X is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0359]

• • • • [0360] wherein
        • [0361] R¹⁶ and R¹⁷ are selected from hydrogen, aryl, heteroaryl, C_1-6alkyl, C_1-6-alkoxy, aryl-C_1-6alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6-alkoxy-arylene-, C_1-6-alkoxy-heteroarylene-, heteroarylaryl-C_1-6-alkoxy-, or aryl-C_1-6alkoxy-; and
  • [0362] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
    Embodiment 77: A compound according to embodiment 86, wherein
  • [0363] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0364] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0365] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6alkyl, or aryl-C_1-6-alkylene-;
    • [0366] or
    • [0367] R¹³ and R¹⁴ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R¹³ and R¹⁴ are attached, wherein
      • [0368] o and p are independently of each other are 1, 2, 3, or 4; and
      • [0369] X is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0370]

• • • • [0371] wherein
        • [0372] R¹⁶ and R¹⁷ are hydrogen; and
  • [0373] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
    Embodiment 78: A compound according to embodiment 87, wherein
  • [0374] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0375] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0376] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6-alkyl, or aryl-C_1-6-alkylene-;
    • [0377] or
    • [0378] R¹³ and R¹⁴ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R¹³ and R¹⁴ are attached, wherein
      • [0379] o and p are independently of each other are 1, 2, 3, or 4;
      • [0380] X is a direct bond; and
  • [0381] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
    Embodiment 79: A compound according to embodiment 88, wherein.
  • [0382] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0383] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0384] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6alkyl, or aryl-C_1-6-alkylene-; and
    • [0385] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
      Embodiment 80: A compound according to embodiment 89, wherein
  • [0386] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0387] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0388] R¹³ and R¹⁴ are hydrogen; and
    • [0389] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
      Embodiment 81: A compound according to embodiment 90, wherein
  • [0390] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0391] Y is a direct bond;
    • [0392] W² is a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0393] R¹³ and R¹⁴ are hydrogen; and
    • [0394] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
      Embodiment 82: A compound according to embodiment 90, wherein
  • [0395] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, N(R¹³)(R¹⁴)-alkylene-Y—, and R¹⁵—W²-alkylene-Y—, wherein
    • [0396] Y is a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0397] W² is a direct bond;
    • [0398] R¹³ and R¹⁴ are hydrogen; and
    • [0399] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
      Embodiment 83: A compound according to any of embodiments 90 to 92, wherein
  • [0400] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, NH₂-alkylene-, and R¹⁵-alkylene-, wherein
    • [0401] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, or aryl-alkylene-.
      Embodiment 84: A compound according to embodiment 93, wherein
  • [0402] R¹¹ is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH—C(O)—, aryl-alkylene-NH—C(O)—, alkyl-SO₂—, aryl-alkylene-SO₂—, aryl-SO₂—, SO₂—, alkyl-C(O)—, aryl-alkylene-C(O)—, and NH₂-alkylene-.
    Embodiment 85: A compound according to embodiment 94, wherein
  • [0403] R¹¹ is hydrogen or alkyl.
    Embodiment 86: A compound according to embodiment 95, wherein
  • [0404] R¹¹ is hydrogen.
    Embodiment 87: A compound according to any of embodiments 1 to 96, wherein
  • [0405] R¹² is hydrogen or alkyl.
    Embodiment 88: A compound according to embodiment 97, wherein
  • [0406] R¹² is hydrogen.
    Embodiment 89: A compound according to any of embodiments 1 to 98, wherein
  • [0407] G¹ is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹, —NR¹⁸R¹⁹, C_3-10-cycloalkyl and C_1-6alkyl, wherein
    • [0408] R¹⁸ and R¹⁹ are as defined for embodiment 1.
      Embodiment 90: A compound according to embodiment 99, wherein
  • [0409] G¹ is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-6alkyl, wherein
    • [0410] R¹⁸ and R¹⁹ are as defined for embodiment 1.
      Embodiment 91: A compound according to embodiment 99, wherein
  • [0411] G¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl or C_3-10-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹, C_3-10-cycloalkyl and C_1-6-alkyl, wherein
    • [0412] R¹⁸ and R¹⁹ are as defined for embodiment 1.
      Embodiment 92: A compound according to embodiment 100 or embodiment 101, wherein
  • [0413] G¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl or C_3-10-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-4alkyl, wherein
    • [0414] R¹⁸ and R¹⁹ are as defined for embodiment 1.
      Embodiment 93: A compound according to any of embodiments 99 to 102, wherein
  • [0415] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, heteroaryl-C_1-6-alkylene-, aryl-C_1-6alkylene-, C_1-6alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment 94: A compound according to embodiment 110, wherein
  • [0416] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-aryl-C_1-6-alkylene-, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment 95: A compound according to embodiment 111, wherein
  • [0417] R¹⁸ and R¹⁹, independently of each other, are hydrogen or C_1-6alkyl.
    Embodiment 96: A compound according to embodiment 112, wherein
  • [0418] R¹⁸ is hydrogen.
    Embodiment 97: A compound according to embodiment 112 or 113, wherein
  • [0419] R¹⁹ is hydrogen.
    Embodiment 98: A compound according to embodiment 100 or embodiment 102, wherein
  • [0420] R¹⁸ and R¹⁹, when attached to the same nitrogen atom, together with the said nitrogen atom forms a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 99: A compound according to any of embodiments 1 to 98, wherein
  • [0421] G¹ is alkyl or cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-6alkyl,
  • [0422] or G¹ is aryl optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein R¹⁸, R¹⁹, R⁴⁰, R⁴¹, and R⁴² are as defined for embodiment 1.
    Embodiment 100: A compound according to embodiment 116, wherein
  • [0423] G¹ is C_1-6-alkyl or C_3-10-cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹8, —NR¹⁸R¹⁹ and C_1-6-alkyl,
  • [0424] or G¹ is C_3-10-aryl optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein R¹⁸, R¹⁹, R⁴⁰, R⁴¹, and R⁴² are as defined for embodiment 1.
    Embodiment 101: A compound according to embodiment 116 or embodiment 117, wherein
  • [0425] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment 102: A compound according to embodiment 119, wherein
  • [0426] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-aryl-C_1-6-alkylene-, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment 103: A compound according to embodiment 120, wherein
  • [0427] R¹⁸ and R¹⁹, independently of each other, are hydrogen or C_1-6alkyl.
    Embodiment 104: A compound according to embodiment 121, wherein
  • [0428] R¹⁸ is hydrogen.
    Embodiment 105: A compound according to embodiment 121 or 122, wherein
  • [0429] R¹⁹ is hydrogen.
    Embodiment 106: A compound according to embodiment 116 or embodiment 117, wherein
  • [0430] R¹⁸ and R¹⁹, when attached to the same nitrogen atom, together with the said nitrogen atom forms a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 107: A compound according to any of embodiments 116 to 124, wherein
  • [0431] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [0432] halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵—S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵—NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, and —C(O)OR⁵⁴; or
  • [0433] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵ and C_1-6-alkyl, wherein
    • [0434] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [0435] or
    • [0436] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment 108: A compound according to embodiment 125, wherein
  • [0437] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, or C_1-6alkyl, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-aryl-C_1-6alkylene-, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment 109: A compound according to embodiment 128, wherein
  • [0438] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6alkyl.
    Embodiment 110: A compound according to embodiment 129, wherein
  • [0439] R⁵⁴ is hydrogen.
    Embodiment 111: A compound according to embodiment 129 or embodiment 130, wherein
  • [0440] R⁵⁵ is hydrogen.
    Embodiment 112: A compound according to any of embodiments 1 to 98, wherein
  • [0441] G¹ is aryl or heteroaryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [0442] R⁴⁰, R⁴¹, and R⁴² are as defined for embodiment 1.
      Embodiment 113: A compound according to embodiment 133, wherein
  • [0443] G¹ is C_3-10-aryl or C_3-10-heteroaryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [0444] R⁴⁰, R⁴¹, and R⁴² are as defined for embodiment 1.
      Embodiment 114: A compound according to embodiment 133, wherein
  • [0445] G¹ is aryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [0446] R⁴⁰, R⁴¹, and R⁴² are as defined for embodiment 1.
      Embodiment 115: A compound according to embodiment 135, wherein
  • [0447] G¹ is C_3-10-aryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [0448] R⁴⁰, R⁴¹, and R⁴² are as defined for embodiment 1.
      Embodiment 116: A compound according to any of embodiments 133 to 136, wherein
  • [0449] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [0450] halogen, —CN, —NO₂, C_1-6alkyl, —CHF₂, —CF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵—S(O)R⁵⁴, —S(O)₂R⁵⁴—C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵—NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, and —C(O)OR⁵⁴; or
  • [0451] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵ and C_1-6-alkyl, wherein
    • [0452] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6alkyl, C_1-6-alkyl-arylene-, C_1-6alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6alkylene-, heteroaryl, or aryl;
    • [0453] or
    • [0454] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment 117: A compound according to embodiment 138, wherein
  • [0455] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, or C_1-6-alkyl, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-aryl-C_1-6-alkylene-, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-heteroaryl, or C_3-10-aryl
    Embodiment 118: A compound according to embodiment 141, wherein
  • [0456] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6alkyl.
    Embodiment 119: A compound according to embodiment 142, wherein
  • [0457] R⁵⁴ is hydrogen.
    Embodiment 120: A compound according to embodiment 142 or embodiment 143, wherein
  • [0458] R⁵⁵ is hydrogen.
    Embodiment 121: A compound according to embodiment 135, wherein
• [0459] G¹ is

[0460]

