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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
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  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D277/38—Nitrogen atoms
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Definitions

• 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.
• GK glucokinase
• 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 7-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 ⁇ -ce ⁇ function besides a range of other abnormalities.
• IDDM insulin demanding diabetes mellitus
• NIDDM non-insulin dependent diabetes mellitus
• Type 1 diabetic patients are currently treated with insulin, while the majority of type 2 diabetic patients are treated either with sulphonylureas that stimulate 7-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin.
• agents applied to enhance tissue sensitivity towards insulin metformin is a representative example.
• 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.
• type 2 diabetes the regulation of hepatic glucose output is poorly controlled and is increased, and may be doubled after an overnight fast.
• hepatic glucose production will be increased in type 1 diabetes, if the disease is not properly controlled by insulin treatment.
• 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.
• 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.
• CVD cardiovascular disease
• 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.
• 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.
• Hypertension 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.
• 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.
• 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. 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.
• 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.
• 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.
• 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.
• perioperative myocardial infarction is estimated to ocur in 5% and death in 1-2%.
• drug therapy is anticipated to be life- saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
• 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.
• diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably currently exist.
• 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.
• 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.
• a feeding centre in the ventrolateral nucleus of the hypothalamus VLH
• a satiety centre in the ventromedial hypothalamus VH
• 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.
• 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.
• the hypothalamic centres are sensitive to catecholamines, and beta-adrenergic stimulation inhibits eating behaviour.
• 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.
• 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.
• WO 00/58293 discloses compounds as glucokinase activators.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of metabolic disorders.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for blood glucose lowering.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for prevention of hyperglycemia.
• 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.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of Syndrome X.
• 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).
• IGF impaired fasting glucose
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of type 2 diabetes.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of type 1 diabetes.
• 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.
• ITT impaired glucose tolerance
• 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.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of dyslipidemia or hyperlipidemia.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for treatment of hypertension.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for the treatment of obesity.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for lowering of food intake
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for appetite regulation.
• the present invention provides the use of a compound or a pharmaceutical preparation according to the present invention for regulating feeding behaviour.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the present invention provides the use of a compound according to the present invention for the preparation of a medicament for blood glucose lowering.
• 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.
• 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.
• 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.
• 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).
• IGF impaired fasting glucose
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the present invention provides the use of a compound according to the present invention for the preparation of a medicament for appetite regulation.
• 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.
• the present invention provides the use of a compound according to the present invention for the preparation of a medicament for regulating feeding behaviour.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• atom A adjacent to atom B means that the two atoms A and B share a bond.
• halogen or halo means fluorine, chlorine, bromine or iodine.
• perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.
• 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.
• alkyl refers to a straight or branched chain saturated monovalent hydrocarbon radical having from one to ten carbon atoms, for example C ⁇ -alkyl or C 1-6 -alkyl.
• Typical C 1-8 -alkyl groups and C 1- ⁇ -alkyl groups include, but are not limited to e.g.
• C 1-8 -alkyl as used herein also includes secondary C ⁇ -alkyl and tertiary C ⁇ -alkyl.
• C 1- ⁇ -alkyl as used herein also includes secondary C ⁇ -alkyl and tertiary C ⁇ -alkyl.
• alkylene 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 Ci-e-alkylene.
• alkylene as used herein include, but are not limited to, methylene, ethylene, and the like.
• alkenyl 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- ⁇ -alkenyl.
• Typical C 2-8 -alkenyl groups and C 2- ⁇ -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.
• alkenylene 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 ⁇ -alkenylene.
• Typical C 2 ⁇ -alkenylene groups and C 2 _ ⁇ -alkenylene groups include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1 ,1-diyl, and the like.
• alkynyl 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 - ⁇ -alkynyl. Typical C 2 .
• 8 - alkynyl groups and C 2 -e-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.
• alkynylene 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 ⁇ -alkynylene.
• Typical C- 2 - ⁇ -alkynylene groups and C 2 . ⁇ -alkynylene groups include, but are not limited to, ethyne-1 ,2- diyl, propyne-1 ,3-diyl, and the like.
• cycloalkyl 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).
• C M -cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and the like.
• 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 M -cycloalkyl- ene.
• Such a ring may be optionally fused to one or more benzene rings or to one or more of other cycloalkyl ring(s).
• Typical Cs- ⁇ -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.
• heterocyclic or the term “heterocyclyi” 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, SO , O, or N, for example C 3 - ⁇ -heterocyclyl. Such a ring may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s).
• Typical C ⁇ -heterocyclyl groups include, but are not limited to, tetrahydrofuran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.
• heterocyclylene 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, SO 2 , 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.
• heterocyclylene examples 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, pi perid ine-2,4-d iyl , piperidine-1 ,4-diyl, pyrrolidine-1 ,3-diyl, morpholine- 2,4-diyl, piperazine-1 ,4-dyil, and the like.
• alkoxy refers to the monovalent radical R a O-, where R a is alkyl as defined above, for example C ⁇ -alky! 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, terf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
• alkylthio 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.
• alkoxycarbonyl refers to the monovalent radical R a OC(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.
• carbamoyl refers to NH 2 C(O)-.
• 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.
• heteroaryl 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.
• 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-pyrroly
• the present invention also relates to partly or fully saturated analogues of the ring systems mentioned above.
• two such terms are used in combination, such as in aryl-alkyl-, heteroaryl- alkyl-, cycloalkyl-C ⁇ -alkyl- 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 aryl-alkyl- :
• arylene refers to carbocyclic aromatic ring diradical or to a aromatic ring system diradical.
• arylene include, but are not limited to, benzene-1 ,4-diyl, naphthalene-1 ,8-diyl, and the like.
• arylene alone or in combination also include other divalent radicals of the monovalent radicals mentioned in the definition of aryl.
• heteroarylene 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.
• 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.
• heteroarylene alone or in combination also include other divalent radicals of the monovalent radicals mentioned in the definition of heteroaryl.
• 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.
• fused cycloalkylaryl used herein include 5-indanyl, 5,6,7,8- tetrahydro-2-naphthyl,
• fused cycloalkylarylene refers to a fused cycloalkylaryl, wherein the aryl group is divalent. Examples include
• 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
• fused arylcycloalkyl used herein include 1-indanyl, 2- indanyl, 1-(1 ,2,3,4-tetrahydronaphthyl),
• fused arylcycloalkylene refers to a fused arylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include
• fused heterocyclylaryl refers to a heterocyclyi group fused to an aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution.
• fused heterocyclylaryl used herein include 3,4- methylenedioxy-1 -phenyl,
• fused heterocyclylarylene refers to a fused heterocyclylaryl, wherein the aryl group is divalent. Examples include
• fused arylheterocyclyl refers to an aryl group fused to a heterocyclyi group, the two having two atoms in common, and wherein the heterocyclyi group is the point of substitution.
• fused arylheterocyclyl used herein include 2-(1,3- benzodioxolyl),
• fused arylheterocyclylene refers to a fused arylheterocyclyl, wherein the heterocyclyi group is divalent. Examples include
• 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.
• fused cycloalkylheteroaryl used herein include 5-aza-6-indanyl
• fused heteroarylcycloalkylene refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include
• fused heterocyclylheteroaryl refers to a heterocyclyi group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution.
• fused heterocyclylheteroaryl used herein include 1 ,2,3,4-tetrahydro-beta-carbolin-8-yl,
• fused heterocyclylheteroarylene refers to a fused heterocyclylheteroaryl, wherein the heteroaryl group is divalent. Examples include
• fused heteroarylheterocyclyl refers to a heteroaryl group fused to a heterocyclyi group, the two having two atoms in common, and wherein the heterocyclyi group is the point of substitution.
• fused heteroarylheterocyclyl used herein include 5-aza-2,3-dihydrobenzofuran-2-yl,
• fused heteroarylheterocyclylene refers to a fused heteroarylheterocyclyl, wherein the heterocyclyi group is divalent. Examples include
• alkylsulfanyl refers to the group R a S-, where R a is alkyl as described above.
• alkylsulfenyl refers to the group R a S(O)-, where R a is alkyl as described above.
• alkylsulfonyl refers to the group R a SO 2 -, where R a is alkyl as described above.
• acyl refers to the group R a C(O)-, where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyi as described above.
• aroyl refers to the group R a C(O)-, where R a is aryl as described above.
• heteroaroyl refers to the group R a C(O)-, where R a is heteroaryl as described above.
• aryloxycarbonyl refers to the group R a -O-C(O)-, where R a is aryl as described above.
• acyloxy refers to the group R a C(O)O-, where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyi as described above.
• aryloxy refers to the group R a -O-, where R a is aryl as described above.
• aroyloxy refers to the group R a C(O)O-, where R a is aryl as described above.
• heteroaroyloxy refers to the group R a C(O)O-, where R a is heteroaryl as described above.
• alkyl cycloalkyl
• aryl aryl
• heteroaryl or the like or either of their prefix roots
• substituent e.g. arylalkoxyaryloxy
• mercapto shall refer to the substituent -SH.
• carboxy shall refer to the substituent -COOH.
• cyano shall refer to the substituent -CN.
• aminosulfonyl shall refer to the substituent -SO 2 NH 2 .
• sulfenyl shall refer to the substituent -S(O)-.
• sulfonyl shall refer to the substituent -S(O) 2 -.
• 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”.
• lower refers to an group having between one and six carbons, and may be indicated with the prefix C x- ⁇ -.
• Lower alkyl may thus be indicated as C 1-6 -alkyl, while lower alkylene may be indicated as C 2-6 -alkylene.
• 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.
• 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.
• substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
• 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, SO 2 , N, or N-alkyl, including, for example, -CH 2 -O-CH 2 -, -CH 2 -SO 2 -CH 2 -, -CH2-NH-CH3 and so forth.
• solvate is a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I)) and a solvent.
• 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.
• 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.
• a drug substance in this invention, a compound of formula (I)
• 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.
• biohydrolyzable amide is an amide of a drug substance
• 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, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
• 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).
• 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.
• pharmaceutically 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.
• 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.
• treatment 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.
• 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.