• [0461] R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰, independently of each other, are hydrogen or halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁶¹, —NR⁶¹R⁶², —SR⁶¹, —NR⁶¹S(O)₂R⁶², —S(O)₂NR⁶¹R⁶², —S(O)NR⁶¹R⁶², —S(O)R⁶¹, —S(O)₂R⁶¹—C(O)NR⁶¹R⁶², —OC(O)NR⁶¹R⁶², —NR⁶¹C(O)R⁶², —CH₂C(O)NR⁶¹R⁶², —CH₂C(O)OR⁶¹, —OCH₂C(O)NR⁶¹R⁶²—CH₂OR⁶¹, —CH₂NR⁶¹R⁶²—OC(O)R⁶¹, —C(O)R⁶¹ and —C(O)OR⁶¹; or C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁶¹, —NR⁶¹R⁶² and C₁ alkyl; C_3-10-cycloalkyl, C_4-8-cycloalkenyl, heterocyclyl, C_3-10-cycloalkyl-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkoxy-, C_3-10-cycloalkyloxy, C_3-10-cycloalkyl-C_1-6alkylthio-, C_3-10-cycloalkylthio, C_3-10-cycloalkyl-C_2-6-alkenylene-, C_3-10-cycloalkyl-C_2-6-alkynylene-, C_4-8-cycloalkenyl-C_1-6-alkylene-, C_4-8-cycloalkenyl-C_2-6-alkenylene-, C_4-8-cycloalkenyl-C_2-6-alkynylene-, heterocyclyl-C_1-6-alkylene-, heterocyclyl-C_2-6-alkenylene-, heterocyclyl-C_2-6-alkynylene-; or aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C_1-6-alkoxy-, aryl-C_1-6-alkylene-, aryl-C_2-6-alkenylene-, aryl-C_2-6-alkynylene-, heteroaryl, heteroaryl-C_1-6-alkylene-, heteroaryl-C_2-6-alkenylene- and heteroaryl-C_2-6-alkynylene-, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR⁶¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁶¹, —NR⁶¹R⁶² or C_1-6-alkyl, wherein
  • [0462] R⁶¹ and R⁶² independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
  • [0463] or
  • [0464] R⁶¹ and R⁶², when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 122: A compound according to embodiment 146, wherein
  • [0465] R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ independently of each other are halogen, —CN, —NO₂, C_1-6alkyl, —CHF₂, —CF₃, —OR⁶¹, —NR⁶¹R⁶²—SR⁶¹, —NR⁶¹S(O)₂R⁶²—S(O)₂NR⁶¹R⁶², —S(O)NR⁶¹R⁶², —S(O)R⁶¹, —S(O)₂R⁶¹, —C(O)NR⁶¹R⁶², —OC(O)NR⁶¹R⁶². —NR⁶¹C(O)R⁶², —CH₂C(O)NR⁶¹R⁶², —CH₂C(O)OR⁶¹, —OCH₂C(O)NR⁶¹R⁶², —CH₂OR⁶¹, —CH₂NR⁶¹R⁶², and —C(O)OR⁶¹; or
  • [0466] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁶¹, —NR⁶¹R⁶² and C_1-6-alkyl, wherein
    • [0467] R⁶¹ and R⁶² independently of each other are hydrogen, C_1-6alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [0468] or
    • [0469] R⁶¹ and R⁶², when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment 123: A compound according to embodiment 146 or embodiment 147, wherein
• [0470] R²⁴ or R²⁵ is —OR⁶¹.
  Embodiment 124: A compound according to embodiment 147, wherein
  • [0471] R⁶¹ and R⁶² independently of each other are hydrogen, or C_1-6-alkyl, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-aryl-C_1-6-alkylene-, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment 125: A compound according to embodiment 150, wherein
  • [0472] R⁶¹ and R⁶² independently of each other are hydrogen or C_1-5-alkyl.
    Embodiment 126: A compound according to embodiment 151, wherein
  • [0473] R⁶¹ is hydrogen.
    Embodiment 127: A compound according to embodiment 151 or embodiment 152, wherein
  • [0474] R⁶² is hydrogen.
    Embodiment 128: A compound according to any of embodiments 146 to 153, wherein
  • [0475] at least one of R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ are hydrogen.
    Embodiment 129: A compound according to embodiment 154, wherein
  • [0476] at least two of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment 130: A compound according to embodiment 155, wherein
  • [0477] at least three of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment 131: A compound according to any of embodiments 1 to 156, wherein
  • [0478] L² is a direct bond, C_1-6-alkylene, C_2-6-alkenylene, C_2-6-alkynylene, —N—R²⁰—, —C_1-6-alkylene-N(R²⁰)—, —C_2-6-alkenylene-N(R²⁰)—, or —C_2-6-alkynylene-N(R²⁰)—, wherein
    • [0479] R²⁰ is as defined for embodiment 1.
      Embodiment 132: A compound according to any of embodiments 1 to 153, wherein
  • [0480] L² is —N—R²⁰—, -alkylene-N(R²⁰)—, -alkenylene-N(R²⁰)—, or -alkynylene-N(R²⁰)—, wherein
    • [0481] R²⁰ is as defined for embodiment 1.
      Embodiment 133: A compound according to embodiment 157 or embodiment 158, wherein
  • [0482] L² is —N—R²⁰—, —C_1-6-alkylene-N(R²⁰)—, —C_2-6-alkenylene-N(R²⁰)—, or —C_2-6-alkynylene-N(R²⁰)—, wherein
    • [0483] R²⁰ is as defined for embodiment 1.
      Embodiment 134: A compound according to embodiment 159, wherein
  • [0484] L² is —N—R²⁰—, wherein
    • [0485] R²⁰ is as defined for embodiment 1.
      Embodiment 135: A compound according to embodiment 157, wherein
  • [0486] L² is a direct bond.
    Embodiment 136: A compound according to any of embodiments 1 to 160, wherein
  • [0487] R²⁰ is hydrogen, or
  • [0488] R²⁰ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl-W³—, C_3-10-heterocyclyl-W³—, C_3-10-aryl-W³—, or C_4-10-heteroaryl-W³—, optionally substituted with one or more substituents R³⁰, R³¹, and R³², wherein
    • [0489] W³, R³⁰, R³¹, and R³² are as defined for embodiment 1.
      Embodiment 137: A compound according to embodiment 162, wherein
  • [0490] W³ is alkylene.
    Embodiment 138: A compound according to embodiment 163, wherein
  • [0491] W³ is C_2-6-alkylene.
    Embodiment 139: A compound according to embodiment 162, wherein
  • [0492] W³ is a direct bond.
    Embodiment 140: A compound according to any of embodiments 1 to 160, wherein
  • [0493] R²⁰ is hydrogen, alkyl, alkenyl, or alkynyl, optionally substituted with one or more substituents R³⁰, R³¹, and R³² wherein
    • [0494] R³⁰, R³¹, and R³² are as defined for embodiment 1.
      Embodiment 141: A compound according to any of embodiments 162 to 166, wherein
  • [0495] R²⁰ is hydrogen, or
  • [0496] R²⁰ is C_1-6-alkyl, C_1-6-alkenyl, or C_1-6-alkynyl, optionally substituted with one or more substituents R³⁰, R³¹, and R³², wherein
    • [0497] R³⁰, R³¹, and R³² are as defined for embodiment 1.
      Embodiment 142: A compound according to any of embodiments 1 to 167, wherein
  • [0498] R³⁰, R³¹, and R³² independently of each other are selected from —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵², —NR⁵²R⁵³, —SR₅₂, —NR⁵²S(O)₂R⁵³, —S(O)₂NR⁵²R⁵³, —S(O)NR⁵²R⁵³, —S(O)R⁵², —S(O)₂R⁵², —C(O)NR⁵²R⁵³, —OC(O)NR⁵²R⁵³, —NR⁵²C(O)R⁵³, —CH₂C(O)NR⁵²R⁵³, —OCH₂C(O)NR⁵²R⁵³, —CH₂OR⁵², —CH₂NR⁵²R⁵³, —OC(O)R⁵², —C(O)R⁵² and —C(O)OR⁵², wherein
    • [0499] R⁵² and R⁵³ are as defined for embodiment 1.
      Embodiment 143: A compound according to embodiment 168, wherein
  • [0500] R⁵² and R⁵³, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 144: A compound according to any of embodiments 1 to 168, wherein
  • [0501] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-heteroaryl-C_1-6-alkylene- heteroaryl, or aryl.
    Embodiment 145: A compound according to embodiment 170, wherein
  • [0502] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-or aryl.
    Embodiment 146: A compound according to embodiment 171, wherein
  • [0503] R⁵² and R⁵³ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment 147: A compound according to embodiment 172, wherein
  • [0504] R⁵² is hydrogen.
    Embodiment 148: A compound according to embodiment 172 or embodiment 173, wherein
  • [0505] R⁵³ is hydrogen.
    Embodiment 149: A compound according to embodiment 167, wherein
  • [0506] R²⁰ is hydrogen.
    Embodiment 150: A compound according to any of embodiments 1 to 175, wherein
  • [0507] L³ is —C(O)—.
    Embodiment 151: A compound according to any of embodiments 1 to 176, wherein
  • [0508] R¹ is hydrogen, or
  • [0509] R¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl-W⁴—, C_3-10-heterocyclyl-W⁴—, C_3-10-aryl-W⁴—, or C_4-10-heteroaryl-W⁴—, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵ wherein
    • [0510] W⁴, R³³, R³⁴, and R³⁵ are as defined for embodiment 1.
      Embodiment 152: A compound according to embodiment 180, wherein
  • [0511] W⁴ is alkylene.
    Embodiment 153: A compound according to embodiment 181, wherein
  • [0512] W⁴ is C_2-6-alkylene.
    Embodiment 154: A compound according to embodiment 180, wherein
  • [0513] W⁴ is a direct bond.
    Embodiment 155: A compound according to any of embodiments 1 to 176, wherein
  • [0514] R¹ is hydrogen, alkyl, alkenyl, or alkynyl, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵, wherein
    • [0515] R³³, R³⁴, and R³⁵ are as defined for embodiment 1.
      Embodiment 156: A compound according to any of embodiments 180 to 184, wherein
  • [0516] R¹ is hydrogen, C_1-6alkyl, C_2-6-alkenyl, or C_2-6-alkynyl, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵, wherein
    • [0517] R³³, R³⁴, and R³⁵ are as defined for embodiment 1.
      Embodiment 157: A compound according to embodiment 185, wherein
  • [0518] R¹ is hydrogen or C_1-6-alkyl optionally substituted with one or more substituents R³³, R³⁴ and R³⁵, wherein
    • [0519] R³³, R³⁴, and R³⁵ are as defined for embodiment 1.
      Embodiment 158: A compound according to any of embodiments 1 to 186, wherein
  • [0520] R³³, R³⁴, and R³⁵ independently of each other are selected from —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵², —NR⁵²R⁵³, —SR₅₂, —NR⁵²S(O)₂R⁵³, —S(O)₂NR⁵²R⁵³, —S(O)NR⁵²R⁵³, —S(O)R⁵², —S(O)₂R⁵², —C(O)NR⁵²R⁵³, —OC(O)NR⁵²R⁵³, —NR⁵²C(O)R⁵³, —CH₂C(O)NR⁵²R⁵³, —OCH₂C(O)NR⁵²R⁵³, —CH₂OR⁵², —CH₂NR⁵²R⁵³, —OC(O)R⁵², —C(O)R⁵² and —C(O)OR⁵², wherein
    • [0521] R⁵² and R⁵³ are as defined for embodiment 1.
      Embodiment 159: A compound according to embodiment 186, wherein
  • [0522] R⁵² and R⁵³, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 160: A compound according to embodiment 186, wherein
  • [0523] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-heteroaryl-C_1-6alkylene- heteroaryl, or aryl.
    Embodiment 161: A compound according to embodiment 189, wherein
  • [0524] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-or aryl.
    Embodiment 162: A compound according to embodiment 190, wherein
  • [0525] R⁵² and R⁵³ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment 163: A compound according to embodiment 191, wherein
  • [0526] R⁵² is hydrogen.
    Embodiment 164: A compound according to embodiment 191 or embodiment 192, wherein
  • [0527] R⁵³ is hydrogen.
    Embodiment 165: A compound according to embodiment 186, wherein
  • [0528] R¹ is hydrogen.
    Embodiment 166: A compound according to any of embodiments 1 to 194, wherein
  • [0529] G² is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G² with —N(R¹)—, and wherein
    • [0530] R⁴³, R⁴⁴, and R⁴⁵ are as defined for embodiment 1.
      Embodiment 167: A compound according to embodiment 195, wherein
  • [0531] G² is heteroaryl optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G² with —N(R¹)—, and wherein
    • [0532] R⁴³, R⁴⁴, and R⁴⁵ are as defined for embodiment 1.
      Embodiment 168: A compound according to embodiment 199, wherein
  • [0533] G² is furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, or indazolyl, optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵ wherein
    • [0534] R⁴³, R⁴⁴, and R⁴⁵ are as defined for embodiment 1.
      Embodiment 169: A compound according to any of embodiments 1 to 200, wherein
  • [0535] R⁴³, R⁴⁴, and R⁴⁵ independently of each other are selected from halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵—S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, —OC(O)R⁵⁴, —C(O)R⁵⁴ and —C(O)OR⁵⁴, wherein
    • [0536] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
      Embodiment 170: A compound according to embodiment 207, wherein
  • [0537] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, and optionally substituted with one or more C_1-6-alkyl groups.
    Embodiment 171: A compound according to embodiment 208, wherein
  • [0538] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 172: A compound according to embodiment 207, wherein
  • [0539] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6alkylene- or aryl.
    Embodiment 173: A compound according to embodiment Error! Reference source not found., wherein
  • [0540] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, C_3-10-aryl-C_1-6-alkylene- or C_3-10-aryl.
    Embodiment 174: A compound according to embodiment Error! Reference source not found., wherein
  • [0541] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment 175: A compound according to embodiment Error! Reference source not found., wherein
  • [0542] R⁵⁴ is hydrogen.
    Embodiment 176: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0543] R⁵⁵ is hydrogen.
    Embodiment 177: A compound according to embodiment 207, wherein
  • [0544] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or —(CHR⁶³)_u—(CHR⁶⁴)_v-Z, wherein
    • [0545] u is 1 or 2;
    • [0546] v is 0, 1 or 2;
    • [0547] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6alkyl, C_1-6-alkyl-C_3-10-arylene- C_3-10-aryl, hydroxy, hydroxy-C_1-6-alkyl, amino, or amino-C_1-6-alkyl;
    • [0548] Z is hydrogen, —C—O—R⁶⁵, —C(O)O—R⁶⁵—CONR⁶⁵R⁶⁶, C_1-6-alkylamino, or di(C_1-6alkyl)-amino, wherein
      • [0549] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6alkyl;
    • [0550] or
    • [0551] Z is a five or six membered ring wherein at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen.
      Embodiment 178: A compound according to embodiment Error! Reference source not found., wherein
  • [0552] u is 1; and
  • [0553] v is 0, or 1.
    Embodiment 179: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0554] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6alkyl, hydroxy, hydroxy-C_1-6-alkyl, amino, or amino-C_1-6-alkyl.
    Embodiment 180: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0555] Z is —C—O—R⁶⁵, or —C(O)O—R⁶⁵, wherein
    • [0556] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6alkyl.
      Embodiment 181: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0557] Z is a five or six membered ring where at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen.
    Embodiment 182: A compound according to embodiment Error! Reference source not found., wherein
  • [0558] Z is a five or six membered ring wherein at least one ring atom is nitrogen, one ring atom is oxygen and the remaining ring atoms are carbon.
    Embodiment 183: A compound according to embodiment Error! Reference source not found., wherein
  • [0559] Z is a five or six membered ring wherein at least one ring atom is nitrogen, and the remaining ring atoms are carbon.
    Embodiment 184: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0560] Z is a five or six membered ring wherein one ring atom is nitrogen.
    Embodiment 185: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0561] a nitrogen atom is the point of attachment of the Z group to the —(CHR⁶³)_u—(CHR⁶⁴)_v— group.
    Embodiment 186: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0562] R⁵⁵ is hydrogen.
    Embodiment 187: A compound according to any of embodiments 195 to 207, wherein
  • [0563] G² is substituted with a substituent R⁴³, wherein
    • [0564] R⁴³ is halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴—NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, —OC(O)R⁵⁴—C(O)R⁵⁴ or —C(O)OR⁵⁴, wherein
      • [0565] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
        Embodiment 188: A compound according to embodiment Error! Reference source not found., wherein
  • [0566] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, and optionally substituted with one or more C_1-6alkyl groups.
    Embodiment 189: A compound according to embodiment Error! Reference source not found., wherein
  • [0567] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 190: A compound according to embodiment Error! Reference source not found., wherein
  • [0568] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6alkyl, aryl-C_1-6alkylene- or aryl.
    Embodiment 191: A compound according to embodiment Error! Reference source not found., wherein
  • [0569] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6alkyl, C_3-10-aryl-C_1-6-alkylene- or C_3-10-aryl.
    Embodiment 192: A compound according to embodiment Error! Reference source not found., wherein
  • [0570] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment 193: A compound according to embodiment Error! Reference source not found., wherein
  • [0571] R⁵⁴ is hydrogen.
    Embodiment 194: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0572] R⁵⁵ is hydrogen.
    Embodiment 195: A compound according to embodiment Error! Reference source not found., wherein
  • [0573] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or —(CHR⁶³)_u—(CHR⁶⁴)_v-Z, wherein
    • [0574] u is 1 or 2;
    • [0575] v is 0, 1 or 2;
    • [0576] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-C_3-10-arylene- C_3-10-aryl, hydroxy, hydroxy-C_1-6-alkyl, amino, or amino-C_1-6-alkyl;
    • [0577] Z is hydrogen, —C—O—R⁶⁵, —C(O)O—R⁶⁵, —CONR⁶⁵R⁶⁶, C_1-6-alkylamino or di(C_1-6-alkyl)-amino, wherein
      • [0578] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6alkyl;
    • [0579] or
    • [0580] Z is a five or six membered ring wherein at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen.
      Embodiment 196: A compound according to embodiment Error! Reference source not found., wherein
  • [0581] u is 1; and
  • [0582] v is 0, or 1.
    Embodiment 197: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0583] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6-alkyl, hydroxy, hydroxy-C_1-6-alkyl, amino, or amino-C_1-6alkyl.
    Embodiment 198: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0584] Z is —C—O—R⁶⁵, or —C(O)O—R⁶⁵, wherein
    • [0585] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6-alkyl.
      Embodiment 199: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0586] Z is a five or six membered ring where at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen.
    Embodiment 200: A compound according to embodiment Error! Reference source not found., wherein
  • [0587] Z is a five or six membered ring wherein at least one ring atom is nitrogen, one ring atom is oxygen and the remaining ring atoms are carbon.
    Embodiment 201: A compound according to embodiment Error! Reference source not found., wherein
  • [0588] Z is a five or six membered ring wherein at least one ring atom is nitrogen, and the remaining ring atoms are carbon.
    Embodiment 202: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0589] Z is a five or six membered ring wherein one ring atom is nitrogen.
    Embodiment 203: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0590] a nitrogen atom is the point of attachment of the Z group to the —(CHR⁶³)_u—(CHR⁶⁴)_v— group.
    Embodiment 204: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0591] R⁵⁵ is hydrogen.
    Embodiment 205: A compound according to embodiment Error! Reference source not found., wherein
  • [0592] R⁴³ is —CH₂C(O)OR⁵⁴, wherein
    • [0593] R⁵⁴ is as defined for embodiment 1.
      Embodiment 206: A compound according to embodiment Error! Reference source not found., wherein
  • [0594] R⁵⁴ is hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene- or aryl.
    Embodiment 207: A compound according to embodiment Error! Reference source not found., wherein
  • [0595] R⁵⁴ is hydrogen, C_1-6-alkyl, C_3-10-aryl-C_1-6-alkylene- or C_3-10-aryl.
    Embodiment 208: A compound according to embodiment Error! Reference source not found., wherein
  • [0596] R⁵⁴ is hydrogen or C_1-6-alkyl.
    Embodiment 209: A compound according to embodiment Error! Reference source not found., wherein
  • [0597] R⁵⁴ is hydrogen.
    Embodiment 210: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0598] R⁴³ is attached to the atom adjacent to the nitrogen atom adjacent to the atom joining G² with —N(R¹)—.
    Embodiment 211: A compound according to any of embodiments 195 to Error! Reference source not found., wherein
• [0599] G² is

[0600]

• • [0601] R⁴³, R⁴⁴, and R⁴⁵ independently of each other are hydrogen or as defined for embodiment 1.
    Embodiment 212: A compound according to embodiment Error! Reference source not found., wherein
• [0602] G² is

[0603]

• • [0604] R⁴³, R⁴⁴, and R⁴⁵ independently of each other are hydrogen or as defined for embodiment 1.
    Embodiment 213: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0605] R⁴³, R⁴⁴, and R⁴⁵ independently of each other are selected from hydrogen, halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR ⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, —OC(O)R⁵⁴, —C(O)R⁵⁴ and —C(O)OR⁵⁴, wherein
    • [0606] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
      Embodiment 214: A compound according to embodiment Error! Reference source not found., wherein
  • [0607] R⁴³ is halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵—SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, —OC(O)R⁵⁴, —C(O)R⁵⁴ or —C(O)OR⁵⁴, wherein
    • [0608] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
      Embodiment 215: A compound according to embodiment Error! Reference source not found. or Error! Reference source not found., wherein
  • [0609] R⁴³ is —C(O)OR⁵⁴, —CH₂C(O)OR⁵⁴, —C(O)NR⁵⁴R⁵⁵, or —CH₂C(O)NR⁵R⁵⁵, wherein
    • [0610] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
      Embodiment 216: A compound according to embodiment Error! Reference source not found. or Error! Reference source not found., wherein
  • [0611] R⁴⁴ is alkyl or hydrogen.
    Embodiment 217: A compound according to embodiment Error! Reference source not found., wherein
  • [0612] R⁴⁴ is C_1-6alkyl or hydrogen.
    Embodiment 218: A compound according to embodiment Error! Reference source not found., wherein
  • [0613] R⁴⁴ is hydrogen.
    Embodiment 219: A compound according to embodiment Error! Reference source not found., wherein
  • [0614] R⁴⁴ is halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, —OC(O)R⁵⁴, —C(O)R⁵⁴ or —C(O)OR⁵⁴, wherein
    • [0615] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
      Embodiment 220: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0616] R⁴⁴ is —C(O)OR⁵⁴, —CH₂C(O)OR⁵⁴, —C(O)NR⁵⁴R⁵⁵, or —CH₂C(O)NR⁵⁴R⁵⁵, wherein
    • [0617] R⁵⁴ and R⁵⁵ are as defined for embodiment 1.
      Embodiment 221: A compound according to embodiment Error! Reference source not found. or Error! Reference source not found., wherein
  • [0618] R⁴³ is alkyl or hydrogen.
    Embodiment 222: A compound according to embodiment Error! Reference source not found., wherein
  • [0619] R⁴³ is C_1-6-alkyl or hydrogen.
    Embodiment 223: A compound according to embodiment Error! Reference source not found., wherein
  • [0620] R⁴³ is hydrogen.
    Embodiment 224: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0621] R⁴⁵ is hydrogen.
    Embodiment 225: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0622] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, and optionally substituted with one or more C_1-6alkyl groups.
    Embodiment 226: A compound according to embodiment Error! Reference source not found., wherein
  • [0623] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment 227: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0624] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6alkyl, aryl-C_1-6-alkylene- or aryl.
    Embodiment 228: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0625] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6alkyl, aryl-C_1-6-alkylene- or aryl.
    Embodiment 229: A compound according to embodiment Error! Reference source not found., wherein
  • [0626] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6alkyl.
    Embodiment 230: A compound according to embodiment Error! Reference source not found., wherein
  • [0627] R⁵⁴ is hydrogen.
    Embodiment 231: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0628] R⁵⁵ is hydrogen.
    Embodiment 232: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0629] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or —(CHR⁶³)_u—(CHR⁶⁴)_v-Z, wherein
    • [0630] u is 1 or 2;
    • [0631] v is 0, 1 or 2;
    • [0632] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6alkyl, C_1-6-alkyl-C_3-10-arylene-C_3-10-aryl, hydroxy, hydroxy-C_1-6-alkyl, amino, or amino-C_1-6alkyl;
    • [0633] Z is hydrogen, —C—O—R⁶⁵, —C(O)O—R⁶⁵, —CONR⁶⁵R⁶⁶, C_1-6-alkylamino, or di(C_1-6-alkyl)-amino, wherein
      • [0634] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6alkyl;
    • [0635] or
    • [0636] Z is a five or six membered ring wherein at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen.
      Embodiment 233: A compound according to embodiment Error! Reference source not found., wherein
  • [0637] u is 1; and
  • [0638] v is 0, or 1.
    Embodiment 234: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0639] R⁶³ and R⁶⁴ independently of each other are hydrogen, C_1-6alkyl, hydroxy, hydroxy-C_1-6alkyl, amino, or amino-C_1-6-alkyl.
    Embodiment 235: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0640] Z is —C—O—R⁶⁵, or —C(O)O—R⁶⁵, wherein
    • [0641] R⁶⁵ and R⁶⁶ independently of each other is hydrogen or C_1-6-alkyl.
      Embodiment 236: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0642] Z is a five or six membered ring where at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen.
    Embodiment 237: A compound according to embodiment Error! Reference source not found., wherein
  • [0643] Z is a five or six membered ring wherein at least one ring atom is nitrogen, one ring atom is oxygen and the remaining ring atoms are carbon.
    Embodiment 238: A compound according to embodiment Error! Reference source not found., wherein
  • [0644] Z is a five or six membered ring wherein at least one ring atom is nitrogen, and the remaining ring atoms are carbon.
    Embodiment 239: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0645] Z is a five or six membered ring wherein one ring atom is nitrogen.
    Embodiment 240: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0646] a nitrogen atom is the point of attachment of the Z group to the —(CHR⁶³)_u—(CHR⁶⁴)_v— group.
    Embodiment 241: A compound according to any of embodiments Error! Reference source not found. to Error! Reference source not found., wherein
  • [0647] R⁵⁵ is hydrogen.
    Embodiment 242: A compound according to embodiment Error! Reference source not found., wherein
  • [0648] R⁴⁴ is hydrogen.
    Embodiment 243: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0649] R⁴³ is hydrogen.
    Embodiment 244: A compound according to embodiment Error! Reference source not found. or embodiment Error! Reference source not found., wherein
  • [0650] R⁴⁵ is hydrogen.
    Embodiment 245: A compound according to embodiment 1, which is,
• [0651] N-(2-phenoxyphenyl)-N′-(thiazol-2-yl)urea,
• [0652] N-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]-N′-(thizol-2-yl)sulfamide,
• [0653] 1-(2-phenoxyphenyl)-5-(thiazol-2-yl)biuret,
• [0654] 2-[([[(2-phenoxyanilino)sulfonyl]amino]carbonyl)amino]thiazole,
• [0655] N-(2-phenylsulfanylphenyl)-N′-(thiazol-2-yl)urea,
• [0656] N-(2-phenylsulfonylphenyl)-N′-(thiazol-2-yl)urea,
• [0657] N-(2-benzylphenyl)-N′-(thiazol-2-yl)urea,
• [0658] N-(2-benzoylphenyl)-N′-(thiazol-2-yl)urea,
• [0659] N-[2-(phenylamino)phenyl]-N′-(thiazol-2-yl)urea,
• [0660] N-[2-fluoro-6-(4-methoxyphenoxy)benzyl]-N′-(thiazol-2-yl)urea,
• [0661] N-(2-benzyloxyphenyl)-N′-(thiazol-2-yl)urea,
• [0662] N-[2-(2,3,4-trimethoxybenzyloxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0663] N-(2-ethoxyphenyl)-N′-(thiazol-2-yl)urea,
• [0664] N-(2-phenoxyphenyl)-N′-(pyridin-2-yl)urea,
• [0665] N-(2-phenoxyphenyl)-N′-[(4-methoxycarbonylmethyl)thiazol-2-yl]urea,
• [0666] N-methyl-N-(2-phenoxyphenyl)-N′-(thiazol-2-yl)urea,
• [0667] N-isopropyl-N-(2-phenoxyphenyl)-N′-(thiazol-2-yl)urea,
• [0668] N-[2-(4-methoxyphenoxy)phenyl)-N′-(thiazol-2-yl)urea,
• [0669] N-[2-(4-fluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0670] N-[2-(4-chlorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0671] N-[2-(4-cyanophenoxy)phenyl]-N′-thiazolylurea,
• [0672] N-[2-(4-methoxycarbonylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0673] N-[2-(4-isopropylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0674] N-[2-(3,4-difluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0675] N-[2-(3,4-dichlorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0676] N-[2-(4-chloro-3-methylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0677] N-[2-(3,4-dimethoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0678] N-[2-(3,4-methylenedioxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0679] N-[2-(2,4-dichlorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0680] N-[2-(2,4-difluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0681] N-[2-(4-fluoro-2-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0682] N-[2-(4-methoxy-2-methoxycarbonylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0683] N-[2-(3-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0684] N-[2-(3-fluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0685] N-[2-(3-trifluoromethylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0686] N-[2-(2-methylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0687] N-[2-2-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0688] N-[2-(2-isopropoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0689] N-[2-2-fluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0690] N-[2-(2-methylsulfanylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0691] N-[2-(2-methylsulfonylphenoxy)phenyl]-N′-thiazolylurea,
• [0692] N-[2-(2-trifluoromethylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0693] N-[2-(2,6-dimethoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0694] N-[2-(2,6-difluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0695] N-[2-(2-fluoro-6-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0696] N-[2-2-methoxy-6-methoxycarbonylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0697] N-[(3-methoxy-2-methoxycarbonylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0698] N-[2-(2,3-dimethoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0699] N-[2-(2,3,4-trichlorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0700] N-[2-(2,4,6-trifluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0701] N-[2-(2,4-dichloronaphth-1-oxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0702] N-[2-(2-methoxyphenoxy)-5-(methylsulfonyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0703] N-[5-cyano-2-(2-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0704] N-[5-fluoro-2-(2-methylsulfanylphenoxy)phenyl]-N′-thiazolylurea,
• [0705] N-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0706] N-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]-N′-(thiazol-2-yl)urea,
• [0707] N-[2-(3,4-difluorophenoxy)-5-fluorophenyl]-N′-(thiazol-2-yl)urea,
• [0708] N-[5-fluoro-2-(4-fluorophenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0709] N-[2-(2,4-dichlorophenoxy)-5-fluorophenyl]-N′-(thiazol-2-yl)urea,
• [0710] N-[5-fluoro-2-(4-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0711] N-[5-fluoro-2-(2-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0712] N-[5-fluoro-2-(2-trifluoromethylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0713] N-[5-fluoro-2-(naphth-2-oxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0714] N-[2-(2,3-dimethoxyphenoxy)-6-fluorophenyl]-N′-(thiazol-2-yl)urea,
• [0715] N-[2-(4-fluoro-2-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0716] N-[2-(2,3-dimethoxyphenoxy)-4-fluorophenyl]-N′-(thiazol-2-yl)urea,
• [0717] N-[4-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0718] N-[2-(2-fluoro-6-methoxyphenoxy)-4-methoxyphenyl]-N′-(thiazol-2-yl)urea,
• [0719] N-[3-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0720] N-[2-2,3-dimethoxyphenoxy)-5-methoxyphenyl]-N′-thiazol-2-ylurea,
• [0721] N-[2-(2,3-dimethoxyphenoxy)-4-methylphenyl]-N′-(thiazol-2-yl)urea,
• [0722] N-[2-2,3-dimethoxyphenoxy)-3-methylphenyl]-N′-(thiazol-2-yl)urea,
• [0723] N-[2-(2-chlorophenoxy)-5-chlorophenyl]-N′-(thiazol-2-yl)urea,
• [0724] N-[5-chloro-2-(4-chloro-3-methylphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0725] N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0726] N-[4,5-difluoro-2-(2,3-dimethoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0727] N-[4,5-dichloro-2-(2,3-dimethoxyphenoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0728] N-[5-chloro-2-(2,3-dimethoxyphenoxy)-4-dimethylaminophenyl]-N′-(thiazol-2-yl)urea,
• [0729] N-[5-chloro-2-(2,3-dimethoxyphenoxy)-4-(4-morpholino)phenyl]-N′-(thiazol-2-yl)urea,
• [0730] N-[2-(2,4-difluorophenoxy)pyridin-3-yl]-N′-(thiazol-2-yl)urea,
• [0731] N-[2-(2-fluorophenoxy)pyridin-3-yl]-N′-[thiazol-2-yl]urea,
• [0732] N-[2-(2-methoxyphenoxy)pyridin-3-yl]-N′-(thiazol-2-yl)urea,
• [0733] N-[2-(2,3-dimethoxyphenoxy)pyridin-3-yl]-N-(thiazol-2-yl)urea,
• [0734] N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0735] N-[4-chloro-2-(2-fluorobenzoyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0736] N-[2-(2,4-difluorophenylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0737] 1-[2-(2-fluorophenylsulfanyl)phenyl]-3-(thiazol-2-yl)urea,
• [0738] N-[2-(2-chloro-4-fluorophenylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0739] N-[2-(2,3-dichlorophenylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0740] N-[2-(3,5-dimethylphenylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0741] N-[2-(2-methoxycarbonylphenylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0742] N-[2-(2-methoxyphenylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0743] N-[2-(2-pyridinylsulfanyl)phenyl]-N′-(thiazol-2-yl)urea,
• [0744] N-(2-propyloxyphenyl)-N′-(thiazol-2-yl)urea,
• [0745] N-(2-butyloxyphenyl)-N′-(thiazol-2-yl)urea,
• [0746] N-(2-(cyclopentyloxyphenyl)-N′-(thiazol-2-yl)urea,
• [0747] N-(2-isopropoxyphenyl)-N′-(thiazol-2-yl)urea,
• [0748] N-[2-(2-methylpropoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0749] N-[2-(cyclopentylmethoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0750] N-[2-(3-pentoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0751] N-[2-(2-pentoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0752] N-[2-(2-methoxyethoxy)phenyl]-N′-(thiazol-2-yl)urea,
• [0753] (2-[3-(2-benzylphenyl)ureido]thiazol-4-yl)acetic acid,
• [0754] (2-[3-(2-benzoyl-4-chlorophenyl)ureido]thiazol-4-yl)acetic acid,
• [0755] (2-[3-(2-(2-methylphenoxy)phenyl)ureido]thiazol-4-yl)acetic acid,
• [0756] (2-[3-(2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl)ureido]thiazol-4-yl)acetic acid,
• [0757] {2-[3-(2-phenoxyphenyl)ureido]thiazol-4-y}acetic acid,
• [0758] 2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazole-4-carboxylic acid,
• [0759] 2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazole-4-carboxylic acid ethyl ester,
• [0760] (2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazol-4-yl)acetic acid ethyl ester,
• [0761] (2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazol-4-yl)acetic acid,
• [0762] 2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazole-4-carboxylic acid,
• [0763] (2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazol-4-yl)acetic acid,
• [0764] 2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}-4-methylthiazole-5-carboxylic acid ethyl ester,
• [0765] 2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}-4-methylthiazole-5-carboxylic acid,
• [0766] N-ethyl-2-(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazol-4-yl)acetamide,
• [0767] 2-(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazol-4-yl)-N-(2-methoxy-ethyl)acetamide,
• [0768] 2-(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazol-4-yl)-N-(2-morpholin-4-ylethyl)acetamide,
• [0769] [2-(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazol-4-yl)acetylamino]acetic acid methyl ester,
• [0770] 2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazole-4-carboxylic acid (2-methoxyethyl)amide,
• [0771] [2-(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazol-4-yl)acetylamino]acetic acid,
• [0772] 2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazole-4-carboxylic acid ethylamide,
• [0773] [(2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazole-4-carbonyl)amino]acetic acid methyl ester,
• [0774] (5-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}-[1,3,4]thiadiazol-2-yl)acetic acid ethyl ester,
• [0775] [(2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazole-4-carbonyl)amino]acetic acid,
• [0776] (5-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}-[1,3,4]thiadiazol-2-yl)acetic acid,
• [0777] 5-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester,
• [0778] (5-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}-[1,3,4]thiadiazol-2-yl) acetic acid ethyl ester,
• [0779] 3-[2-(2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazol-4-yl)acetylamino]propionic acid methyl ester,
• [0780] 2-(2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazol-4-yl)-N-(2-morpholin-4-ylethyl)acetamide,
• [0781] [(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazole-4-carbonyl)amino]acetic acid methyl ester,
• [0782] 3-[2-(2-{3-[2-(2,3-dimethoxyphenoxy)-5-fluorophenyl]ureido}thiazol-4-yl)acetylamino]propionic acid,
• [0783] [(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazole-4-carbonyl)amino]acetic acid,
• [0784] (R) 3-[(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazole-4-carbonyl)amino]-2-hydroxy-propionic acid,
• [0785] 2-[(2-{3-[5-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]ureido}thiazole-4-carbonyl)amino]-3-hydroxy-propionic acid,
• [0786] 1-(2-cyclopentanecarbonyl-4-methylphenyl)-3-thiazol-2-yl-urea,
• [0787] 1-(2-isobutyryl-4-methylphenyl)-3-thiazol-2-yl-urea,
• [0788] 1-[5-fluoro-2-(3-methylbutyryl)phenyl]-3-thiazol-2-yl-urea,
• [0789] 1-[5-methyl-2-(3-methylbutyryl)phenyl]-3-thiazol-2-yl-urea,
• [0790] [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]acetic acid ethyl ester,
• [0791] [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]acetic acid,
• [0792] 2-[3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]-N-methylacetamide,
• [0793] {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester,
• [0794] {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}acetic acid,
• [0795] {3-cyclopentanecarbonyl-4-{3-(4-ethoxycarbonylmethylthiazol-2-yl)-ureido}phenyl}acetic acid ethyl ester,
• [0796] 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(5-methanesulfonyl-thiazol-2-yl)-urea,
• [0797] 2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxylic acid ethyl ester,
• [0798] 2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxylic acid,
• [0799] 2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxamide,
• [0800] 2-{2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-yl}-acetamide,
• [0801] 2-{2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-N-methyl-acetamide,
• [0802] 4-(2-{2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazinium chloride,
• [0803] 1-[4-methyl-2-(2-methylpropoxy)phenyl]-3-thiazol-2-yl-urea,
• [0804] {2-[3-(4-methyl-2-[2-methylpropoxy]phenyl)-ureido]-thiazol-4-yl}-acetic acid, or
• [0805] {2-[3-(4-methyl-2-[2-methylpropoxy]phenyl)-ureido]-thiazol-4-yl)-N-methyl-acetamide.
  Embodiment 246: A compound according to any of embodiments 1 to Error! Reference source not found., which compound is an activator of glucokinase, when tested in the Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 2 mM.
  Embodiment 247: A compound according to any of embodiments 1 to 281, which compound is an activator of glucokinase, when tested in the Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of from 10 to 15 mM.
  Embodiment 248: A compound according to any of embodiments 1 to 282, which compound, at a concentration of 30 μM, is capable of providing an at least 1.5, such as at least 1.7, for instance at least 2.0 fold activation of glucokinase in the Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 2 mM.
  Embodiment 249: A compound according to any of embodiments 1 to 283, which compound, at a concentration of 30 μM, is capable of providing an at least 1.5, such as at least 1.7, for instance at least 2.0 fold activation of glucokinase in the Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of from 10 to 15 mM.
  Embodiment 250: A compound according to any of embodiments 1 to 284, which at a concentration of 5 μM is capable of providing an at least 1.5, such as at least 1.7, for instance at least 2.0 fold activation of glucokinase in the Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 2 mM.
  Embodiment 251: A compound according to any of embodiments 1 to 285, which at a concentration of 5 μM is capable of providing an at least 1.5, such as at least 1.7, for instance at least 2.0 fold activation of glucokinase in the Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of from 10 to 15 mM.
  Embodiment 252: A glucose kinase activator compound defined as a compound which at a compound concentration of at or below 30 μM at a glucose concentration of 2 mM in the Glucokinase Activation Assay (I) disclosed herein gives 1.5-fold higher glucokinase activity than measured at a glucose concentration of 2 mM in the Glucokinase Activation Assay (I) without compound, where the increase in glucokinase activity provided by the compound increases with decreasing concentrations of glucose.
  Embodiment 253: A compound according to any of embodiments 1 to 286, which compound provides an increase in glucokinase activity, where the increase in glucokinase activity provided by the compound increases with decreasing concentrations of glucose.
  Embodiment 254: A compound according to embodiment 287 or embodiment 288, which provides an increase in glucokinase activity in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 5 mM, which increase is significantly higher than the increase in glucokinase activity provided by the compound in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 15 mM.
  Embodiment 255: A compound according to any of embodiments 287 to 289, which at a compound concentration of 10 μM provides an increase in glucokinase activity in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 5 mM, which increase is significantly higher than the increase in glucokinase activity provided by the compound at a compound concentration of 10 μM in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 15 mM.
  Embodiment 256: A compound according to any of embodiments 287 to 290, which at a compound concentration of 10 μM provides an increase in glucokinase activity in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 5 mM, which increase is at least 1.1 fold higher, such as at least 1.2 fold higher, for instance at least 1.3 fold higher, such as at least 1.4 fold higher, for instance 1.5 fold higher, such as at least 1.6 fold higher, for instance at least 1.7 fold higher, such as at least 1.8 fold higher, for instance at least 1.9 fold higher, such as at least 2.0 fold higher than the increase in glucokinase activity provided by the compound at a compound concentration of 10 μM in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 15 mM.
  Embodiment 257: A glucose kinase activator compound defined as a compound which at a compound concentration of at or below 30 μM at a glucose concentration of 2 mM in the Glucokinase Activation Assay (I) disclosed herein gives 1.5-fold higher glucokinase activity than measured at a glucose concentration of 2 mM in the Glucokinase Activation Assay (I) without compound, which glucose kinase activator compound increases glucose utilization in the liver without inducing any increase in insulin secretion in response to glucose.
  Embodiment 258: A glucose kinase activator compound defined as a compound which at a compound concentration of at or below 30 μM at a glucose concentration of 2 mM in the Glucokinase Activation Assay (I) disclosed herein gives 1.5-fold higher glucokinase activity than measured at a glucose concentration of 2 mM in the Glucokinase Activation Assay (I) without compound, which glucokinase activator compound shows a significantly higher activity in isolated hepatocytes compared to the activity of the glucokinase compound in Ins-1 cells.
  Embodiment 259: A compound according to any of embodiments 1 to 291, which compound increases glucose utilization in the liver without inducing any increase in insulin secretion in response to glucose.
  Embodiment 260: A compound according to any of embodiments 1 to 291, which compound shows a significantly higher activity in isolated hepatocytes compared to the activity of the compound in Ins-1 cells.
  Embodiment 261: A compound according to any of embodiments 292 to 295, which compound shows a significantly higher activity in isolated hepatocytes measured as described in the Glucokinase Activity Assay (II) compared to the activity of the compound in Ins-1 cells measured as described in the Glucokinase Activity Assay (III).
  Embodiment 262: A compound according to embodiment 296, which compound shows an activity in isolated hepatocytes measured as described in the Glucokinase Activity Assay (II) which activity is at least 1.1 fold higher, such as at least 1.2 fold higher, for instance at least 1.3 fold higher, such as at least 1.4 fold higher, for instance 1.5 fold higher, such as at least 1.6 fold higher, for instance at least 1.7 fold higher, such as at least 1.8 fold higher, for instance at least 1.9 fold higher, such as at least 2.0 fold higher, for instance at least a 3.0 fold higher, such as at least a 4.0 fold higher, for instance at least 5.0 fold higher, such as at least 10 fold higher than the activity of the compound in Ins-1 cells measured as described in the Glucokinase Activity Assay (III).
  Embodiment 263: A compound according to embodiment 296, which compound shows no activity in the Ins-1 cells measured as described in the Glucokinase Activity Assay (III).
  Embodiment 264: A compound according to any one of embodiments 1 to 298, which is an agent useful for the treatment of an indication selected from the group consisting of hyperglycemia, IGT, insulin resistance syndrome, syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hypertension, and obesity.
  Embodiment 265: A compound according to any one of embodiments 1 to 301 for use as a medicament.
  Embodiment 266: A compound according to any one of embodiments 1 to 301 for treatment of hyperglycemia, for treatment of IGT, for treatment of Syndrome X, for treatment of type 2 diabetes, for treatment of type 1 diabetes, for treatment of dyslipidemia, for treatment of hyperlipidemia, for treatment of hypertension, for treatment of obesity, for lowering of food intake, for appetite regulation, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins, such as GLP-1.
  In a further aspect the invention provides in an Embodiment A1 a compound of the general formula (I)