• insulin derivative 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.
• 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.
• Glucokinase plays an essential role in blood glucose homeostasis. GK catalyses glucose phosphorylation, and is the rate-limiting reaction for glycolysis in hepatocytes and pancreatic ⁇ -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 ⁇ - 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.
• GK has two main distinctive characteristics: its expression, which is limited to tissues that require glucose-sensing (mainly liver and pancreatic ?-cells), and its S 05 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.
• Activators of glucokinase may thus be useful for treating diseases where increasing the activity of glucokinase is beneficial.
• agents which activate glucokinase and increase glucokinase enzymatic activity would be useful for the treatment of type I diabetes and type II diabetes.
• 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.
• 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.
• 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)).
• 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)).
• 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 )).
• GK 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.
• the GK/GK regulatory protein system can be described as a potential target of benefit in both diabetes and obesity.
• GLP-1 glucose-like peptide 1
• GIP gastrointestinal hormones
• 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.
• 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.
• GLP-1 secretion from GLUTag cells is triggered by glucose through a mechanism similar to that found in ?-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 ?-cells.
• the present invention provides compounds of the general formula (I).
• a 1 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 R 23 , R 24 , R 25 , R 26 , and R 27 , wherein
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C 1-6 -alkyl-Z-, C 2- e-alkenyl-Z-, C 2-6 -alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-C ⁇ -alkylene-Z-, heteroaryl-Ci-e-alkylene-Z-, heterocyclyl-C ⁇ -alkylene-Z-, cycloalkyl-C 1-6 -alkylene-Z-, N(R 4 R 5 )-C 1-6 -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W
• R 2 and R 3 independently of each other are hydrogen, C ⁇ -alkyl, aryl-Ci-6-alkylene-, heteroaryl-C ⁇ -alkylene-, C ⁇ -alkyl-arylene-, C 1- ⁇ -alkyl-heteroarylene-, heteroaryl, or aryl; or R 2 and R 3 , 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; Z and W 1 independently of each other are a direct bond, -O-, -N(R 7 )-, -S-, -SO 2 -, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )CON(R 8 )-, -N(R 7 )SO 2 -, -SO 2 N(R 7
• R 7 and R 8 in each individual case independently of each other are hydrogen or alkyl; and R 4 , R 5 , and R 6 independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl-alkylene-, and aryl-alkylene-; or
• R 4 and R 5 may be taken together to form a ring having the formula
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-,
• R 9 and R 10 independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, and aryl-alkylene-;
• D and E independently of each other are a direct bond, -O- or -S-;
• R 11 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-SO 2 -, aryl-alkylene-SO 2 -, heteroaryl-alkylene-SO 2 -, aryl-SO 2 -, heteroaryl-SO 2 -, alkyl-NH-SO 2 -, aryl-alkylene-NH-SO 2 -, heteroaryl-alkylene-NH-SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, heteroaryl-alkylene-C
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -,
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, heteroaryl, C 1-6 -alkyl, aryl-C 1-6 -alkylene-, heteroaryl-C 1- ⁇ -alkylene-, aryl-C 1-6 -alkoxy-, heteroaryl-C 1-6 -alkoxy-, Ci- ⁇ -alkyl-arylene-, C 1-6 -alkyl-heteroarylene-, C 1-6 -alkoxy-heteroarylene-, or
• R 13 and R i may be taken together to form a ring having the formula -(CH 2 ) 0 -X-(CH 2 ) p - bonded to the nitrogen atom to which R ⁇ 3 and R 14 are attached, wherein o and p are independently of each other are 1 , 2, 3, or 4; and X is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -CON(H)-, -NHC(O)-, -NHCON(H)-, -NHSO 2 -, -SO 2 N(H)-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 1 ⁇ and R 17 are selected from hydrogen, aryl, heteroaryl, C 1-6 -alkyl, C ⁇ -alkoxy, aryl-C 1-6 -alkylene-, heteroaryl-C 1-6 -alkylene-, C ⁇ -alkyl-arylene-,
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, heteroaryl-alkylene-, or aryl-alkylene-;
• R 12 is selected from hydrogen, aryl, heteroaryl, alkyl, aryl-alkylene-, heteroaryl-alkylene-, alkyl-arylene-, alkyl-heteroarylene-, alkoxy-heteroarylene-, or alkoxy-arylene-;
• G 1 is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyi, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 , wherein R 18 and R 19 independently of each other are hydrogen, C ⁇ -alkyl, heteroaryl-C 1 . ⁇ -alkylene-, aryl-C ⁇ -alkylene-, C ⁇ -alkyl-arylene-, d ⁇ -alkyl-heteroarylene-, heteroaryl, or aryl; or
• R 18 and R 19 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
• G 1 is aryl, heteroaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, or fused cycloalkylaryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 ;
• L 2 is a direct bond, alkylene, alkenylene, alkynylene, -N(R 20 )-, -alkylene-N(R 20 )-, -alkenylene-NfR 20 )-, -alkynylene-N(R 20 )-, wherein R 20 is hydrogen, or
• R 20 is alkyl, alkenyl, alkynyl, cycloalkyl-W 3 -, heterocyclyl-W 3 -, aryl-W 3 -, heteroaryl-W 3 -, optionally substituted with one or more substituents R 30 , R 31 , and R 32 wherein
• W 3 is alkylene or a direct bond; wherein L 1 and L 2 are attached to adjacent atoms in A 1 ; L 3 is -C(O)-, or -S(O) 2 -; R 1 is hydrogen, or R 1 is alkyl, alkenyl, alkynyl, cycloalkyl-W 4 -, heterocyclyl-W 4 -, aryl-W 4 -, or heteroaryl-W 4 -, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• W 4 is alkylene or a direct bond
• G 2 is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R 43 , R 44 , and R 45 , wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining said heteroaryl group to -N(R 1 )-; or a group of the formula wherein
• G 3 and G 5 independently of each other are alkyl, alkenyl, alkynyl, cycloalkyl-R 22 -, heterocyclyl-R 22 -, aryl-R 22 -, heteroaryl-R 22 -, optionally substituted with one or more substituents R 46 , R 47 , and R 48 , wherein
• R 22 is alkylene or a direct bond; and R 21 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl-W 5 -, or heterocyclyl-W 5 -, optionally substituted with one or more substituents R 36 , R 37 , and R 38 , or R 21 is aryl-W 5 -, or heteroaryl-W 5 -, optionally substituted with one or more substituents R 49 , R 50 , and R 51 , wherein
• W 5 is alkylene or a direct bond
• R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , and R 38 independently of each other are selected from -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 52 , -NR R 53 , -SR 52 , -NR ⁇ SfOkR 53 , -S OkNR ⁇ R 53 , -S(O)NR 52 R 53 , -S(O)R 52 , -S(O) 2 R 52 , -CfOJNR R 53 , -OC(O)NR 52 R 53 , -NR dOJR 53 , -CH 2 C(O)NR 52 R 53 , -OCH 2 C(O)NR 52 R 53 , -CH 2 OR 52 ,
• C 2- ⁇ -alkenyl and C 2-6 -alkynyl which may optionally be substituted with one or more substituents selected from -CN, -CF 3 , -OCF 3 , -OR 52 , -NR ⁇ R 53 and C ⁇ -alkyl; or Cs- 10 -cycloalkyl, C ⁇ -cycloalkenyl, heterocyclyi, C 3-1 o-cycloalkyl-C 1 .
• R 52 and R 53 independently of each other are hydrogen, C ⁇ -alkyl, aryl-C 1-6 -alkylene- heteroaryl-C 1-6 -alkylene- heteroaryl, or aryl; or
• R 52 and R 53 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;
• R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 and R 51 independently of each other are halogen, -CN, -NO 2 , C ⁇ -alkyl, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR ⁇ SfOkR 55 , -StO ⁇ NR ⁇ R 55 , -SfOJNR ⁇ R 55 , -SfC R 54 , -StOJzR 54 , -C ONR ⁇ R 55 , -OCfOJNR ⁇ R 55 , -NR 54 C(O)R 55 , -CH 2 C(O
• C 2- ⁇ -alkenyl and C 2 ⁇ -alkynyl which may optionally be substituted with one or more substituents selected from -CN, -CF 3 , -OCF 3 , -OR 54 , -NR ⁇ R 55 and d- ⁇ -alkyl; C- M i-cycloalkenyl, heterocyclyi, C 3 . 10 -cycloalkyl-C 1 . 6 -alkylene-, C 3 . 10 -cycloalkyl-C 1 . 6 -alkoxy-, Cs ⁇ o-cycloalkyloxy, C 3- ⁇ 0 -cycloalkyl-C 1- ⁇ -alkylthio-,
• R 54 and R 55 independently of each other are hydrogen or -(CHR ⁇ 3 ) u -(CHR 64 ) v -Z, wherein u is 1 or 2; v is O, 1 or 2;
• R 63 and R 64 independently of each other are hydrogen, C 1- ⁇ -alkyl, d- ⁇ -alkyl-arylene- aryl, hydroxy, hydroxyalkyl, amino, or aminoalkyl;
• Z is hydrogen, -O-R 65 , -C(O)O-R 65 , -CONR 65 R 66 , alkylamino, or dialkylamino, wherein
• R 65 and R 6 ⁇ independently of each other is hydrogen or Ci- ⁇ -alkyI; or 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
• R 54 and R 55 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 Ci-e-alkyl groups; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• Embodiment 2 A compound according to embodiment 1 , wherein
• a 1 is arylene or heteroarylene, optionally substituted with one or more substitutents R 23 , R 24 ,
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C 1-6 -alkyl-Z-, C M -alkenyl-Z-, C 2-6 -alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-d- ⁇ -alkylene-Z-, heteroaryl-C 1-6 -alkylene-Z-, heterocyclyl-C 1-6 -alkylene-Z-, cycloalkyl-C ⁇ -alkylene-Z-, N(R 4 R 5 )-C ⁇ -alkylene-Z-, R e -W 1 -Z-, R ⁇ -W
• Embodiment 3 A compound according to embodiment 2, wherein A 1 is C ⁇ - 10 -arylene or Cuo-heteroarylene, optionally substituted with one or more substitutents R 23 , R 24 , R 25 , R 26 , and R 27 , wherein R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C 1- ⁇ -alkyl-Z-, C 2- ⁇ -alkenyl-Z-, C 2-6 -alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-,
• Embodiment 4 A compound according to any of embodiments 1 to 3, wherein R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R 4 R 5 )-C 1 .