[0806]

• [0807] A¹ is selected from the group consisting of arylene, heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene, fused cycloalkylheteroarylene, or fused heterocyclylheteroarylene; optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷, wherein
  • [0808] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0809] halogen, —C(O)OR², —C(O)R², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—C_1-6-alkylene-Z-, R⁶—W¹—C_1-6-arylene-Z-, R⁶—W¹-heteroarylene-Z-, R⁶—W¹-heterocyclylene-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, R⁶—W¹—C_1-6-alkylene-Z-, heterocyclyl-Z-C_1-6-alkylene-, heterocyclyl-C_1-6-alkylene-Z-C_1-6-alkylene-, C_3-10-cycloalkyl-Z-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkylene-Z-C_1-6-alkylene-, C_3-10-cycloalkyl-arylene-Z-, heterocyclyl-arylene-Z-, C_3-10-cycloalkyl-heteroarylene-Z-, heterocyclyl-heteroarylene-Z-, aryl-C_3-10-cycloalkylene-Z-, aryl-heterocyclylene-Z-, heteroaryl-C_3-10-cycloalkylene-Z-, heteroaryl-heterocyclylene-Z-, heterocyclyl-C_3-10-cycloalkylene-Z-, aryl-heteroarylene-Z-, heteroaryl-arylene-Z-, aryl-arylene-Z-, heteroaryl-heteroarylene-Z-, wherein any mono- or diva lent C_1-6-alkyl, C_3-10-cycloalkyl, heterocyclyl, aryl or heteroaryl moiety can optionally be substituted with one or more substituents independently selected from R², and wherein
    • [0810] R² and R³ independently of each other are hydrogen, halogen, hydroxy, —CN, —CF₃, —OCF₃, —NO₂, —C(O)OH, —NH₂, C_1-6-alkyl, C_1-6-alkoxy, aryloxy, R⁶-Z-, aryl-C_1-6alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl;
  • [0811] or
    • [0812] R² and R³, when attached to the same nitrogen atom, together with said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
  • [0813] Z and W¹ independently of each other are a direct bond, —O—, —N(R⁷)—, —N(R⁷)C(R⁷R⁸)—, —S—, —SO₂—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)C(O)C(R⁷R⁸)—, —N(R⁷)CON(R⁸)—, —N(R⁷)SO₂—, —SO₂N(R⁷)—, —C(O)—, —C(O)—O—, —N(R⁷)SO₂N(R⁸)—, or —O—C(O)—, wherein
    • [0814] R⁷ and R⁸ in each individual case independently of each other are hydrogen or C_1-6-alkyl; and
  • [0815] R⁴, R⁵, and R⁶ independently of each other are selected from the group consisting of hydrogen, cyano, halogen, aryl, heteroaryl, heteroaryl-C_1-6alkylene-, aryl-C_1-6-alkylene-, C_3-10-cycloalkyl, heterocyclyl optionally substituted with one or more C_1-6-alkyl, or C_1-6alkyl optionally substituted with halogen, —S(O)₂CH₃ or COOH;
  • [0816] or
  • [0817] R⁴ and R⁵ may be taken together to form a ring having the formula —(CH₂)_j-Q-(CH₂)_k-bonded to the nitrogen atom to which R⁴ and R⁵ are attached, wherein
    • [0818] j and k independently of each other is 1, 2, 3, or 4; and
    • [0819] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0820]

• • • [0821] wherein
      • [0822] R⁹ and R¹⁰ independently of each other are selected from the group consisting of hydrogen, aryl, C_1-6alkyl, and aryl-alkylene-;
  • [0823] L¹ is a bond, -D-C_1-6alkylene-E-, -D- C_2-6-alkenylene-E-, -D- C_2-6-alkynylene-E-, -D-cycloalkylene-E-, -D-heterocyclylene-E-, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —N(R¹¹)—, or —C(═N—OR¹²)—, wherein
  • [0824] D and E independently of each other are a direct bond, —O— or —S—;
  • [0825] R¹¹ is selected from hydrogen, C_1-6-alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, heteroaryl-C_1-6alkylene-, C_1-6-alkyl-O—C(O)—, aryl-C_1-6alkylene-O—C(O)—, heteroaryl-C_1-6-alkylene-O—C(O)—, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, heteroaryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, heteroaryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, heteroaryl-SO₂—, C_1-6alkyl-NH—SO₂—, aryl-C_1-6-alkylene-NH—SO₂—, heteroaryl-C_1-6-alkylene-NH—SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, heteroaryl-C_1-6-alkylene-C(O)—, C_1-6-alkyl-Y—, aryl-Y—, heteroaryl-Y—, aryl-C_1-6-alkylene-Y—, heteroaryl-C_1-6-alkylene-Y—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [0826] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [0827] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, heteroaryl, C_1-6-alkyl, C_1-6-alkoxy, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkoxy-, heteroaryl-C_1-6-alkoxy-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6-alkoxy-heteroarylene-, or C_1-6-alkoxy-arylene-;
    • [0828] or
    • [0829] R₁₃ and R₁₄ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R₁₃ and R₁₄ are attached, wherein
      • [0830] o and p are independently of each other are 1, 2, 3, or 4; and
      • [0831] X is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0832]