• Embodiment 5 A compound according to any of embodiments 1 to 4, wherein
• R 4 , R 5 , and R ⁇ 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 5, wherein R 4 , R 5 , and R 6 independently of each other are hydrogen or alkyl.
• Embodiment 7 A compound according to embodiment 6, wherein
• Embodiment 8 A compound according to any of embodiments 1 to 4, wherein
• R 4 and R 5 is taken together to form a ring having the formula -(CH 2 ) j -Q-(CH 2 ) k - bonded to the nitrogen atom to which R 4 and R 5 are attached, wherein j and k independently of each other is 1 , 2, 3, or 4;
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 9 and R 10 independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, and arylalkyl-.
• Embodiment 9 A compound according to embodiment 8, wherein Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 9 and R 10 independently of each other are hydrogen or alkyl.
• Embodiment 10 A compound according to embodiment 9, wherein
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• Embodiment 11 A compound according to embodiment 10, wherein Q is a direct bond.
• Embodiment 12 A compound according to any of embodiments 1 to 11, wherein
• W 1 is a direct bond, -O-, -NH-, -S-, -SOr, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment 13 A compound according to embodiment 12, wherein W 1 is a direct bond, -O-, -S-, or -SO 2 -.
• Embodiment 14 A compound according to embodiment 13, wherein W 1 is a direct bond.
• Embodiment 15 A compound according to embodiment 4, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , d ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
• Embodiment 16 A compound according to embodiment 15, wherein at least one of R 23 , R 24 , R 25 , R 2 ⁇ , and R 27 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, Cs ⁇ o-cycloalkyl-Z-, Cs-io-heterocyclyl-Z-, Cs-io-aryl-Z-, or C ⁇ o-heteroaryl-Z-, wherein R 2 , R 3 , and Z are as defined for embodiment 1.
• Embodiment 17 A compound according to embodiment 16, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , -NR 2 R 3 , d ⁇ -alkyl-Z-, Cs-io-cycloalkyl-Z-, Cs-io-heterocyclyl-Z-, Cs-io-aryl-Z-, or Cs-io-heteroaryl-Z-, wherein
• Embodiment 18 A compound according to embodiment 17, wherein at least one of R 23 , R 24 , R 25 , R 2 ⁇ , and R 27 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , or -NR 2 R 3 , wherein R 2 , R 3 , and Z are as defined for embodiment 1.
• Embodiment 19 A compound according to any of embodiments 1 to 18, wherein
• R 2 and R 3 independently of each other are hydrogen, C 1-6 -alkyl, aryl-d- ⁇ -alkylene-, heteroaryl-C 1-6 -alkylene-, C 1- ⁇ -alkyl-arylene-, C 1-6 -alkyl-heteroarylene-, heteroaryl, or aryl.
• Embodiment 20 A compound according to embodiment 19, wherein
• R 2 and R 3 independently of each other, are hydrogen, C 1-6 -alkyl, aryl-d ⁇ -alkylene- or aryl.
• Embodiment 21 A compound according to embodiment 20, wherein R 2 is hydrogen or d ⁇ -alkyl.
• Embodiment 22 A compound according to embodiment 21 , wherein R 2 is hydrogen.
• Embodiment 23 A compound according to any of embodiments 1 to 22, wherein
• R 3 is hydrogen or C 1-6 -alkyl.
• Embodiment 24 A compound according to embodiment 23, wherein R 3 is hydrogen.
• Embodiment 25 A compound according to any of embodiments 1 to 15, wherein
• R 2 and R 3 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 25, wherein
• Z is a direct bond, -O-, -NH-, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment 27 A compound according to embodiment 26, wherein Z is a direct bond, -O-, -S-, or -SO 2 -.
• Embodiment 28 A compound according to embodiment 27, wherein
• Embodiment 29 A compound according to embodiment 2, wherein A 1 is
• R 23 , R 24 , R 25 , and R 26 are hydrogen or as defined for embodiment 1.
• Embodiment 30 A compound according to embodiment 29, wherein
• R 23 , R 24 , R 25 , and R 26 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R 4 R 5 )-C 1-6 -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W 1 -N(R 4 )-Z-, R 6 -N(R 4 )-Z, and R 6 -W 1 -C ⁇ -alkylene-Z-, wherein R 2 , R 3 , R 4 , R 5 , R 6 , Z, and W 1 are as defined for embodiment 1.
• Embodiment 31 A compound according to embodiment 29 or 30, wherein
• R 4 , R 5 , and R 6 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 31, wherein
• R 4 , R 5 , and R 6 independently of each other are hydrogen or alkyl.
• Embodiment 33 A compound according to embodiment 32, wherein R 4 , R 5 , and R 6 are hydrogen.
• Embodiment 34 A compound according to embodiment 29 or 30, wherein
• R 4 and R 5 is taken together to form a ring having the formula -(CH 2 ) r Q-(CH 2 ) k - bonded to the nitrogen atom to which R 4 and R 5 are attached, wherein j and k independently of each other is 1 , 2, 3, or 4;
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-, wherein
• R 9 and R 10 independently of each other are selected from the group consisting of hydrogen, aryl, alkyl, and arylalkyl-.
• Embodiment 35 A compound according to embodiment 34, wherein
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 9 and R 10 independently of each other are hydrogen or alkyl.
• Embodiment 36 A compound according to embodiment 35, wherein
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• Embodiment 37 A compound according to embodiment 36, wherein Q is a direct bond.
• Embodiment 38 A compound according to any of embodiments 29 to 37, wherein
• W 1 is a direct bond, -O-, -NH-, -S-, -SOr, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment 39 A compound according to embodiment 38, wherein
• W 1 is a direct bond, -O-, -S-, or -SO r .
• Embodiment 40 A compound according to embodiment 39, wherein W 1 is a direct bond.
• Embodiment 41 A compound according to embodiment 29, wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , d ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
• Embodiment 42 A compound according to embodiment 41 , wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , Qs-nrCycloalkyl-Z-, Q M o-heterocyclyl-Z-, Cs-io-aryl-Z-, or C 3 . 10 -heteroaryl-Z-, wherein
• Embodiment 43 A compound according to embodiment 42, wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , -NR 2 R 3 , d ⁇ -alkyl-Z-, Cs-io-cycloalkyl-Z-, C 3 - ⁇ o-heterocyclyl-Z-, Cs- ⁇ -aryl-Z-, or d-io-heteroaryl-Z-, wherein
• Embodiment 44 A compound according to any of embodiments 29 to 43, wherein
• Z is a direct bond, -O-, -NH-, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(H)S0 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment 45 A compound according to embodiment 44, wherein Z is a direct bond, -O-, -S-, or -SO 2 -.
• Embodiment 46 A compound according to embodiment 45, wherein Z is a direct bond.
• Embodiment 47 A compound according to embodiment 43, wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , -NR 2 R 3 , or C 1-6 -alkyl, wherein R 2 , and R 3 are as defined for embodiment 29.
• Embodiment 48 A compound according to any of embodiments 29 to 47, wherein
• R 2 and R 3 independently of each other are hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkylene-, heteroaryl-d-e-alkylene-, C 1-6 -alkyl-arylene-, C 1- ⁇ -alkyl-heteroarylene-, heteroaryl, or aryl.
• Embodiment 49 A compound according to embodiment 48, wherein R 2 and R 3 independently of each other, are hydrogen, Ci- ⁇ -alkyl, aryl-C 1-6 -alkylene- or aryl.
• Embodiment 50 A compound according to embodiment 49, wherein
• Embodiment 51 A compound according to embodiment 50, wherein
• Embodiment 52 A compound according to any of embodiments 29 to 51 , wherein
• R 3 is hydrogen or d- ⁇ -alkyl.
• Embodiment 53 A compound according to embodiment 52, wherein R 3 is hydrogen.
• Embodiment 54 A compound according to any of embodiments 29 to 41 , wherein
• R 2 and R 3 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 29 to 46, wherein at least one of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment 56 A compound according to embodiment 55, wherein at least two of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment 57 A compound according to claim 56, wherein
• Embodiment 58 A compound according to embodiment 56 or claim 57, wherein at least three of R 23 , R 24 , R 25 , and R 2 ⁇ are hydrogen.
• Embodiment 59 A compound according to any of embodiments 29 to 58, wherein R 24 or R 25 is halogen.
• Embodiment 60 A compound according to embodiment 59, wherein R 24 or R 25 is fluoro.
• Embodiment 61 A compound according to any of embodiments 29 to 58, wherein R 24 or R 25 is Ci- ⁇ -alkyl.
• Embodiment 62 A compound according to embodiment 59, wherein R 24 or R 25 is methyl.
• Embodiment 63 A compound according to any of embodiments 29 to 58, wherein
• Embodiment 64 A compound according to any of embodiments 29 to 63, wherein
• Embodiment 65 A compound according to embodiment 29, wherein R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment 66 A compound according to any of embodiments 1 to 65, wherein
• Embodiment 67 A compound according to embodiment 66, wherein
• Embodiment 68 A compound according to embodiment 66, wherein L 1 is -O-.
• Embodiment 69 A compound according to embodiment 66, wherein L 1 is -S-.
• Embodiment 70 A compound according to embodiment 66, wherein
• Embodiment 71 A compound according to any of embodiments 1 to 67, wherein D is a direct bond or -O-;
• Embodiment 72 A compound according to embodiment 71 , wherein D is a direct bond.
• Embodiment 73 A compound according to embodiment 71 , wherein D is -O-.
• Embodiment 74 A compound according to any of embodiments 71 to 73, wherein
• Embodiment 75 A compound according to any of embodiments 71 to 73, wherein E is -O-.
• Embodiment 76 A compound according to any of embodiments 1 to 75, wherein
• R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -,
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, d- ⁇ -alkyl, or aryl-C 1-6 -alkylene-; or R 13 and R 14 may be taken together to form a ring having the formula -(CH 2 ) 0 -X-(CH 2 ) p - bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein o and p are independently of each other are 1 , 2, 3, or 4; and X is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -CON(H)-, -NHC(O)-, -NHCON(H)-, -NHSO 2 -, -SO 2 N(H)-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 16 and R 17 are selected from hydrogen, aryl, heteroaryl,
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 77 A compound according to embodiment 76, wherein
• R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, d- ⁇ -alkyl, or aryl-Ci- ⁇ -alkylene-; or
• R 13 and R 14 may be taken together to form a ring having the formula
• X is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -CON(H)-, -NHC(O)-, -NHCON(H)-, -NHSO 2 -, -SO 2 N(H)-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 16 and R 17 are hydrogen; and R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 78 A compound according to embodiment 77, wherein R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -
• R 13 and R 14 may be taken together to form a ring having the formula -(CH 2 ) 0 -X-(CH 2 ) P - bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein o and p are independently of each other are 1 , 2, 3, or 4;
• X is a direct bond; and R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 79 A compound according to embodiment 78, wherein
• R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, d- ⁇ -alkyl, or aryl-d ⁇ -alkylene-;
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 80 A compound according to embodiment 79, wherein
• R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 are hydrogen
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 81 A compound according to embodiment 80, wherein R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SOr, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein
• Y is a direct bond
• W 2 is a direct bond, -CH r , -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 are hydrogen;
• R 5 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 82 A compound according to embodiment 80, wherein R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, N(R 13 )(R 14 )-alkylene-Y-, and R 15 -W 2 -alkylene-Y-, wherein Y is a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO
• R 13 and R 14 are hydrogen
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 83 A compound according to any of embodiments 80 to 82, wherein R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, NH 2 -alkylene-, and R 15 -alkylene-, wherein
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, alkyl, or aryl-alkylene-.
• Embodiment 84 A compound according to embodiment 83, wherein
• R 11 is selected from hydrogen, alkyl, aryl, carbamoyl, aryl-alkylene-, alkyl-NH-C(O)-, aryl-alkylene-NH-C(O)-, alkyl-SO 2 -, aryl-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, alkyl-C(O)-, aryl-alkylene-C(O)-, and NH 2 -alkylene-.
• Embodiment 85 A compound according to embodiment 84, wherein R 11 is hydrogen or alkyl.
• Embodiment 86 A compound according to embodiment 85, wherein
• Embodiment 87 A compound according to any of embodiments 1 to 86, wherein R 12 is hydrogen or alkyl.
• Embodiment 88 A compound according to embodiment 87, wherein R 12 is hydrogen.
• Embodiment 89 A compound according to any of embodiments 1 to 88, wherein
• G 1 is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyi, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 , Cs-io-cycloalkyl and C 1-6 -alkyl, wherein
• Embodiment 90 A compound according to embodiment 89, wherein
• G 1 is alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyi, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 and C 1-6 -alkyl, wherein R 18 and R 19 are as defined for embodiment 1.
• Embodiment 91 A compound according to embodiment 89, wherein
• G 1 is d- ⁇ -alkyl, C 2- ⁇ -alkenyl, C 2-6 -alkynyl, d-io-cycloalkyl or C ⁇ o-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 , Cg-io-cycloalkyl and C 1- ⁇ -alkyl, wherein
• Embodiment 92 A compound according to embodiment 90 or embodiment 91 , wherein G 1 is C ⁇ . ⁇ -alkyl, C 2 ⁇ -alkenyl, C 2-6 -alkynyl, d-io-cycloalkyl or C ⁇ o-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 and d ⁇ -alkyl, wherein R 18 and R 19 are as defined for embodiment 1.
• Embodiment 93 A compound according to any of embodiments 89 to 92, wherein R 18 and R 19 , independently of each other, are hydrogen, d- ⁇ -alkyl, heteroaryl-d-e-alkylene-, aryl-d- ⁇ -alkylene-, d- ⁇ -alkyl-arylene-,
• Embodiment 94 A compound according to embodiment 93, wherein
• R 18 and R 19 independently of each other, are hydrogen, C 1-6 -alkyl, C 3-10 -heteroaryl-C 1-6 -alkylene-, C3. 10 -aryl-C 1-6 -alkylene-, d. ⁇ -alkyl-03- ⁇ rarylene-, d- ⁇ -alkyl-Qj-io-heteroarylene-, Cs- ⁇ -heteroaryl, or Qj-io-aryl.
• Embodiment 95 A compound according to embodiment 94, wherein
• Embodiment 96 A compound according to embodiment 95, wherein R 18 is hydrogen.
• Embodiment 97 A compound according to embodiment 95 or 96, wherein R 19 is hydrogen.
• Embodiment 98 A compound according to embodiment 90 or embodiment 92, wherein R 18 and R 19 , 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 88, wherein
• G 1 is alkyl or cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 and C 1- ⁇ -alkyl, or G 1 is aryl optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein R 18 , R 19 , R 40 , R 41 , and R 42 are as defined for embodiment 1.
• Embodiment 100 A compound according to embodiment 99, wherein
• G 1 is d. ⁇ -alkyl or Q M o-cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 ,
• G 1 is Q o-aryl optionally substituted with one or more substituents R 40 , R 41 , and
• Embodiment 101 A compound according to embodiment 99 or embodiment 100, wherein R 18 and R 19 , independently of each other, are hydrogen, C 1-6 -alkyl, heteroaryl-C ⁇ -alkylene-, aryl-C ⁇ -alkylene-, C ⁇ -6-alkyl-arylene-,
• Embodiment 102 A compound according to embodiment 101, wherein
• R 18 and R 19 independently of each other, are hydrogen, C 1-6 -alkyl, Q o-heteroaryl-C ⁇ - 6 -alkylene-, Qj.io-aryl-d. ⁇ -alkylene-, d-e-alkyl-C ⁇ o-arylene-, d- ⁇ -alkyl-d- K rheteroarylene-, C ⁇ o-heteroaryl, or C ⁇ o-aryl.
• Embodiment 103 A compound according to embodiment 102, wherein
• R 18 and R 19 independently of each other, are hydrogen or d- ⁇ -alkyl.
• Embodiment 104 A compound according to embodiment 103, wherein R 18 is hydrogen.
• Embodiment 105 A compound according to embodiment 103 or 104, wherein
• Embodiment 106 A compound according to embodiment 99 or embodiment 100, wherein
• Embodiment 107 A compound according to any of embodiments 99 to 106, wherein
• R 40 , R 41 , and R 42 independently of each other are halogen, -CN, -NO 2 , C 1- ⁇ -alkyl, -CHF 2 , -CF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR ⁇ S ⁇ R 55 ,
• R 54 and R 55 independently of each other are hydrogen, C ⁇ - 6 -alkyl, C 1-6 -alkyl-arylene-, d- ⁇ -alkyl-heteroarylene-, aryl-C 1- ⁇ -alkylene-, heteroaryl-C ⁇ -alkylene-, heteroaryl, or aryl; or
• Embodiment 108 A compound according to embodiment 107, wherein
• R 54 and R 55 independently of each other are hydrogen, or C 1- ⁇ -alkyl, d-e-alkyl-Q o-arylene-, Ci- ⁇ -alkyl-Q o-heteroarylene-, Cs ⁇ o-aryl-d-e-alkylene-, C 3 . 1 o-heteroaryl-C 1 . e -alkylene-, C ⁇ o-heteroaryl, or C ⁇ o-aryl.
• Embodiment 109 A compound according to embodiment 108, wherein
• Embodiment 110 A compound according to embodiment 109, wherein R 54 is hydrogen.
• Embodiment 111 A compound according to embodiment 109 or embodiment 110, wherein R 55 is hydrogen.
• Embodiment 112 A compound according to any of embodiments 1 to 88, wherein
• G 1 is aryl or heteroaryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein R 40 , R 41 , and R 42 are as defined for embodiment 1.
• Embodiment 113 A compound according to embodiment 112, wherein
• G 1 is C ⁇ o-aryl or d-io-heteroaryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• Embodiment 114 A compound according to embodiment 112, wherein
• G 1 is aryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• Embodiment 115 A compound according to embodiment 114, wherein G 1 is C ⁇ o-aryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• Embodiment 116 A compound according to any of embodiments 112 to 115, wherein R 40 , R 41 , and R 42 independently of each other are halogen, -CN, -NO 2 , C ⁇ -alkyl, -CHF 2 , -CF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , - R ⁇ OkR 55 , -S(O) 2 NR 54 R 55 , -S(O)NR M R 55 , -SfOJR 54 , -SfC zR 54 , -CfOJNR ⁇ R 55 , -OC JNR ⁇ R 55 , -NR 54 C(O)R 55 , -CHzC ⁇ JNR ⁇ R 55 , -CHzC O R 54 , -OCHzCfOJNR ⁇ R 55 , -CHzOR 54 , -CHzNR ⁇ R 55 ,
• R 54 and R 55 independently of each other are hydrogen, C 1-6 -alkyl, C 1-6 -alkyl-heteroarylene-, aryl-C 1-6 -alkylene-, heteroaryl-C 1- ⁇ -alkylene-, heteroaryl, or aryl; or
• R 54 and R 55 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 116, wherein
• R 54 and R 55 independently of each other are hydrogen, or C 1-6 -alkyl, C ⁇ -alkyl-C3- ⁇ o-heteroarylene-, d-io-aryl-d- ⁇ -alkylene-, C 3- ⁇ o-heteroaryl-C 1 .
• ⁇ -alkylene-, C ⁇ o-heteroaryl, or C ⁇ o-aryl are hydrogen, or C 1-6 -alkyl, C ⁇ -alkyl-C3- ⁇ o-heteroarylene-, d-io-aryl-d- ⁇ -alkylene-, C 3- ⁇ o-heteroaryl-C 1 .