• • • • [0833] wherein
        • [0834] R¹⁶ and R¹⁷ are selected from hydrogen, aryl, heteroaryl, C_1-6-alkyl, C_1-6alkoxy, aryl-C_1-6-alkylene-, heteroaroyl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6-alkoxy-arylene-, C_1-6-alkoxy-heteroarylene-, heteroarylaryl-C_1-6-alkoxy-, or aryl-C_1-6alkoxy-; and
    • [0835] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, heteroaryl-C_1-6-alkylene-, or aryl-C_1-6-alkylene-; and
  • [0836] R¹² is selected from hydrogen, aryl, heteroaryl, C_1-6alkyl, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6-alkoxy-heteroarylene-, or C_1-6-alkoxy-arylene-;
• [0837] G¹ is C_1-6-alkyl, C_3-10-cycloalkyl, C_3-10-cycloalkyl-C_1-6alkylene-, C_2-6-alkenyl, or C_2-6-alkynyl, all of which may optionally be substituted with one or more substituents independently selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹, C_3-10-cycloalkyl and C_1-6-alkyl, wherein
  • [0838] R¹⁸ and R¹⁹ independently of each other are hydrogen, C_1-6-alkyl, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl;
  • [0839] or
  • [0840] R¹⁸ and R¹⁹, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
    or
• [0841] G¹ is aryl, heteroaryl, heterocyclyl, fused cycloalkylheteroaryl, fused heterocyclylaryl, fused arylheterocyclyl, or fused cycloalkylaryl, all of which may optionally be substituted with one or more substituents selected from R⁴⁰, R⁴¹, and R⁴²;
• [0842] L² is a direct bond, C_1-6alkylene, C_2-6-alkenylene, C_2-6-alkynylene, —N(R²⁰)—, —C_1-6alkylene-N(R²⁰)—, —C_2-6-alkenylene-N(R²⁰)—, —C_2-6-alkynylene-N(R²⁰)—, wherein
  • [0843] R²⁰ is hydrogen, or
  • [0844] R²⁰ is C_1-6alkyl, C_2-6-alkenyl, C_2-6-alkynyl, cycloalkyl-W³—, heterocyclyl-W³—, aryl-W³—, heteroaryl-W³—, optionally substituted with one or more substituents R³⁰, R³¹, and R³² wherein
    • [0845] W³ is C_1-6alkylene or a direct bond;
      wherein L¹ and L² are attached to adjacent atoms in A¹;
• [0846] L³ is —C(O)—, —C(O)—C(O)—, —C(O)CH₂C(O)— or —S(O)₂—;
• [0847] R¹ is hydrogen, or
• [0848] R¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, cycloalkyl-W⁴—, heterocyclyl-W⁴—, aryl-W⁴—, or heteroaryl-W⁴—,
  optionally substituted with one or more substituents R³³, R³⁴, and R³⁵ wherein
  • [0849] W⁴ is C_1-6alkylene or a direct bond;
• [0850] G² is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl,
  optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining said heteroaryl group to —N(R¹)—;
  or a group of the formula

[0851]
wherein

• • [0852] G³ and G⁵ independently of each other are C_1-6alkyl, C_2-6-alkenyl, C_2-6-alkynyl, cycloalkyl-R²²—, heterocyclyl-R²²—, aryl-R²²—, heteroaryl-R²²-optionally substituted with one or more substituents R⁴⁶, R⁴⁷, and R⁴⁸, wherein
    • [0853] R²² is alkylene or a direct bond; and
  • [0854] R²¹ is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, cycloalkyl-W⁵—, or heterocyclyl-W⁵—,
  • [0855] optionally substituted with one or more substituents R³⁶, R³⁷, and R³⁸, or
  • [0856] R²¹ is aryl-W⁵—, or heteroaryl-W⁵—, optionally substituted with one or more substituents R⁴⁹, R⁵⁰, and R⁵¹, wherein
    • [0857] W⁵ is C_1-6alkylene or a direct bond;
      wherein
• [0858] R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, and R³⁸ independently of each other are selected from —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵², —NR⁵²R⁵³, —SR₅₂, —NR⁵²S(O)₂R⁵³, —S(O)₂NR⁵²R⁵³, —S(O)NR⁵²R⁵³, —S(O)R⁵², —S(O)₂R⁵², —C(O)NR⁵²R⁵³, —OC(O)NR⁵²R⁵³, —NR⁵²C(O)R⁵³, —CH₂C(O)NR⁵²R⁵³, —OCH₂C(O)NR⁵²R⁵³, —CH₂OR⁵², —CH₂NR⁵²R⁵³, —OC(O)R⁵², —C(O)R⁵² and —C(O)OR⁵²; or
• [0859] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁵², —NR⁵²R⁵³ and C_1-6-alkyl; or C_3-10-cycloalkyl, C_4-8-cycloalkenyl, heterocyclyl, C_3-10-cycloalkyl-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkoxy-, C_3-10-Cycloalkyloxy, C_3-10-cycloalkyl-C_1-6-alkylthio-, C_3-10-cycloalkylthio, C_3-10-cycloalkyl-C_2-6-alkenylene-, C_3-10-cycloalkyl-C_2-6-alkynylene-, C_4-8-cycloalkenyl-C_1-6-alkylene-, C_4-8-cycloalkenyl-C_2-6-alkenylene-, C_4-8-cycloalkenyl-C_2-6-alkynylene-, heterocyclyl-C_1-6-alkylene-, heterocyclyl-C_2-6-alkenylene-, heterocyclyl-C_2-6-alkynylene-, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C_1-6-alkoxy-, aryl-C_1-6-alkylene-, aryl-C_2-6-alkenylene-, aryl-C_2-6-alkynylene-, heteroaryl, heteroaryl-C_1-6-alkylene-, heteroaryl-C_2-6-alkenylene- and heteroaryl-C_2-6-alkynylene-, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR⁵², —CN, —CF₃, —OCF₃, —NO₂, —OR⁵², —NR⁵²R⁵³ and C_1-6alkyl, wherein
  • [0860] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6alkyl, aryl-C_1-6-alkylene-heteroaryl-C_1-6-alkylene- heteroaryl, or aryl;
  • [0861] or
  • [0862] R⁵² and R⁵³, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
• [0863] R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰ and R⁵¹ independently of each other are —CN, —NO₂, —S(O)₂CF₃, —SCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, halogen, —S—C_1-6alkylene-OR⁵⁴, —S(O)₂—C_1-6alkylene-OR⁵⁴, —C_1-6-alkylene-S—R⁵, —C_1-6-alkylene-S(O)R⁵⁴, —C_1-6-alkylene-S(O)₂R⁵⁴, —C_1-6alkylene-N(R⁵⁴)S(O)₂R⁵⁵, —N(R⁵⁴)S(O)₂R⁵⁵, —C_1-1alkylene-CN, —C_1-6alkylene-C(O)NR⁵⁴R⁵⁵, —C_1-6alkylene-N(R⁵⁴)C(O)R⁵⁵, —N(R⁵⁴)C(O)R⁵⁵, —C_1-6alkylene-N(R⁵⁴)C(O)NR⁵⁵R⁵⁶, —C_1-6-alkylene-NHC(═NR⁵⁴)NR⁵⁵R⁵⁶, —C_1-6alkylene-N(R⁵⁴)C(O)OR⁵⁵, —N(R⁵⁴)C(O)OR⁵⁵, —C_1-6-alkylene-C(O)OR⁵⁴, —C_1-6alkylene-N(R⁵⁴)S(O)₂R⁵⁵, —OCH₂C(O)NR⁵⁴R⁵⁵, —O(CH₂)_1-3OR⁵⁴, —C_1-6-alkylene-O—R⁵⁴, —C_1-6-alkylene-C(O)R⁵⁴, —C_1-6alkylene-NR⁵⁴R⁵⁵, —C(═NR⁵⁴)—O—R⁵⁵, —C(═N(OR⁵⁴))C(O)OR⁵⁵, —C(═N(OR⁵⁴))C(O)R⁵⁵, —C_1-6-alkylene-C(═N(OR⁵⁴))C(O)R⁵⁵, —C_1-6-alkylene=N—O—R⁵⁴, —C_1-6-alkylene-N(R ⁵⁴)S(O)₂NR⁵⁵R⁵⁶, —N(R⁵⁴)S(O)₂NR⁵⁵R⁵⁶, —N(R⁵⁴)S(O)₂NR⁵⁵R ⁵⁶, —OC(O)R⁵⁴, —C_1-6-alkylene-C(O)N(R⁵⁴)S(O)₂R⁵⁵, —C(O)N(R⁵⁴)S(O)₂R⁵⁵, —C_1-6alkylene-C(R⁵⁴)═N—OR⁵⁵, —NHC(═NR⁵⁴)NR⁵⁵R⁵⁶, —C_1-6-alkylene-NHC(═NR⁵⁴)NR⁵⁴R⁵⁵, —C_1-6alkylene-N═C(N(R⁵⁴R⁵⁵))₂, —N═C(N(R⁵⁴R⁵⁵))₂, —C(O)R⁵⁴ and —C(O)OR⁵⁴; or
• [0864] C_1-6alkyl, C_2-6-alkenyl and C_2-6-alkynyl, each of which may optionally be substituted with one or more substituents independently selected from halogen, R⁵⁴, —CN, —CF₃, —OCF₃, —OR⁵⁴, —C(O)OR⁵⁴, —NR⁵⁴R⁵⁵ and C_1-6-alkyl; or
• [0865] C_3-10-cycloalkyl, C_4-8-cycloalkenyl, heterocyclyl, C_3-10-cycloalkyl-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkoxy-, C_3-10-cycloalkyloxy, C_3-10-cycloalkyl-C_1-6alkylthio-, C_3-10-cycloalkylthio, C_3-10-cycloalkyl-C_2-6-alkenylene-, C_3-10-cycloalkyl-C_2-6-alkynylene-, C_4-8-cycloalkenyl-C_1-6-alkylene-, C_4-4-cycloalkenyl-C_2-6-alkenylene-, C_4-8-cycloalkenyl-C_2-6-alkynylene-, heterocyclyl-C_1-6-alkylene-, heterocyclyl-C_2-6-alkenylene-, heterocyclyl-C_2-6-alkynylene- of which the heterocyclyl moieties optionally may be substituted with one or more substituents independently selected from R⁷⁰; or
  aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C_1-6-alkoxy-, aryl-C_1-6-alkylene-, aryl-C_2-6-alkenylene-, aryl-C_2-6-alkynylene-, heteroaryl, heteroaryl-C_1-6-alkylene-, heteroaryl-S—C_1-6-alkylene-, heteroaryl-C_2-6-alkenylene- and heteroaryl-C_2-6-alkynylene-, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR⁵⁴, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁴, —NR⁵⁴R⁵⁵ or C_1-6-alkyl, wherein
  • [0866] R⁵⁴, R⁵⁵ and R⁵⁶ independently of each other are hydrogen, C_1-6alkyl, —Si(C_1-6-alkyl)₃, C_1-6alkyl-arylene-, C_1-6alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heterocyclyl, heterocyclyl-C_1-6alkylene-, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹;
  • [0867] or
  • [0868] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or —(CHR⁷²)_u—(CHR⁷³)_v—W⁶, wherein
    • [0869] u is 0, 1 or 2;
    • [0870] v is 0, 1 or 2;
    • [0871] R⁷² and R⁷³ independently of each other are hydrogen, C_1-6alkyl, C_1-6-alkyl-arylene- aryl, hydroxy, hydroxyalkyl, —C(O)O—R⁷⁵, amino, or aminoalkyl;
    • [0872] W⁶ is hydrogen, —O—R⁷⁵, —C(O)O—R⁷⁵, —C(O)—R⁷⁵, —CONR⁷⁵R⁷⁶, —NR⁷⁵R⁷⁶, —NHCH₂C(O)R⁷⁵, —NHC(O)R⁷⁵, —NHC(O)OR⁷⁵, —S(O)₂R⁷⁵, —NHS(O)₂R⁷⁵, alkylamino, or dialkylamino, or
    • [0873] W⁶ is a five or six membered ring wherein at least one ring atom is nitrogen and the remaining ring atoms are either carbon or oxygen or optionally substituted with C_1-6alkyl, —C(O)O—R⁷⁵, —(CH₂)_1-3C(O)O—R⁷⁵, ═O;
    • [0874] or
    • [0875] W⁶ is phathalimido or heterocyclyl.
  • [0876] or
  • [0877] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, and optionally substituted with one or more C_1-6-alkyl groups;
  • [0878] R⁷⁰ is ═O, —C(O)CH₃, —S(O)₂CH₃, —CF₃, —C(O)O—R⁷⁵, —(CH₂)_1-3C(O)O—R⁷⁵ or C_1-6-alkyl;
  • [0879] R⁷¹ is ═O, C_1-6alkyl, cycloalkyl, —C(O)O—R⁷⁵, —(CH₂)_1-3C(O)O—R⁷⁵, —(CH₂)_1-3NR⁷⁵R⁷⁶, —OH or amino;
  • [0880] R⁷⁵ and R⁷⁶ independently of each other is hydrogen, halogen, —OH, —CF₃, or C_1-6-alkyl optionally substituted with —NH₂;
    or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
    Embodiment A2. A compound according to embodiment A1, wherein
• [0881] A¹ is arylene or heteroarylene, optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷, wherein
  • [0882] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0883] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6-alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0884] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
      Embodiment A3. A compound according to embodiment A2, wherein
• [0885] A¹ is C_6-10-arylene or C_4-10-heteroarylene, optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷ wherein
  • [0886] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0887] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6-alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6alkylene-Z-, wherein
    • [0888] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
      Embodiment A4. A compound according to embodiment A3 wherein
• [0889] A¹ is phenylene optionally substituted with one or more substitutents R²³, R²⁴, R²⁵, R²⁶, and R²⁷, wherein
  • [0890] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0891] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_2-6-alkenyl-Z-, C_2-6-alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C_1-6-alkylene-Z-, heteroaryl-C_1-6-alkylene-Z-, heterocyclyl-C_1-6-alkylene-Z-, cycloalkyl-C_1-6-alkylene-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
    Embodiment A5. A compound according to embodiment A4 of the formula (Ia)