• ⁇ -alkylene-, C ⁇ o-heteroaryl, or C ⁇ o-aryl are hydrogen, or C 1-6 -alkyl, C ⁇ -alkyl-C3- ⁇ o-heteroarylene-, d-io-aryl-d- ⁇ -alkylene-, C 3- ⁇
• Embodiment 119 A compound according to embodiment 118, wherein
• Embodiment 120 A compound according to embodiment 118 or embodiment 119, wherein R 55 is hydrogen.
• Embodiment 121 A compound according to embodiment 114, wherein G 1 is , wherein
• R 56 , R 57 , R 58 , R 59 , and R 60 are hydrogen or halogen, -CN, -NO 2 , C ⁇ -alkyl, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 61 , -NR 61 R 62 , -SR 61 , -NR 61 S(O) 2 R 62 , -S(O) 2 NR 61 R 62 , -S(O)NR 61 R 62 , -S(O)R 61 , -S(O) 2 R 61 , -C(O)NR 61 R 62 , -OC(O)NR 61 R 62 , -NR 61 C(O)R 62 , -OR 61 ,
• R 61 and R 62 independently of each other are hydrogen, C 1-6 -alkyl, C ⁇ -alkyl-arylene-, d- ⁇ -alkyl-heteroarylene-, aryl-C 1-6 -alkylene-, heteroaryl-C 1- ⁇ -alkylene-, heteroaryl, or aryl; or
• R 61 and R 62 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 121, wherein R 56 , R 57 , R 58 , R 59 , and R 60 independently of each other are halogen, -CN, -NO 2l C 1-6 -alkyl, -CHF 2 , -CF 3 , -OR 61 , -NR 61 R 62 , -SR 61 , -NR 61 S(O) 2 R 62 , -S(O) 2 NR 61 R 62 , -S(O)NR 61 R 62 , -S(O)NR 61 R 62 , -S(O)R 61 , -S(O) 2 R 61 , -C(O)NR 61 R 62 , -OC(O)NR 61 R 62 , -NR 61 C(O)R 62 , -CH 2 C(O)NR 61 R 62 , -CH 2 C(O)OR 61
• R 61 and R 62 independently of each other are hydrogen, C ⁇ -alkyl, d- ⁇ -alkyl-arylene-, C 1-6 -alkyl-heteroarylene-, aryl-d- ⁇ -alkylene-, heteroaryl-C 1- ⁇ -alkylene-, heteroaryl, or aryl; or R 61 and R 62 , 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 121 or embodiment 122, wherein R 24 or R 25 is -OR 61 .
• Embodiment 124 A compound according to embodiment 122, wherein
• R 61 and R 62 independently of each other are hydrogen, or C 1-6 -alkyl, d- ⁇ -alkyl-Qj-io-arylene-, d- ⁇ -alkyl-Cs-io-heteroarylene-, Cs- ⁇ -aryl-C ⁇ -alkylene-, Cs- K rheteroaryl-d-e-alkylene-, Qj-io-heteroaryl, or Q ⁇ o-aryl.
• Embodiment 125 A compound according to embodiment 124, wherein
• Embodiment 126 A compound according to embodiment 125, wherein
• Embodiment 127 A compound according to embodiment 125 or embodiment 126, wherein R 62 is hydrogen.
• Embodiment 128 A compound according to any of embodiments 121 to 127, wherein at least one of R 56 , R 57 , R 58 , R 59 , and R 60 are hydrogen.
• Embodiment 129 A compound according to embodiment 128, wherein at least two of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment 130 A compound according to embodiment 129, wherein at least three of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment 131 A compound according to any of embodiments 1 to 130, wherein L 2 is a direct bond, C 1-6 -alkylene, C 2-6 -alkenylene, C 2-6 -alkynylene, -N-R 20 -, -C 2-6 -alkenylene-N(R 20 )-, or -C 2- ⁇ -alkynylene-N(R 20 )-, wherein R 20 is as defined for embodiment 1.
• Embodiment 132 A compound according to any of embodiments 1 to 127, wherein
• L 2 is -N-R 20 -, -alkylene-N(R 20 )-, -alkenylene-N(R 20 )-, or -alkynylene-N(R 20 )-, wherein R 20 is as defined for embodiment 1.
• Embodiment 133 A compound according to embodiment 131 or embodiment 132, wherein L 2 is -N-R 20 -, -C 1 ⁇ -alkylene-N(R 20 )-, -C 2 ⁇ -alkenylene-N(R 20 )-, or
• Embodiment 134 A compound according to embodiment 133, wherein L 2 is -N-R 20 -, wherein R 20 is as defined for embodiment 1.
• Embodiment 135 A compound according to embodiment 131 , wherein
• Embodiment 136 A compound according to any of embodiments 1 to 134, wherein R 20 is hydrogen, or R 20 is C 1-6 -alkyl, C 2 ⁇ -alkenyl, C 2 ⁇ -alkynyl, C ⁇ o-cycloalkyl-W 3 -,
• Embodiment 137 A compound according to embodiment 136, wherein W 3 is alkylene.
• Embodiment 138 A compound according to embodiment 137, wherein
• W 3 is C 2-6 -alkylene.
• Embodiment 139 A compound according to embodiment 136, wherein W 3 is a direct bond.
• Embodiment 140 A compound according to any of embodiments 1 to 134, wherein
• R 20 is hydrogen, alkyl, alkenyl, or alkynyl, optionally substituted with one or more substituents R 30 , R 3 , and R 32 wherein
• Embodiment 141 A compound according to any of embodiments 136 to 140, wherein R 20 is hydrogen, or
• R 20 is C 1-6 -alkyl, C ⁇ -alkenyl, or C 1-6 -alkynyl, optionally substituted with one or more substituents R 30 , R 31 , and R 32 wherein
• Embodiment 142 A compound according to any of embodiments 1 to 141, wherein R 30 , R 31 , and R 32 independently of each other are selected from -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 52 , -NR R 53 , -SR5 2 , -NR ⁇ StOJzR 53 , -S JzNR ⁇ R 53 , -S(O)NR 52 R 53 , -S(O)R 52 , -S(O) 2 R 52 , -CfOJNR R 53 , -OC(O)NR 52 R 53 , -NR ⁇ CfOJR 53 , -CHzCfOJNR ⁇ R 53 , -OCH 2 C
• Embodiment 143 A compound according to embodiment 142, wherein
• Embodiment 144 A compound according to any of embodiments 1 to 142, wherein
• R 52 and R 53 independently of each other are hydrogen, C 1- ⁇ -alkyl, aryl-Ci- ⁇ -alkylene- heteroaryl-C ⁇ -alkylene- heteroaryl, or aryl.
• Embodiment 145 A compound according to embodiment 144, wherein
• Embodiment 146 A compound according to embodiment 145, wherein
• R 52 and R 53 independently of each other are hydrogen or C 1-6 -alkyl.
• Embodiment 147 A compound according to embodiment 146, wherein R 52 is hydrogen.
• Embodiment 148 A compound according to embodiment 146 or embodiment 147, wherein
• Embodiment 149 A compound according to embodiment 141, wherein R 20 is hydrogen.
• Embodiment 150 A compound according to any of embodiments 1 to 149, wherein
• Embodiment 151 A compound according to any of embodiments 1 to 150, wherein R 1 is hydrogen, or R 1 is C ⁇ . 6 -alkyl, C 2-6 -alkenyl, C 2- ⁇ -alkynyl, C 3 - ⁇ o-cycloalkyl-W 4 -, C 3 - ⁇ o-heterocyclyl-W 4 -, d-io-aryl-W 4 -, or d-urheteroaryl-W 4 -, optionally substituted with one or more substituents R 33 , R 34 , and R 35 wherein
• Embodiment 152 A compound according to embodiment 151, wherein W 4 is alkylene.
• Embodiment 153 A compound according to embodiment 152, wherein
• W 4 is C 2 . ⁇ -alkylene.
• Embodiment 154 A compound according to embodiment 151, wherein W 4 is a direct bond.
• Embodiment 155 A compound according to any of embodiments 1 to 150, wherein
• R 1 is hydrogen, alkyl, alkenyl, or alkynyl, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• Embodiment 156 A compound according to any of embodiments 151 to 155, wherein R 1 is hydrogen, d ⁇ -alkyl, C 2-6 -alkenyl, or C 2 ⁇ -alkynyl, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• Embodiment 157 A compound according to embodiment 156, wherein
• R 1 is hydrogen or d ⁇ -alkyl optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• Embodiment 158 A compound according to any of embodiments 1 to 157, wherein
• R 33 , R 34 , and R 35 independently of each other are selected from -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 52 , -NR ⁇ R 53 , -SR 52 , -NR 52 S(O) 2 R 53 , -S ⁇ NR R 53 , -S(O)NR 52 R 53 , -S(O)R 52 , -S(O) 2 R 52 , -C(O)NR 52 R 53 ,
• Embodiment 159 A compound according to embodiment 157, wherein R 52 and R 53 , 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 157, wherein R 52 and R 53 independently of each other are hydrogen, d-e-alkyl, aryl-C ⁇ . 6 -alkylene- heteroaryl-d- ⁇ -alkylene- heteroaryl, or aryl.
• Embodiment 161 A compound according to embodiment 160, wherein
• R 52 and R 53 independently of each other are hydrogen, C ⁇ -alkyl, aryl-d-e-alkylene-or aryl.
• Embodiment 162 A compound according to embodiment 161 , wherein R 52 and R 53 independently of each other are hydrogen or C 1-6 -alkyl.
• Embodiment 163 A compound according to embodiment 162, wherein
• Embodiment 164 A compound according to embodiment 162 or embodiment 163, wherein R 53 is hydrogen.
• Embodiment 165 A compound according to embodiment 157, wherein
• Embodiment 166 A compound according to any of embodiments 1 to 165, wherein G 2 is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R 43 , R 44 , and R 45 , wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G 2 with -N(R 1 )-, and wherein
• Embodiment 167 A compound according to embodiment 166, wherein G 2 is heteroaryl optionally substituted with one or more substituents R 43 , R 44 , and
• Embodiment 168 A compound according to embodiment 167, wherein G 2 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 R 43 , R 44 , and R 45 , wherein R 43 , R 44 , and R 45 are as defined for embodiment 1.