[0892]
wherein L¹, G¹, L², L³, R¹, G² and R²⁵ are as defined in embodiment A1.
Embodiment A6. A compound according to embodiment A4 of the formula (Ib)

[0893]
wherein L¹, G¹, L², L³, R¹, G² and R²⁴ are as defined in embodiment A1.
Embodiment A7. A compound according to any one of the embodiments A1 to A6, wherein

• • [0894] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0895] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0896] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
      Embodiment A8. A compound according to embodiment A7 wherein
  • [0897] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0898] halogen, —CN, —CF₃, —OR², —NR²R³, C_1-6alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0899] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
      Embodiment A9. a compound according to embodiment A8 wherein
  • [0900] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
  • [0901] halogen, —OR², —NR²R³, C_1-6-alkyl-Z-, R⁶—W¹-Z-, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0902] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
      Embodiment A10. A compound according to embodiment A9 wherein
  • [0903] R²³, R²⁴, R²⁵, R²⁶, and R²⁷ independently of each other are selected from the group consisting of
    • [0904] F, Cl, Br, and methyl.
      Embodiment A11. A compound according to any one of the embodiments A1 to A10, wherein
  • [0905] R⁴, R⁵, and R⁶ independently of each other are selected from the group consisting of hydrogen, aryl, C_1-6alkyl, heteroaryl-C_1-6-alkylene-, and aryl-C_1-6-alkylene-.
    Embodiment A12. A compound according to embodiment A11, wherein
  • [0906] R⁴, R⁵, and R⁶ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment A13. A compound according to embodiment A12, wherein
  • [0907] R⁴, R⁵, and R⁶ are hydrogen.
    Embodiment A14. A compound according to any one of the embodiments A1 to A9, wherein
  • [0908] R⁴ and R⁵ is taken together to form a ring having the formula —(CH₂)_j-Q-(CH₂)_k-bonded to the nitrogen atom to which R⁴ and R⁵ are attached, wherein
    • [0909] j and k independently of each other is 1, 2, 3, or 4;
    • [0910] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0911]

• • • [0912] wherein
      • [0913] R⁹ and R¹⁰ independently of each other are selected from the group consisting of hydrogen, aryl, C_1-6-alkyl, and aryl-C_1-6alkyl-.
        Embodiment A15. A compound according to embodiment A14, wherein
  • [0914] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0915]

• • [0916] wherein
    • [0917] R⁹ and R¹⁰ independently of each other are hydrogen or C_1-6-alkyl.
      Embodiment A16. A compound according to embodiment A15, wherein
  • [0918] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0919]
Embodiment A17. A compound according to embodiment A16, wherein Q is a direct bond.
Embodiment A18. A compound according to any one of the embodiments A1 to A17, wherein

• • [0920] W¹ is a direct bond, —O—, —C(O)—, —NH—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment A19. A compound according to embodiment A18, wherein
  • [0921] W¹ is a direct bond, —O—, —C(O)—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)SO₂—, —C(O)—O—, or —O—C(O)—.
    Embodiment A20. A compound according to embodiment A19, wherein W¹ is a direct bond or —C(O)—O—.
    Embodiment A21. A compound according to embodiment A20, wherein W¹ is a direct bond.
    Embodiment A22. A compound according to embodiment A7, wherein
  • [0922] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
    • [0923] R², R³, and Z are as defined in embodiment A1.
      Embodiment A23. A compound according to embodiment A22, wherein
  • [0924] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0925] R², R³, and Z are as defined in embodiment A1.
      Embodiment A24. A compound according to embodiment A23, wherein
  • [0926] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0927] R², R³, and Z are as defined in embodiment A1.
      Embodiment A25. A compound according to embodiment A24, wherein
  • [0928] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is F, Cl, Br, or methyl.
    Embodiment A26. A compound according to embodiment A24, wherein
  • [0929] at least one of R²³, R²⁴, R²⁵, R²⁶, and R²⁷ is halogen, —C(O)OR², —CN, —NO₂, —OR², or —NR²R³, wherein
    • [0930] R², R³, and Z are as defined in embodiment A1.
      Embodiment A27. A compound according to any one of the embodiments A1 to A26, wherein
  • [0931] R² and R³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment A28. A compound according to embodiment A27, wherein
  • [0932] R² and R³ independently of each other, are hydrogen, C_1-6alkyl, aryl-C_1-6alkylene- or aryl.
    Embodiment A29. A compound according to embodiment A28, wherein
  • [0933] R² is hydrogen or C_1-6-alkyl.
    Embodiment A30. A compound according to embodiment A29, wherein
  • [0934] R² is hydrogen.
    Embodiment A31. A compound according to any one of the embodiments A1 to A30, wherein
  • [0935] R³ is hydrogen or C_1-6-alkyl.
    Embodiment A32. A compound according to embodiment A31, wherein
  • [0936] R³ is hydrogen.
    Embodiment A33. A compound according to any one of the embodiments A1 to A22, wherein
  • [0937] R² and R³, when attached to the same nitrogen atom, together with said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A34. A compound according to any one of the embodiments A1 to A33, wherein
  • [0938] Z is a direct bond, —O—, —NH—, —NHCH₂—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(CH₃)CONH—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment A35. A compound according to embodiment A34, wherein
  • [0939] Z is a direct bond, —O—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)SO₂—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment A36. A compound according to embodiment A35, wherein
  • [0940] Z is a direct bond, —NHC(O)—, or —NHS(O)₂—.
    Embodiment A37. A compound according to embodiment A2, wherein
• [0941] A¹ is

[0942]

• [0943] R²³, R²⁴, R²⁵, and R²⁶, independently of each other, are hydrogen or as defined in embodiment A1.
  Embodiment A38. A compound according to embodiment A37, wherein
  • [0944] R²³, R²⁴, R²⁵, and R²⁶ independently of each other are selected from the group consisting of
  • [0945] halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R⁴R⁵)—C_1-6-alkylene-Z-, R⁶—W¹-Z-, R⁶—W¹—N(R⁴)-Z-, R⁶—N(R⁴)-Z-, and R⁶—W¹—C_1-6-alkylene-Z-, wherein
    • [0946] R², R³, R⁴, R⁵, R⁶, Z, and W¹ are as defined in embodiment A1.
      Embodiment A39. A compound according to embodiment A37 or A38, wherein
  • [0947] R⁴, R⁵, and R⁶ independently of each other are selected from the group consisting of hydrogen, aryl, C_1-6alkyl, heteroaryl-C_1-6-alkylene-, and aryl-C_1-6-alkylene-.
    Embodiment A40. A compound according to embodiment A39, wherein
  • [0948] R⁴, R⁵, and R⁶ independently of each other are hydrogen or C_1-6alkyl.
    Embodiment A41. A compound according to embodiment A40, wherein
  • [0949] R⁴, R⁵, and R⁶ are hydrogen.
    Embodiment A42. A compound according to embodiment A37 or A38, wherein
  • [0950] R⁴ and R⁵ is taken together to form a ring having the formula —(CH₂)_j-Q-(CH₂)_k-bonded to the nitrogen atom to which R⁴ and R⁵ are attached, wherein
    • [0951] j and k independently of each other is 1, 2, 3, or 4;
    • [0952] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂), —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0953]

• • • [0954] wherein
      • [0955] R⁹ and R¹⁰ independently of each other are selected from the group consisting of hydrogen, aryl, C_1-6-alkyl, and arylalkyl-.
        Embodiment A43. A compound according to embodiment A42, wherein
  • [0956] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0957]

• • [0958] wherein
    • [0959] R⁹ and R¹⁰ independently of each other are hydrogen or alkyl.
      Embodiment A44. A compound according to embodiment A43, wherein
  • [0960] Q is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —NHSO₂—, —SO₂NH—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0961]
Embodiment A45. A compound according to embodiment A44, wherein

• • [0962] Q is a direct bond.
    Embodiment A46. A compound according to any one of the embodiments A37 to A45, wherein
  • [0963] W¹ is a direct bond, —O—, —C(O)—, —NH—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment A47. A compound according to embodiment A46 wherein
  • [0964] W¹ is a direct bond, —O—, —C(O)—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)SO₂—, —C(O)—O—, or —O—C(O)—.
    Embodiment A48. A compound according to embodiment A47, wherein
  • [0965] W¹ is a direct bond, or —C(O)—O—.
    Embodiment A49. A compound according to embodiment A48, wherein
  • [0966] W¹ is a direct bond.
    Embodiment A50. A compound according to embodiment A37, wherein
  • [0967] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃—NO₂—OR², —NR²R³, C_1-6-alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
    • [0968] R², R³, and Z are as defined in embodiment A37.
      Embodiment A51. A compound according to embodiment A50, wherein
  • [0969] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR², —CN, —CF₃, —OCF₃, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0970] R², R³, and Z are as defined in embodiment A37.
      Embodiment A52. A compound according to embodiment A51, wherein
  • [0971] at least one of R²³, R²⁴, R²⁵ and R²⁶ is halogen, —C(O)OR², —CN, —NO₂, —OR², —NR²R³, C_1-6-alkyl-Z-, C_3-10-cycloalkyl-Z-, C_3-10-heterocyclyl-Z-, C_3-10-aryl-Z-, or C_3-10-heteroaryl-Z-, wherein
    • [0972] R², R³, and Z are as defined in embodiment A37.
      Embodiment A53. A compound according to any one of the embodiments A37 to A52, wherein
  • [0973] Z is a direct bond, —O—, —NH—, —NHCH₂—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(CH₃)CON(H)—, —N(H)SO₂—, —SO₂N(H)—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment A54. A compound according to embodiment A53, wherein
  • [0974] Z is a direct bond, —O—, —S—, —SO₂—, —C(O)NH—, —NHC(O)—, —N(H)SO₂—, —C(O)—O—, —N(H)SO₂N(H)—, or —O—C(O)—.
    Embodiment A55. A compound according to embodiment A54, wherein
  • [0975] Z is a direct bond, —NHC(O)—, or —NHS(O)₂.
    Embodiment A56. A compound according to embodiment A52, wherein
  • [0976] at least one of R²³, R²⁴, R²⁵, and R²⁶ is halogen, —C(O)OR², —CN, —NO₂, —OR², —NR²R³, or C_1-6alkyl, wherein
    • [0977] R², and R³ are as defined in embodiment A37.
      Embodiment A57. A compound according to any one of the embodiments A37 to A56, wherein
  • [0978] R² and R³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment A58. A compound according to embodiment A57, wherein
  • [0979] R² and R³ independently of each other, are hydrogen, C_1-6-alkyl, aryl-C_1-6alkylene- or aryl.
    Embodiment A59. A compound according to embodiment A58, wherein
  • [0980] R² is hydrogen or C_1-6-alkyl.
    Embodiment A60. A compound according to embodiment A59, wherein
  • [0981] R² is hydrogen.
    Embodiment A61. A compound according to any one of the embodiments A37 to A60, wherein
  • [0982] R³ is hydrogen or C_1-6-alkyl.
    Embodiment A62. A compound according to embodiment A61, wherein
  • [0983] R³ is hydrogen.
    Embodiment A63. A compound according to any one of the embodiments A37 to A50, wherein
  • [0984] R² and R³, when attached to the same nitrogen atom, together with said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A64. A compound according to any one of the embodiments A37 to A55, wherein
  • [0985] at least one of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment A65. A compound according to embodiment A64, wherein
  • [0986] at least two of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment A66. A compound according to embodiment A65, wherein
  • [0987] R²³ and R²⁶ are hydrogen.
    Embodiment A67. A compound according to embodiment A65 or embodiment A66, wherein
  • [0988] at least three of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment A68. A compound according to any one of the embodiments A37 to A67, wherein R²⁴ or R²⁵ is halogen.
    69. A compound according to embodiment A68, wherein R²⁴ or R²⁵ is fluoro.
    Embodiment A70. A compound according to any one of the embodiments A37 to A67, wherein R²⁴ or R²⁵ is C_1-6-alkyl.
    Embodiment A71. A compound according to embodiment A68, wherein R²⁴ or R²⁵ is methyl.
    Embodiment A72. A compound according to any one of the embodiments A37 to A67, wherein
  • [0989] R²⁴ is hydrogen.
    Embodiment A73. A compound according to any one of the embodiments A37 to A72, wherein
  • [0990] R²⁵ is hydrogen.
    Embodiment A74. A compound according to embodiment A37, wherein
  • [0991] R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment A75. A compound according to any one of the embodiments A1 to A74, wherein
  • [0992] L¹ is a bond, -D-alkylene-E-, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —N(R¹¹)—, or —C(═N—OR¹²), wherein
    • [0993] D, E, R¹¹ and R¹² are as defined in embodiment A1.
      Embodiment A76. A compound according to embodiment A75, wherein
  • [0994] L¹ is a bond, -D-alkylene-E-, —O—, —C(O)—, —N(R¹¹)—, or —C(═N—OR¹²)—, wherein
    • [0995] D, E, R¹¹ and R¹² are as defined in embodiment A1.
      Embodiment A77. A compound according to embodiment A75, wherein
  • [0996] L¹ is —O—.
    Embodiment A78. A compound according to embodiment A75, wherein
  • [0997] L¹ is —S—.
    Embodiment A79. A compound according to embodiment A75, wherein
  • [0998] L¹ is a bond.
    80. A compound according to embodiment A75, wherein
  • [0999] L¹ is —C(O)—.
    Embodiment A81. A compound according to any one of the embodiments A1 to A76, wherein
  • [1000] D is a direct bond or —O—;
  • [1001] E is a direct bond or —O—; and
  • [1002] R¹¹ and R¹² are as defined in embodiment A1.
    Embodiment A82. A compound according to embodiment A81, wherein
  • [1003] D is a direct bond.
    Embodiment A83. A compound according to embodiment A81, wherein
  • [1004] D is —O—.
    Embodiment A84. A compound according to any one of the embodiments A81 to A83, wherein
  • [1005] E is a direct bond.
    Embodiment A85. A compound according to any one of the embodiments A81 to A83, wherein
  • [1006] E is —O—.
    Embodiment A86. A compound according to any one of the embodiments A1 to A85, wherein
  • [1007] R¹¹ is selected from hydrogen, C_1-6alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C₁]-alkylene-Y—, wherein
    • [1008] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1009] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6-alkyl, or aryl-C_1-6-alkylene-; or
    • [1010] R¹³ and R¹⁴ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R¹³ and R¹⁴ are attached, wherein
      • [1011] o and p are independently of each other are 1, 2, 3, or 4; and
      • [1012] X is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[1013]

• • • • [1014] wherein
        • [1015] R¹⁶ and R¹⁷ are selected from hydrogen, aryl, heteroaryl, C_1-6-alkyl, C_1-6-alkoxy, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, C_1-6-alkoxy-arylene-, C_1-6-alkoxy-heteroarylene-, heteroarylaryl-C_1-6-alkoxy-, or aryl-C_1-6alkoxy-; and
  • [1016] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
    Embodiment A87. A compound according to embodiment A86, wherein
  • [1017] R¹¹ is selected from hydrogen, C_1-6alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [1018] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1019] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6alkyl, or aryl-C_1-6-alkylene-;
    • [1020] or
    • [1021] R¹³ and R¹⁴ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R¹³ and R¹⁴ are attached, wherein
      • [1022] o and p are independently of each other are 1, 2, 3, or 4; and
      • [1023] X is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[1024]

• • • • [1025] wherein
        • [1026] R¹⁶ and R¹⁷ are hydrogen; and
  • [1027] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
    Embodiment A88. A compound according to embodiment A87, wherein
  • [1028] R¹¹ is selected from hydrogen, C_1-6alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6alkyl-C(O)—, aryl-C_1-6alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [1029] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1030] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6-alkyl, or aryl-C_1-6alkylene-;
    • [1031] or
    • [1032] R¹³ and R¹⁴ may be taken together to form a ring having the formula —(CH₂)_o—X—(CH₂)_p— bonded to the nitrogen atom to which R¹³ and R¹⁴ are attached, wherein
      • [1033] o and p are independently of each other are 1, 2, 3, or 4;
      • [1034] X is a direct bond; and
  • [1035] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
    Embodiment A89. A compound according to embodiment A88, wherein
  • [1036] R¹¹ is selected from hydrogen, C_1-6-alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [1037] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1038] R¹³ and R¹⁴ independently of each other are selected from hydrogen, aryl, C_1-6-alkyl, or aryl-C_1-6-alkylene-; and
    • [1039] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
      Embodiment A90. A compound according to embodiment A89, wherein
  • [1040] R¹¹ is selected from hydrogen, C_1-6-alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [1041] Y and W² independently of each other are a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1042] R¹³ and R¹⁴ are hydrogen; and
    • [1043] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
      Embodiment A91. A compound according to embodiment A90, wherein
  • [1044] R¹¹ is selected from hydrogen, C_1-6-alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6-alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [1045] Y is a direct bond;
    • [1046] W² is a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1047] R¹³ and R¹⁴ are hydrogen; and
    • [1048] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
      Embodiment A92. A compound according to embodiment A90, wherein
  • [1049] R¹¹ is selected from hydrogen, C_1-6alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, N(R¹³)(R¹⁴)—C_1-6alkylene-Y—, and R¹⁵—W²—C_1-6-alkylene-Y—, wherein
    • [1050] Y is a direct bond, —CH₂—, —SO₂—, —N(H)CO—, —N(H)SO₂—, or —O—C(O)—;
    • [1051] W² is a direct bond;
    • [1052] R¹³ and R¹⁴ are hydrogen; and
    • [1053] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6-alkyl, or aryl-C_1-6-alkylene-.
      Embodiment A93. A compound according to any one of the embodiments A90 to A92, wherein
  • [1054] R¹¹ is selected from hydrogen, C_1-6-alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6-alkyl-NH—C(O)—, aryl-C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, NH₂—C_1-6alkylene-, and R¹⁵—C_1-6-alkylene-, wherein
    • [1055] R¹⁵ is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, C_1-6alkyl, or aryl-C_1-6-alkylene-.
      Embodiment A94. A compound according to embodiment A93, wherein
  • [1056] R¹¹ is selected from hydrogen, C_1-6alkyl, aryl, carbamoyl, aryl-C_1-6-alkylene-, C_1-6alkyl-NH—C(O)—, aryl- C_1-6-alkylene-NH—C(O)—, C_1-6-alkyl-SO₂—, aryl-C_1-6-alkylene-SO₂—, aryl-SO₂—, SO₂—, C_1-6-alkyl-C(O)—, aryl-C_1-6-alkylene-C(O)—, and NH₂—C_1-6alkylene-.
    Embodiment A95. A compound according to embodiment A94, wherein
  • [1057] R¹¹ is hydrogen or C_1-6alkyl.
    Embodiment A96. A compound according to embodiment A95, wherein
  • [1058] R¹¹ is hydrogen.
    Embodiment A97. A compound according to any one of the embodiments A1 to A96, wherein
  • [1059] R¹² is hydrogen or C_1-6alkyl.
    Embodiment A98. A compound according to embodiment A97, wherein
  • [1060] R¹² is hydrogen.
    Embodiment A99. A compound according to any one of the embodiments A1 to A98, wherein
  • [1061] G¹ is C_1-6alkyl, C_2-6-alkenyl, C_2-6-alkynyl, cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹, C_3-10-cycloalkyl and C_1-6alkyl, wherein
    • [1062] R¹⁸ and R¹⁹ are as defined in embodiment A1.
      Embodiment A100. A compound according to embodiment A99, wherein
  • [1063] G¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-6alkyl, wherein
    • [1064] R¹⁸ and R¹⁹ are as defined in embodiment A1.
      Embodiment A101. A compound according to embodiment A99, wherein
  • [1065] G¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl or C_3-10-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹, C_3-10-cycloalkyl and C_1-6-alkyl, wherein
    • [1066] R¹⁸ and R¹⁹ are as defined in embodiment A1.
      Embodiment A102. A compound according to embodiment A100 or embodiment A101, wherein
  • [1067] G¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl or C_3-10-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-6alkyl, wherein
    • [1068] R¹⁸ and R¹⁹ are as defined in embodiment A1.
      Embodiment A103. A compound according to any one of the embodiments A99 to A102, wherein
  • [1069] G¹ is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, 2-pentyl, 3-methyl-butyl, 2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, 1,3-dioxolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, hexahydro-pyridazinyl, imidazolidyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1,4-dithianyl, or thiomorpholinyl.
    Embodiment A104. A compound according to embodiment A103 wherein
  • [1070] G¹ is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl, or thiepanyl.
    Embodiment A105. A compound according to embodiment A104 wherein
  • [1071] G¹ is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, or hexahydroazepinyl.
    Embodiment A106. A compound according to embodiment A105 wherein
  • [1072] G¹ is selected from the group consisting of isobutyl, cyclopentyl, and piperidyl.
    Embodiment A107. A compound according to embodiment A105 wherein
  • [1073] G¹ is isobutyl.
    Embodiment A108. A compound according to embodiment A105 wherein
  • [1074] G¹ is cyclopentyl.
    Embodiment A109. A compound according to embodiment A105 wherein
  • [1075] G¹ is piperidyl.
    Embodiment A110. A compound according to any one of the embodiments A99 to A1 O₂, wherein
  • [1076] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkylene-, C_1-6alkyl-arylene-, C_1-6alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment A111. A compound according to embodiment A110, wherein
  • [1077] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6-alkyl, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-aryl-C_1-6-alkylene-, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment A112. A compound according to embodiment A111, wherein
  • [1078] R¹⁸ and R¹⁹, independently of each other, are hydrogen or C_1-6alkyl.
    Embodiment A113. A compound according to embodiment A112, wherein
  • [1079] R¹⁸ is hydrogen.
    Embodiment A114. A compound according to embodiment A112 or A113, wherein
  • [1080] R¹⁹ is hydrogen.
    Embodiment A115. A compound according to embodiment A100 or embodiment A102, wherein
  • [1081] R¹⁸ and R¹⁹, when attached to the same nitrogen atom, together with the said nitrogen atom forms a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A116. A compound according to any one of the embodiments A1 to A98, wherein
  • [1082] G¹ is alkyl or cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-6alkyl,
  • [1083] or G¹ is aryl optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein R¹⁸, R¹⁹, R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
    Embodiment A117. A compound according to embodiment A116, wherein
  • [1084] G¹ is C_1-6alkyl or C_3-10-cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸—NR¹⁸R¹⁹ and C_1-6-alkyl,
  • [1085] or G¹ is C_3-10-aryl optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein R¹⁸, R¹⁹, R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
    Embodiment A118. A compound according to embodiment A117, wherein
  • [1086] G¹ is C_1-6alkyl or C_3-10-cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF₃, —OCF₃, —OR¹⁸, —NR¹⁸R¹⁹ and C_1-6alkyl,
  • [1087] or G¹ is phenyl optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein R¹⁸, R¹⁹, R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
    Embodiment A119. A compound according to embodiment A116, A117, or A118, wherein
  • [1088] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, heteroaryl-C_1-6-alkylene-, aryl-C_1-6-alkylene-, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, heteroaryl, or aryl.
    Embodiment A120. A compound according to embodiment A119, wherein
  • [1089] R¹⁸ and R¹⁹, independently of each other, are hydrogen, C_1-6alkyl, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-aryl-C_1-6-alkylene-, C_1-6alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment A121. A compound according to embodiment A120, wherein
  • [1090] R¹⁸ and R¹⁹, independently of each other, are hydrogen or C_1-6alkyl.
    Embodiment A122. A compound according to embodiment A121, wherein
  • [1091] R¹⁸ is hydrogen.
    Embodiment A123. A compound according to embodiment A121 or A122, wherein
  • [1092] R¹⁹ is hydrogen.
    Embodiment A124. A compound according to embodiment A116 or embodiment A117, wherein
  • [1093] R¹⁸ and R¹⁹, when attached to the same nitrogen atom, together with the said nitrogen atom forms a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A125. A compound according to any one of the embodiments A116 to A124, wherein
  • [1094] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [1095] halogen, —CN, —NO₂, C_1-6alkyl, —CHF₂, —CF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, and —C(O)OR⁵⁴; or
  • [1096] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵ and C_1-6-alkyl,
  • [1097] wherein
    • [1098] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [1099] or
    • [1100] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment A126. A compound according to embodiment A125, wherein
  • [1101] R⁴⁰, R⁴¹, and R⁴² independently of each other are halogen, —CN, C_1-6-alkyl, —CF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —CH₂C(O)OR⁵⁴, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, and —C(O)OR⁵⁴;
  • [1102] wherein
    • [1103] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [1104] or
    • [1105] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment A127. A compound according to embodiment A126 wherein
  • [1106] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [1107] halogen, or —OR⁵⁴
  • [1108] wherein
    • [1109] R⁵⁴ is hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl.
      Embodiment A128. A compound according to embodiment A126, wherein
  • [1110] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, or C_1-6-alkyl, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-aryl-C_1-6-alkylene-, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment A129. A compound according to embodiment A128, wherein
  • [1111] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment A130. A compound according to embodiment A129, wherein
  • [1112] R⁵⁴ is hydrogen.
    Embodiment A131. A compound according to embodiment A129 or embodiment A130, wherein
  • [1113] R⁵⁵ is hydrogen.
    Embodiment A132. A compound according to embodiment A127 wherein
  • [1114] R⁵⁴ is methyl.
    Embodiment A133. A compound according to any one of the embodiments A1 to A98, wherein
  • [1115] G¹ is aryl or heteroaryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [1116] R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
      Embodiment A134. A compound according to embodiment A133, wherein
  • [1117] G¹ is C_3-10-aryl or C_3-10-heteroaryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [1118] R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
      Embodiment A135. A compound according to embodiment A133, wherein
  • [1119] G¹ is aryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [1120] R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
      Embodiment A136. A compound according to embodiment A135, wherein
  • [1121] G¹ is C_3-10-aryl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [1122] R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
      Embodiment A137. A compound according to embodiment A136, wherein
  • [1123] G¹ is phenyl, optionally substituted with one or more substituents R⁴⁰, R⁴¹, and R⁴², wherein
    • [1124] R⁴⁰, R⁴¹, and R⁴² are as defined in embodiment A1.
      Embodiment A138. A compound according to any one of the embodiments A133 to A137, wherein
  • [1125] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [1126] halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)₂NR⁵⁴R⁵⁵, —S(O)NR⁵⁴R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —C(O)NR⁵⁴R⁵⁵, —OC(O)NR⁵⁴R⁵⁵, —NR⁵⁴C(O)R⁵⁵, —CH₂C(O)NR⁵⁴R⁵⁵, —CH₂C(O)OR⁵⁴, —OCH₂C(O)NR⁵⁴R⁵⁵, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, and —C(O)OR⁵⁴; or
  • [1127] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —R⁵⁴, —NR⁵⁴R⁵⁵ and C_1-6-alkyl, wherein
    • [1128] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [1129] or
    • [1130] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment A139. A compound according to embodiment A138, wherein
  • [1131] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [1132] halogen, —CN, C_1-6-alkyl, —CF₃, —OR⁵⁴, —NR⁵⁴R⁵⁵, —SR⁵⁴, —NR⁵⁴S(O)₂R⁵⁵, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —CH₂C(O)OR⁵⁴, —CH₂OR⁵⁴, —CH₂NR⁵⁴R⁵⁵, and —C(O)OR⁵⁴;
  • [1133] wherein
    • [1134] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [1135] or
    • [1136] R⁵⁴ and R⁵⁵, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment A140. A compound according to embodiment A139 wherein
  • [1137] R⁴⁰, R⁴¹, and R⁴² independently of each other are
  • [1138] halogen, or —OR⁵⁴
  • [1139] wherein
  • [1140] R⁵⁴ is hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl.
    Embodiment A141. A compound according to any one of the embodiments A138 to A139, wherein
  • [1141] R⁵⁴ and R⁵⁵ independently of each other are hydrogen, or C_1-6-alkyl, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-aryl-C_1-6-alkylene-, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment A142. A compound according to embodiment A141, wherein
  • [1142] R⁵⁴ and R⁵⁵ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment A143. A compound according to embodiment A142, wherein
  • [1143] R⁵⁴ is hydrogen.
    Embodiment A144. A compound according to embodiment A142 or embodiment A143, wherein
  • [1144] R⁵⁵ is hydrogen.
    Embodiment A145. A compound according to embodiment A140 wherein
  • [1145] R⁵⁴ is methyl.
    Embodiment A146. A compound according to embodiment A135, wherein
• [1146] G¹ is

[1147]