• Embodiment 169 A compound according to any of embodiments 1 to 168, wherein R 43 , R 44 , and R 45 independently of each other are selected from halogen, -CN, -NO 2 , C 1-6 -alkyl, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR 54 S(O) 2 R 55 , -SfO ⁇ NR ⁇ R 55 , -S OJNR ⁇ R 55 , -SfOJR 54 , -S(O) 2 R 54 , -CfC NR ⁇ R 55 , -OC ⁇ J R ⁇ R 55 ,
• Embodiment 170 A compound according to embodiment 169, wherein R 54 and R 55 , 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 170, wherein
• R 54 and R 55 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 169, wherein
• R 54 and R 55 independently of each other are hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkylene- or aryl.
• Embodiment 173 A compound according to embodiment 172, wherein R 54 and R 55 independently of each other are hydrogen, C 1-6 -alkyl,
• Embodiment 174 A compound according to embodiment 173, wherein
• R 54 and R 55 independently of each other are hydrogen or Ci-e-alkyl.
• Embodiment 175 A compound according to embodiment 174, wherein R 54 is hydrogen.
• Embodiment 176 A compound according to embodiment 174 or embodiment 175, wherein
• Embodiment 177 A compound according to embodiment 169, wherein
• R 54 and R 55 independently of each other are hydrogen or -(CHR ⁇ CHR ⁇ -Z, wherein u is 1 or 2; v is 0, 1 or 2;
• R 63 and R 64 independently of each other are hydrogen, C 1-6 -alkyl, d-e-alkyl-Cs-io-arylene- d-io-aryl, hydroxy, hydroxy-d- ⁇ -alkyl, amino, or amino-C ⁇ -alkyl;
• Z is hydrogen, -C-O-R 65 , -C(O)O-R 65 , -CONR 65 R 66 , C 1-6 -alkylamino, or di(C ⁇ -6-alkyl)-amino, wherein
• R 65 and R 66 independently of each other is hydrogen or C 1-6 -alkyl; or 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 177, wherein u is 1 ; and v is 0, or 1.
• Embodiment 179 A compound according to embodiment 177 or embodiment 178, wherein R 63 and R 64 independently of each other are hydrogen, C ⁇ -alkyl, hydroxy, hydroxy-d-e-alkyl, amino, or amino-C ⁇ -alkyl.
• Embodiment 180 A compound according to any of embodiments 177 to 179, wherein Z is -C-O-R 65 , or -C(O)O-R 65 , wherein
• Embodiment 181 A compound according to any of embodiments 177 to 179, wherein
• Embodiment 182 A compound according to embodiment 181, wherein
• Embodiment 183 A compound according to embodiment 181, wherein
• 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 181 to 183, wherein
• Z is a five or six membered ring wherein one ring atom is nitrogen.
• Embodiment 185 A compound according to any of embodiments 181 to 184, wherein a nitrogen atom is the point of attachment of the Z group to the -(CHR 63 ) U -(CHR 64 ) V - group.
• Embodiment 186 A compound according to any of embodiments 177 to 185, wherein
• Embodiment 187 A compound according to any of embodiments 166 to 169, wherein G 2 is substituted with a substituent R 43 , wherein R 43 is halogen, -CN, -NO 2 , C 1-6 -alkyl, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 ,
• Embodiment 188 A compound according to embodiment 187, wherein
• R 54 and R 55 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 189 A compound according to embodiment 188, wherein
• Embodiment 190 A compound according to embodiment 187, wherein
• R 54 and R 55 independently of each other are hydrogen, d ⁇ -alkyl, aryl-d- ⁇ -alkylene- or aryl.
• Embodiment 191 A compound according to embodiment 190, wherein
• R 54 and R 55 independently of each other are hydrogen, d- ⁇ -alkyl, C 3-10 -aryl-C 1 . 6 -alkylene- or Q o-aryl.
• Embodiment 192 A compound according to embodiment 191, wherein R 54 and R 55 independently of each other are hydrogen or C ⁇ -alkyl.
• Embodiment 193 A compound according to embodiment 192, wherein
• Embodiment 194 A compound according to embodiment 192 or embodiment 193, wherein R 55 is hydrogen.
• Embodiment 195 A compound according to embodiment 187, wherein
• R 54 and R 55 independently of each other are hydrogen or -(CHR ⁇ -tCHR 64 ) ⁇ , wherein u is 1 or 2; v is 0, 1 or 2; R 63 and R 64 independently of each other are hydrogen, C 1- ⁇ -alkyl, d-e-alkyl-Q o-arylene- d-io-aryl, hydroxy, hydroxy-C 1-6 -alkyl, amino, or amino-C ⁇ .6-alkyl;
• Z is hydrogen, -C-O-R 65 , -C(O)O-R 65 , -CONR 65 R 66 , C 1- ⁇ -alkylamino, or di(d. ⁇ -alkyl)-amino, wherein R 65 and R 66 independently of each other is hydrogen or C 1-6 -alkyl; or
• 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 195, wherein u is 1 ; and v is 0, or 1.
• Embodiment 197 A compound according to embodiment 195 or embodiment 196, wherein R 63 and R 64 independently of each other are hydrogen, C 1-6 -alkyl, hydroxy, hydroxy-d- ⁇ -alkyl, amino, or
• Embodiment 198 A compound according to any of embodiments 195 to 197, wherein Z is -C-O-R 65 , or -C(O)O-R 65 , wherein
• Embodiment 199 A compound according to any of embodiments 195 to 197, wherein
• 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 199, wherein
• 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 199, wherein 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 199 to 201 , wherein
• Z is a five or six membered ring wherein one ring atom is nitrogen.
• Embodiment 203 A compound according to any of embodiments 199 to 202, wherein a nitrogen atom is the point of attachment of the Z group to the -(CHR 63 ) U -(CHR 64 ) V - group.
• Embodiment 204 A compound according to any of embodiments 195 to 203, wherein
• Embodiment 205 A compound according to embodiment 187, wherein R 43 is -CH 2 C(O)OR 54 , wherein
• Embodiment 206 A compound according to embodiment 205, wherein
• R 54 is hydrogen, or aryl.
• Embodiment 207 A compound according to embodiment 206, wherein R 54 is hydrogen, d-e-alkyl, Q o-aryl-d- ⁇ -alkylene- or C 3 . 10 -aryl.
• Embodiment 208 A compound according to embodiment 207, wherein
• Embodiment 209 A compound according to embodiment 208, wherein
• Embodiment 210 A compound according to any of embodiments 187 to 209, wherein
• Embodiment 211 A compound according to any of embodiments 166 to 210, wherein G 2 is
• Embodiment 212 A compound according to embodiment 211, wherein G 2 is
• R 43 , R 44 , and R 45 independently of each other are hydrogen or as defined for embodiment 1.
• Embodiment 213 A compound according to embodiment 211 or embodiment 212, wherein R 43 , R 44 , and R 45 independently of each other are selected from hydrogen, halogen, -CN, -NO 2 , d-e-alkyl, -CHF 2 , -CF 3 , -OCF 3> -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 ,
• Embodiment 214 A compound according to embodiment 213, wherein
• R 43 is halogen, -CN, -NO 2 , C ⁇ -alkyl, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR ⁇ S ⁇ R 55 , -NR 54 C(O)R 55 , -CH 2 C(O)NR 54 R 55 , -CH 2 C(O)OR 54 , -OCHzCfOJNR ⁇ R 55 , -CHzOR 54 , -CHzNR ⁇ R 55 , -OC(O)R 54 , -C(O)R M or -CfO R 54 , wherein R 54 and R 55 are as defined for embodiment 1.
• Embodiment 215 A compound according to embodiment 213 or 214, wherein
• R 43 is -C OOR 54 , -CHzCtOOR 54 , -C OJNR ⁇ R 55 , or -CHzCfOJNR ⁇ R 55 , wherein R 54 and R 55 are as defined for embodiment 1.
• Embodiment 216 A compound according to embodiment 214 or 215, wherein R 44 is alkyl or hydrogen.
• Embodiment 217 A compound according to embodiment 216, whereinR 44 is d-e-alkyl or hydrogen.
• Embodiment 218 A compound according to embodiment 217, wherein
• R 44 is hydrogen.
• Embodiment 219 A compound according to embodiment 213, wherein R 44 is halogen, -CN, -NO 2 , C ⁇ -alkyl, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 ,
• Embodiment 220 A compound according to embodiment 213 or embodiment 219, wherein R 44 is -CfC OR 54 , -CH 2 C(O)OR 54 , -CfOJNR ⁇ R 55 , or -CHzC ⁇ R ⁇ R 55 , wherein R 54 and R 55 are as defined for embodiment 1.
• Embodiment 221 A compound according to embodiment 219 or 220, wherein R 43 is alkyl or hydrogen.
• Embodiment 222 A compound according to embodiment 221 , wherein
• R 43 is C 1-6 -alkyl or hydrogen.
• Embodiment 223 A compound according to embodiment 222, wherein R 43 is hydrogen.
• Embodiment 224 A compound according to any of embodiments 211 to 223, wherein R 45 is hydrogen.
• Embodiment 225 A compound according to any of embodiments 211 to 224, wherein R 54 and R 55 , 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- ⁇ -alkyl groups.
• Embodiment 226 A compound according to embodiment 225, wherein
• Embodiment 227 A compound according to any of embodiments 211 to 224, wherein
• R 54 and R 55 independently of each other are hydrogen, d- ⁇ -alkyl, aryl-Ci- ⁇ -alkylene- or aryl.
• Embodiment 228 A compound according to any of embodiments 211 to 224, wherein
• R 54 and R 55 independently of each other are hydrogen, d ⁇ -alkyl, aryl-Ci-e-alkylene- or aryl.
• Embodiment 229 A compound according to embodiment 228, wherein R 54 and R 55 independently of each other are hydrogen or d- ⁇ -alkyl.
• Embodiment 230 A compound according to embodiment 229, wherein
• R 54 is hydrogen.