• [1148] R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰, independently of each other, are hydrogen or halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁶¹, —NR⁶¹R⁶², —SR⁶¹, —NR⁶¹S(O)₂R⁶², —S(O)₂NR⁶¹R⁶², —S(O)NR⁶¹R⁶², —S(O)R⁶¹, —S(O)₂R⁶¹, —C(O)NR⁶¹R⁶², —OC(O)NR⁶¹R⁶², —NR⁶¹C(O)R⁶², —CH₂C(O)NR⁶¹R⁶², —CH₂C(O)OR⁶¹, —OCH₂C(O)NR⁶¹R⁶², —CH₂OR⁶¹, —CH₂NR⁶¹R⁶², —OC(O)R⁶¹, —C(O)R⁶¹ and —C(O)OR⁶¹; or
• [1149] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁶¹, —NR⁶¹R⁶² and C_1-6-alkyl;
• [1150] C_3-10-cycloalkyl, C_4-8-cycloalkenyl, heterocyclyl, C_3-10-cycloalkyl-C_1-6-alkylene-, C_3-10-cycloalkyl-C_1-6-alkoxy-, C_3-10-cycloalkyloxy, C_3-10-cycloalkyl-C_1-6-alkylthio-, C_3-10-cycloalkylthio, C_3-10-cycloalkyl-C_2-6-alkenylene-, C_3-10-cycloalkyl-C_2-6-alkynylene-, C_4-8-cycloalkenyl-C_1-6-alkylene-, C_4-8-cycloalkenyl-C_2-6-alkenylene-, C_4-8-cycloalkenyl-C_2-6-alkynylene-, heterocyclyl-C_1-6-alkylene-, heterocyclyl-C_2-6-alkenylene-, heterocyclyl-C_2-6-alkynylene-; or
• [1151] aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C_1-6-alkoxy-, aryl-C_1-6-alkylene-, aryl-C_2-6-alkenylene-, aryl-C_2-6-alkynylene-, heteroaryl, heteroaryl-C_1-6-alkylene-, heteroaryl-C_2-6-alkenylene- and heteroaryl-C_2-6-alkynylene-, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR⁶¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁶¹, —NR⁶¹R⁶² or C_1-6-alkyl, wherein
  • [1152] R⁶¹ and R⁶² independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
  • [1153] or
  • [1154] R⁶¹ and R⁶², when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A147. A compound according to embodiment A146, wherein
  • [1155] R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ independently of each other are
  • [1156] halogen, —CN, —NO₂, C_1-6-alkyl, —CHF₂, —CF₃, —OR⁶¹, —NR⁶¹R⁶², —SR⁶¹, —NR⁶¹S(O)₂R⁶², —S(O)₂NR⁶¹R⁶², —S(O)NR⁶¹R⁶², —S(O)R⁶¹, —S(O)₂R⁶¹, —C(O)NR⁶¹R⁶², —OC(O)NR⁶¹R⁶², —NR⁶¹C(O)R⁶², —CH₂C(O)NR⁶¹R⁶², —CH₂C(O)OR⁶¹, —OCH₂C(O)NR⁶¹R⁶², —CH₂OR⁶¹, —CH₂NR⁶¹R⁶², and —C(O)OR⁶¹; or
  • [1157] C_2-6-alkenyl and C_2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF₃, —OCF₃, —OR⁶¹, —NR⁶¹R⁶² and C_1-6-alkyl,
  • [1158] wherein
    • [1159] R⁶¹ and R⁶² independently of each other are hydrogen, C_1-6-alkyl, C_1-6-alkyl-arylene-, C_1-6-alkyl-heteroarylene-, aryl-C_1-6-alkylene-, heteroaryl-C_1-6-alkylene-, heteroaryl, or aryl;
    • [1160] or
    • [1161] R⁶¹ and R⁶², when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
      Embodiment A148. A compound according to embodiment A146 or embodiment A147, wherein R⁵⁶ or R⁵⁷ is —OR⁶¹.
      Embodiment A149. A compound according to embodiment A148 wherein R⁶¹ is methyl.
      Embodiment A150. A compound according to embodiment A147, wherein
  • [1162] R⁶¹ and R⁶² independently of each other are hydrogen, or C_1-6-alkyl, C_1-6-alkyl-C_3-10-arylene-, C_1-6-alkyl-C_3-10-heteroarylene-, C_3-10-aryl-C_1-6-alkylene-, C_3-10-heteroaryl-C_1-6-alkylene-, C_3-10-heteroaryl, or C_3-10-aryl.
    Embodiment A151. A compound according to embodiment A150, wherein
  • [1163] R⁶¹ and R⁶² independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment A152. A compound according to embodiment A151, wherein
  • [1164] R⁶¹ is hydrogen.
    Embodiment A153. A compound according to embodiment A151 or embodiment A152, wherein
  • [1165] R⁶² is hydrogen.
    Embodiment A154. A compound according to any one of the embodiments A146 to A153, wherein
  • [1166] at least one of R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ are hydrogen.
    Embodiment A155. A compound according to embodiment A154, wherein
  • [1167] at least two of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment A156. A compound according to embodiment A155, wherein
  • [1168] at least three of R²³, R²⁴, R²⁵, and R²⁶ are hydrogen.
    Embodiment A157. A compound according to any one of the embodiments A1 to A156, wherein
  • [1169] L² is a direct bond, C_1-6-alkylene, C_2-6-alkenylene, C_2-6-alkynylene, —N—R²⁰—, —C_1-6-alkylene-N(R²⁰)—, —C_2-6-alkenylene-N(R²⁰)—, or —C_2-6-alkynylene-N(R²⁰)—, wherein
    • [1170] R²⁰ is as defined in embodiment A1.
      Embodiment A158. A compound according to any one of the embodiments A1 to A153, wherein
  • [1171] L² is —N—R²⁰—, -alkylene-N(R²⁰)—, -alkenylene-N(R²⁰)—, or -alkynylene-N(R²⁰)—, wherein
    • [1172] R²⁰ is as defined in embodiment A1.
      Embodiment A159. A compound according to embodiment A157 or embodiment A158, wherein
  • [1173] L² is —N—R²⁰—, —C_1-6-alkylene-N(R²⁰)—, —C_2-6-alkenylene-N(R²⁰)—, or —C_2-6-alkynylene-N(R²⁰)—, wherein
    • [1174] R²⁰ is as defined in embodiment A1.
      Embodiment A160. A compound according to embodiment A159, wherein
  • [1175] L² is —N—R²⁰—, wherein
    • [1176] R²⁰ is as defined in embodiment A1.
      Embodiment A161. A compound according to embodiment A157, wherein
  • [1177] L² is a direct bond.
    Embodiment A162. A compound according to any one of the embodiments A1 to A160, wherein
  • [1178] R²⁰ is hydrogen, or
  • [1179] R²⁰ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl-W³—, C_3-10-heterocyclyl-W³—, C_3-10-aryl-W³—, or C_4-10-heteroaryl-W³—, optionally substituted with one or more substituents R³⁰, R³¹, and R³², wherein
    • [1180] W³, R³⁰, R³¹, and R³² are as defined in embodiment A1.
      Embodiment A163. A compound according to embodiment A162, wherein
  • [1181] W³ is alkylene.
    Embodiment A164. A compound according to embodiment A163, wherein
  • [1182] W³ is C_2-6-alkylene.
    Embodiment A165. A compound according to embodiment A162, wherein
  • [1183] W³ is a direct bond.
    Embodiment A166. A compound according to any one of the embodiments A1 to A160, wherein
  • [1184] R²⁰ is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, or C_2-6-alkynyl, optionally substituted with one or more substituents R³⁰, R³¹, and R³², wherein
    • [1185] R³⁰, R³¹, and R³² are as defined in embodiment A1.
      Embodiment A167. A compound according to any one of the embodiments A162 to A166, wherein
  • [1186] R²⁰ is hydrogen, or
  • [1187] R²⁰ is C_1-6-alkyl, C_1-6-alkenyl, or C_1-6-alkynyl, optionally substituted with one or more substituents R³⁰, R³¹, and R³² wherein
    • [1188] R³⁰, R³¹, and R³² are as defined in embodiment A1.
      Embodiment A168. A compound according to any one of the embodiments A1 to A167, wherein
  • [1189] R³⁰, R³¹, and R³² independently of each other are selected from —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵², —NR⁵²R⁵³, —SR₅₂, —NR⁵²S(O)₂R⁵³, —S(O)₂NR⁵²R⁵³, —S(O)NR⁵²R⁵³, —S(O)R⁵², —S(O)₂R⁵², —C(O)NR⁵²R⁵³, —OC(O)NR⁵²R⁵³, —NR⁵²C(O)R⁵³, —CH₂C(O)NR⁵²R⁵³, —OCH₂C(O)NR⁵²R⁵³, —CH₂OR⁵², —CH₂NR⁵²R⁵³, —OC(O)R⁵², —C(O)R⁵² and —C(O)OR⁵², wherein
    • [1190] R⁵² and R⁵³ are as defined in embodiment A1.
      Embodiment A169. A compound according to embodiment A168, wherein
  • [1191] R⁵² and R⁵³, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A170. A compound according to any one of the embodiments A1 to A168, wherein
  • [1192] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-heteroaryl-C_1-6-alkylene-heteroaryl, or aryl.
    Embodiment A171. A compound according to embodiment A170, wherein
  • [1193] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-or aryl.
    Embodiment A172. A compound according to embodiment A171, wherein
  • [1194] R⁵² and R⁵³ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment A173. A compound according to embodiment A172, wherein
  • [1195] R⁵² is hydrogen.
    Embodiment A174. A compound according to embodiment A172 or embodiment A173, wherein
  • [1196] R⁵³ is hydrogen.
    Embodiment A175. A compound according to embodiment A167, wherein
  • [1197] R²⁰ is hydrogen.
    Embodiment A176. A compound according to any one of the embodiments A1 to A175, wherein
  • [1198] L³ is —C(O)—, —C(O)—C(O)— or —C(O)CH₂C(O)—.
    Embodiment A177. A compound according to embodiment A176 wherein
• [1199] L³ is —C(O)—.
  Embodiment A178. A compound according to embodiment A176 wherein
• [1200] L³ is —C(O)—C(O)—.
  Embodiment A179. A compound according to embodiment A176 wherein
• [1201] L³ is —C(O)CH₂C(O)—.
  Embodiment A180. A compound according to any one of the embodiments A1 to A179, wherein
  • [1202] R¹ is hydrogen, or
  • [1203] R¹ is C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-10-cycloalkyl-W⁴—, C_3-10-heterocyclyl-W⁴—, C_3-10-aryl-W⁴—, or C_4-10-heteroaryl-W⁴—, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵, wherein
    • [1204] W⁴, R³³, R³⁴, and R³⁵ are as defined in embodiment A1.
      Embodiment A181. A compound according to embodiment A180, wherein
  • [1205] W⁴ is alkylene.
    Embodiment A182. A compound according to embodiment A181, wherein
  • [1206] W⁴ is C_2-6-alkylene.
    Embodiment A183. A compound according to embodiment A180, wherein
  • [1207] W⁴ is a direct bond.
    Embodiment A184. A compound according to any one of the embodiments A1 to A176, wherein
  • [1208] R¹ is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, or C_2-6-alkynyl, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵, wherein
    • [1209] R³³, R³⁴, and R³⁵ are as defined in embodiment A1.
      Embodiment A185. A compound according to any one of the embodiments A180 to A184, wherein
  • [1210] R¹ is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, or C_2-6-alkynyl, optionally substituted with one or more substituents R³³, R³⁴, and R³⁵, wherein
    • [1211] R³³, R³⁴, and R³⁵ are as defined in embodiment A1.
      Embodiment A186. A compound according to embodiment A185, wherein
  • [1212] R¹ is hydrogen or C_1-6-alkyl optionally substituted with one or more substituents R³³,
  • [1213] R³⁴, and R³⁵, wherein
    • [1214] R³³, R³⁴, and R³⁵ are as defined in embodiment A1.
      Embodiment A187. A compound according to any one of the embodiments A1 to A186, wherein
  • [1215] R³³, R³⁴, and R³⁵ independently of each other are selected from —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —OR⁵², —NR⁵²R⁵³, —SR₅₂—NR⁵²S(O)₂R⁵³, —S(O)₂NR⁵²R⁵³, —S(O)NR⁵²R⁵³, —S(O)R⁵², —S(O)₂R⁵², —C(O)NR⁵²R⁵³, —OC(O)NR⁵²R⁵³, —NR⁵²C(O)R⁵³, —CH₂C(O)NR⁵²R⁵³, —OCH₂C(O)NR⁵²R⁵³, —CH₂OR⁵², —CH₂NR⁵²R⁵³, —OC(O)R⁵², —C(O)R⁵² and —C(O)OR⁵², wherein
    • [1216] R⁵² and R⁵³ are as defined in embodiment A1.
      Embodiment A188. A compound according to embodiment A186, wherein
  • [1217] R⁵² and R⁵³, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
    Embodiment A189. A compound according to embodiment A186, wherein
  • [1218] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-heteroaryl-C_1-6-alkylene-heteroaryl, or aryl.
    Embodiment A190. A compound according to embodiment A189, wherein
  • [1219] R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-or aryl.
    Embodiment A191. A compound according to embodiment A190, wherein
  • [1220] R⁵² and R⁵³ independently of each other are hydrogen or C_1-6-alkyl.
    Embodiment A192. A compound according to embodiment A191, wherein
  • [1221] R⁵² is hydrogen.
    Embodiment A193. A compound according to embodiment A191 or embodiment A192, wherein
  • [1222] R⁵³ is hydrogen.
    Embodiment A194. A compound according to embodiment A186, wherein
  • [1223] R¹ is hydrogen.
    Embodiment A195. A compound according to any one of the embodiments A1 to A194, wherein
  • [1224] G² is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G² with —N(R¹)—, and wherein
    • [1225] R⁴³, R⁴⁴, and R⁴⁵ are as defined in embodiment A1.
      Embodiment A196. A compound according to embodiment A195, wherein
  • [1226] G² is fused cycloalkylheteroaryl optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G² with —N(R¹)—, and wherein
    • [1227] R⁴³, R⁴⁴, and R⁴⁵ are as defined in embodiment A1.
      Embodiment A197. A compound according to embodiment A196 wherein
  • [1228] G² is fused cycloalkylthiazolyl optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵ and wherein
    • [1229] R⁴³, R⁴⁴, and R⁴⁵ are as defined in embodiment A1.
      Embodiment A198. A compound according to embodiment A197, wherein
  • [1230] G² is fused cycloalkylthiazolyl optionally substituted with —COOH
    Embodiment A199. A compound according to embodiment A195, wherein
  • [1231] G² is heteroaryl optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G² with —N(R¹)—, and wherein
    • [1232] R⁴³, R⁴⁴, and R⁴⁵ are as defined in embodiment A1.
      Embodiment A200. A compound according to embodiment A199, wherein
  • [1233] G² is furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, or indazolyl, optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein
    • [1234] R⁴³, R⁴⁴, and R⁴⁵ are as defined in embodiment A1.
      Embodiment A201. A compound according to embodiment A200 wherein G² is thiazolyl, optionally substituted with one or more substituents R⁴³, R⁴⁴, and R⁴⁵, wherein
  • [1235] R⁴³, R⁴⁴, and R⁴⁵ are as defined in embodiment A1.
    Embodiment A202. A compound according to embodiment A201 wherein G² is