• Embodiment 231 A compound according to any of embodiments 211 to 230, wherein R 55 is hydrogen.
• Embodiment 232 A compound according to any of embodiments 211 to 224, wherein R 54 and R 55 independently of each other are hydrogen or -(CHR 63 ) U -(CHR 64 ) V -Z, wherein u is 1 or 2; v is 0, 1 or 2; R 63 and R 64 independently of each other are hydrogen, C 1- ⁇ -alkyl, d-io-aryl, hydroxy, amino, or amino-d. ⁇ -alkyl;
• Z is hydrogen, -C-O-R 65 , -C(O)O-R 65 , -CONR 65 R 66 , d- ⁇ -alkylamino, or di(C 1-6 -alkyl)-amino, wherein R 65 and R 68 independently of each other is hydrogen or d- ⁇ -alkyl; or
• Embodiment 233 A compound according to embodiment 232, wherein u is 1 ; and v is 0, or 1.
• Embodiment 234 A compound according to embodiment 232 or embodiment 233, wherein R 63 and R 64 independently of each other are hydrogen, d ⁇ -alkyl, hydroxy, hydroxy-d- ⁇ -alkyl, amino, or amino-C 1-6 -alkyl.
• Embodiment 235 A compound according to any of embodiments 232 to 234, wherein Z is -C-O-R 65 , or -C(O)O-R 65 , wherein
• Embodiment 236 A compound according to any of embodiments 232 to 234, wherein
• 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 236, wherein
• 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 236, wherein 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 236 to 238, wherein
• Z is a five or six membered ring wherein one ring atom is nitrogen.
• Embodiment 240 A compound according to any of embodiments 236 to 239, wherein a nitrogen atom is the point of attachment of the Z group to the -(CHR 63 ) U -(CHR 64 ) V - group.
• Embodiment 241 A compound according to any of embodiments 195 to 240, wherein
• Embodiment 242 A compound according to embodiment 213, wherein R 44 is hydrogen.
• Embodiment 243 A compound according to embodiment 213 or embodiment 242, wherein
• Embodiment 244 A compound according to embodiment 242 or embodiment 243, wherein R 45 is hydrogen.
• Embodiment 245 A compound according to embodiment 1 , which is, N-(2-phenoxyphenyl)-N'-(thiazol-2-yl)urea,
• Embodiment 246 A compound according to any of embodiments 1 to 245, 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 246, 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 247, which compound, at a concentration of 30 ⁇ M, 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 248, which compound, at a concentration of 30 ⁇ M, 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 249, which at a concentration of 5 ⁇ M 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 250, which at a concentration of 5 ⁇ M 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 ⁇ M 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 251 , 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 252 or embodiment 253, 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 252 to 254, which at a compound concentration of 10 ⁇ M 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 ⁇ M in Glucokinase Activation Assay (I) disclosed herein at a glucose concentration of 15 mM.
• Embodiment 256 A compound according to any of embodiments 252 to 255, which at a compound concentration of 10 ⁇ M 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 ⁇ M 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 ⁇ M 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 ⁇ M 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 lns-1 cells.
• Embodiment 259 A compound according to any of embodiments 1 to 256, 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 256, which compound shows a significantly higher activity in isolated hepatocytes compared to the activity of the compound in lns-1 cells.
• Embodiment 261 A compound according to any of embodiments 257 to 260, 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 lns-1 cells measured as described in the Glucokinase Activity Assay (III).
• Embodiment 262 A compound according to embodiment 261, 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 lns-1 cells measured as described in the Glucokinase Activity Assay (III).
• II Glucokinase Activity Assay
• Embodiment 263 A compound according to embodiment 261 , which compound shows no activity in the lns-1 cells measured as described in the Glucokinase Activity Assay (III).
• Embodiment 264 A compound according to any one of embodiments 1 to 263, 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 264 for use as a medicament.
• Embodiment 266 A compound according to any one of embodiments 1 to 264 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.
• a 1 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 R 23 , R 24 , R 25 , R 26 , and R 27 , wherein
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group j consisting of halogen, -C(O)OR 2 , -C(O)R 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-,
• R 2 and R 3 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;
• Z and W 1 independently of each other are a direct bond, -O-, -N(R 7 )-,
• R 7 and R 8 in each individual case independently of each other are hydrogen or C 1-6 -alkyl
• R 4 , R 5 , and R 6 independently of each other are selected from the group consisting of hydrogen, cyano, halogen, aryl, heteroaryl, heteroaryl-C 1- ⁇ -alkylene-, aryl-C 1-6 - alkylene-, C 3 . 10 -cycloalkyl, heterocyclyi optionally substituted with one or more d-e-alkyl, or C 1-6 -alkyl optionally substituted with halogen, -S(O) 2 CH 3 or COOH; or
• R 4 and R 5 may be taken together to form a ring having the formula -(CH 2 ) r Q-(CH 2 ) k - bonded to the nitrogen atom to which R 4 and R 5 are attached, wherein j and k independently of each other is 1 , 2, 3, or 4; and Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-,
• R 9 and R 10 independently of each other are selected from the group consisting of hydrogen, aryl, d- ⁇ -alkyl, and aryl-alkylene-;
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, heteroaryl, C 1- ⁇ -alkyl, d ⁇ -alkoxy, aryl-C 1- ⁇ -alkylene-, heteroaryl-d ⁇ -alkylene-, aryl-C 1- ⁇ -alkoxy-, heteroaryl-d- ⁇ -alkoxy-, C 1-e -alkyl-arylene-, Ci- ⁇ -alkyl-heteroarylene-, d-e-alkoxy-heteroarylene-, or d- ⁇ -alkoxy-arylene-; or R 13 and R 14 may be taken together to form a ring having the formula
• X is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -CON(H)-, -NHC(O)-, -NHCON(H)-, -NHSO 2 -, -SO 2 N(H)-, -C(O)-O-, -O-C(O)-,
• R 16 and R 17 are selected from hydrogen, aryl, heteroaryl, d- ⁇ -alkyl, C 1-6 -alkoxy, aryl-C 1-e -alkylene-, heteroaryl-C 1- ⁇ -alkylene-, d- ⁇ -alkyl-arylene-, d- ⁇ -alkyl-heteroarylene-, C 1-6 -alkoxy-arylene-, d- ⁇ -alkoxy-heteroarylene-, heteroarylaryl-C 1-6 -alkoxy-, or aryl-d ⁇ -alkoxy-; and R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, C 1-6 -alkyl, heteroaryl-d- ⁇ -alkylene-, or aryl-d ⁇ -alkylene-; and
• R 12 is selected from hydrogen, aryl, heteroaryl, d- ⁇ -alkyl, aryl-d- ⁇ -alkylene-, heteroaryl-Ci ⁇ -alkylene-, d- ⁇ -alkyl-arylene-, Ci- ⁇ -alkyl-heteroarylene-, C 1- ⁇ -alkoxy-heteroarylene-, or C 1-6 -alkoxy-arylene-;
• G 1 is d- ⁇ -alkyl, C ⁇ o-cycloalkyl, d-io-cycloalkyl-d- ⁇ -alkylene-, C 2-6 -alkenyl, or C 2- ⁇ -alkynyl, all of which may optionally be substituted with one or more substituents independently selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 , Cs-nrcycloalkyl and d- ⁇ -alkyl, wherein
• R 18 and R 19 independently of each other are hydrogen, d- ⁇ -alkyl, heteroaryl-d- 6 -alkylene-, aryl-C 1-6 -alkylene-, C 1- ⁇ -alkyl-arylene-, C 1-6 -alkyl-heteroarylene-, heteroaryl, or aryl; or
• R 18 and R 19 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
• G 1 is aryl, heteroaryl, heterocyclyi, fused cycloalkylheteroaryl, fused heterocyclylaryl, fused arylheterocyclyl, or fused cycloalkylaryl, all of which may optionally be substituted with one or more substituents selected from R 40 , R 41 , and R 42 ;
• L 2 is a direct bond, d- ⁇ -alkylene, C 2-6 -alkenylene, C 2-6 -alkynylene, -N(R 20 )-, -d- ⁇ -alkylene- N(R 20 )-, -C 2 ⁇ -alkenylene-N(R 20 )-, -C 2 ⁇ -alkynylene-N(R 20 )-, wherein R 20 is hydrogen, or
• R 20 is d. ⁇ -alkyl, C 2-e -alkenyl, C 2-6 -alkynyl, cycloalkyl-W 3 -, heterocyclyl-W 3 -, aryl-W 3 -, heteroaryl-W 3 -, optionally substituted with one or more substituents R 30 , R 31 , and R 32 wherein
• W 3 is C ⁇ - 6 -alkylene or a direct bond; wherein L 1 and L 2 are attached to adjacent atoms in A 1 ; L 3 is -C(O)-, -C(O)-C(O)-, -C(O)CH 2 C(O)- or -S(O) 2 -; R 1 is hydrogen, or R 1 is d- ⁇ -alkyl, C 2 ⁇ -alkenyl, C 2-6 -alkynyl, cycloalkyl-W 4 -, heterocyclyl-W 4 -, aryl-W 4 -, or heteroaryl-W 4 -, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• W 4 is d- ⁇ -alkylene or a direct bond
• G 2 is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R 43 , R 44 , and R 45 , wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining said heteroaryl group to -N(R 1 )-; or a group of the formula
• G 3 and G 5 independently of each other are C 1-6 -alkyl, C 2 - 6 -alkenyl, C 2-6 -alkynyl, cycloalkyl-R 22 -, heterocyclyl-R 22 -, aryl-R 22 -, heteroaryl-R 22 -, optionally substituted with one or more substituents R 46 , R 47 , and R 48 , wherein R 22 is alkylene or a direct bond; and R 21 is hydrogen, C ⁇ -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, cycloalkyl-W 5 -, or heterocyclyl-
• W 5 - optionally substituted with one or more substituents R 36 , R 37 , and R 38 , or R 21 is aryl-W 5 -, or heteroaryl-W 5 -, optionally substituted with one or more substituents R 49 , R 50 , and R 51 , wherein
• W 5 is d- ⁇ -alkylene or a direct bond; wherein R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 38 , R 37 , and R 38 independently of each other are selected from -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 52 , -NR ⁇ R 53 , -SRsz, -NR ⁇ S ⁇ JzR 53 , -SfO ⁇ NR ⁇ R 53 , -S OJNR ⁇ R 53 , -S(O)R 52 , -S(O) 2 R 52 , -CfOJNR ⁇ R 53 , -OC(O)NR 52 R 53 , -NR 52 C(O)R 53 , -CHzdOJNR R 53 , -OC
• R 52 and R 53 independently of each other are hydrogen, C ⁇ -alkyl, aryl-C 1-6 -alkylene- heteroaryl-d- ⁇ -alkylene- heteroaryl, or aryl; or
• R 52 and R 53 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;
• R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 and R 51 independently of each other are -CN, -NO 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR ⁇ S ⁇ JzR 55 , -SfO ⁇ NR ⁇ R 55 , -S ⁇ JNR ⁇ R 55 , -S(O)R 54 , ⁇ (OJzR 5 , -dOJNR ⁇ R 55 , -OC(O)NR 54 R 55 , -NR ⁇ CfOJR
• R 54, R 55 and R 56 independently of each other are hydrogen, d- ⁇ -alkyl.-S d- ⁇ -alkylfe, C 1-6 -alkyl-arylene-, Ci- ⁇ -alkyl-heteroarylene-, aryl-C 1-6 -alkylene-, heteroaryl-C ⁇ -alkylene-, heterocyclyi, heterocyclyl-d- ⁇ -alkylene-, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents independently selected from R 71 ; or
• R 54 and R 55 independently of each other are hydrogen or -(CHR 72 ) U -(CHR 73 ) V -W 6 , wherein u is 0, 1 or 2; v is 0, 1 or 2; R 72 and R 73 independently of each other are hydrogen, C 1- ⁇ -alkyl, C 1- ⁇ -alkyl-arylene- aryl, hydroxy, hydroxyalkyl, -C(O)O-R 75 , amino, or aminoalkyl;
• W 6 is hydrogen, -O-R 75 , -C(O)O-R 75 , -C(O)-R 75 , -CONR 75 R 76 , -NR 75 R 76 , -NHCH 2 C(O)R 75 , -NHC(O)R 75 , -NHC(O)OR 75 , -S(O) 2 R 75 , -NHS(O) 2 R 75 , alkylamino, or dialkylamino, or
• W 6 is phathalimido or heterocyclyi.
• R 54 and R 55 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 d- ⁇ -alkyl groups;
• R 70 O, -C(O)CH 3 , , -S(O) 2 CH 3 , -CF 3 , -C(O)O-R 75 , -(CH 2 ) 1-3 C(O)O-R 75 or d- ⁇ -alkyl;
• R 75 and R 76 independently of each other is hydrogen, halogen, -OH, -CF 3 , or d- ⁇ -alkyl optionally substituted with -NH 2 ;
• Embodiment A2 A compound according to embodiment A1 , wherein
• a 1 is arylene or heteroarylene, optionally substituted with one or more substitutents R 23 , R 24 ,
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C 1-6 -alkyl-Z-, C 2-6 -alkenyl-Z-, C 2- ⁇ -alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-d- ⁇ -alkylene-Z-, heteroaryl-d- ⁇ -alkylene-Z-, heterocyclyl-C 1-6 -alkylene-Z-, cycloalkyl-C ⁇ -alkylene-Z-, N(R 4 R 5 )-C ⁇ -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W 1
• R 2 , R 3 , R 4 , R 5 , R 8 , Z, and W 1 are as defined in embodiment A1.
• Embodiment A3 A compound according to embodiment A2, wherein A 1 is C ⁇ -io-arylene or C ⁇ o-heteroarylene, optionally substituted with one or more substitutents R 23 , R 24 , R 25 , R 26 , and R 27 , wherein
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, C 2-6 -alkenyl-Z-, C 2 ⁇ -alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-d- ⁇ -alkylene-Z-, heteroaryl-C 1-6 -alkylene-Z-, heterocyclyl-Ci- ⁇ -alkylene-Z-, cycloalkyl-C ⁇ -alkylene-Z-, N(R 4 R 5 )-C ⁇ -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W 1 -
• R 2 , R 3 , R 4 , R 5 , R 6 , Z, and W 1 are as defined in embodiment A1.
• Embodiment A4 A compound according to embodiment A3 wherein
• a 1 is phenylene optionally substituted with one or more substitutents R 23 , R 24 , R 25 , R 26 , and
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, C 2 _ 6 -alkenyl-Z-, C 2-6 -alkynyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, aryl-d- ⁇ -alkylene-Z-, heteroaryl-C 1-6 -alkylene-Z-, heterocyclyl-Ci- ⁇ -alkylene-Z-, cycloalkyl-d- ⁇ -alkylene-Z-, N(R 4 R 5 )-d -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W
• R 2 , R 3 , R 4 , R 5 , R 6 , Z, and W 1 are as defined in embodiment A1.
• Embodiment A5. A compound according to embodiment A4 of the formula (la) Formula (la)
• L ⁇ G 1 , L 2 , L 3 , R 1 , G 2 and R 25 are as defined in embodiment A1.
• Embodiment A6 A compound according to embodiment A4 of the formula (lb)
• Embodiment A7 A compound according to any one of the embodiments A1 to A6, wherein R 23 , R 24 , R 25 , R 28 , and R 27 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R 4 R 5 )-C 1-6 -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W 1 -N(R 4 )-Z-, R 6 -N(R 4 )-Z, and R 6 -W 1 -C ⁇ -alkylene-Z-, wherein R 2 , R 3 , R 4 , R 5 , R 6 , Z,
• Embodiment A8 A compound according to embodiment A7 wherein R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -CN, -CF 3 , -OR 2 , -NR 2 R 3 , d- ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, R 6 -W 1 -Z-, R 6 -W 1 -N(R 4 )-Z-, R 6 -N(R 4 )-Z, and R 6 -W 1 -d. 6 -alkylene-Z-, wherein R 2 , R 3 , R 4 , R 5 , R 6 , Z, and W 1 are as defined in embodiment A1.
• Embodiment A9 a compound according to embodiment A8 wherein
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of halogen, -OR 2 , -NR 2 R 3 , Ci- ⁇ -alkyl-Z-, R 6 -W 1 -Z-, and R 6 -W 1 -C 1-6 -alkylene-Z-, wherein R 2 , R 3 , R 4 , R 5 , R 6 , Z, and W 1 are as defined in embodiment A1.
• Embodiment A10 A compound according to embodiment A9 wherein
• R 23 , R 24 , R 25 , R 26 , and R 27 independently of each other are selected from the group consisting of
• Embodiment A11 A compound according to any one of the embodiments A1 to A10, wherein R 4 , R 5 , and R 6 independently of each other are selected from the group consisting of hydrogen, aryl, d- ⁇ -alkyl, heteroaryl-d ⁇ -alkylene-, and aryl-C ⁇ -alkylene-.
• Embodiment A12 A compound according to embodiment A11 , wherein
• R 4 , R 5 , and R 6 independently of each other are hydrogen or d_ ⁇ -alkyl.
• Embodiment A13 A compound according to embodiment A12, wherein R 4 , R 5 , and R 6 are hydrogen.
• Embodiment A14 A compound according to any one of the embodiments A1 to A9, wherein R 4 and R 5 is taken together to form a ring having the formula -(CH 2 ) r Q-(CH 2 ) k - bonded to the nitrogen atom to which R 4 and R 5 are attached, wherein j and k independently of each other is 1 , 2, 3, or 4; Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-, -C(O)-O-, -
• R 9 and R 10 independently of each other are selected from the group consisting of hydrogen, aryl, Ci- ⁇ -alkyI, and aryl-d- ⁇ -alkyl-
• Embodiment A15 A compound according to embodiment A14, wherein Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 9 and R 10 independently of each other are hydrogen or d- ⁇ -alkyl.
• Embodiment A16 A compound according to embodiment A15, wherein
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• 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 W 1 is a direct bond, -O-, -C(O)-, -NH-, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment A19 A compound according to embodiment A18, wherein
• W 1 is a direct bond, -O-, -C(O)-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)SO 2 -, -C(O)-O-, or -O-C(O)-.
• Embodiment A20 A compound according to embodiment A19, wherein W 1 is a direct bond or -C(O)-O-.
• Embodiment A21 A compound according to embodiment A20, wherein W 1 is a direct bond.
• Embodiment A22 A compound according to embodiment A7, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , d- ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
• R 2 , R 3 , and Z are as defined in embodiment A1.
• Embodiment A23 A compound according to embodiment A22, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , Cs-nrheterocyclyl-Z-, C ⁇ o-aryl-Z-, or Cs-io-heteroaryl-Z-, wherein
• R 2 , R 3 , and Z are as defined in embodiment A1.
• Embodiment A24 A compound according to embodiment A23, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , -NR 2 R 3 , d- ⁇ -alkyl-Z-, C 3 . 10 -cycloalkyl-Z-, C3. 10 -heterocyclyl-Z-, d-io-aryl-Z-, or d-io-heteroaryl-Z-, wherein
• R 2 , R 3 , and Z are as defined in embodiment A1.
• Embodiment A25 A compound according to embodiment A24, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is F, Cl, Br, or methyl.
• Embodiment A26 A compound according to embodiment A24, wherein at least one of R 23 , R 24 , R 25 , R 26 , and R 27 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , or
• R 2 , R 3 , and Z are as defined in embodiment A1.
• Embodiment A27 A compound according to any one of the embodiments A1 to A26, wherein R 2 and R 3 independently of each other are hydrogen, C 1- ⁇ -alkyl, aryl-C ⁇ -6-alkylene-, heteroaryl-d-e-alkylene-, C 1-6 -alkyl-heteroarylene-, heteroaryl, or aryl.
• Embodiment A28 A compound according to embodiment A27, wherein R 2 and R 3 independently of each other, are hydrogen, C 1-6 -alkyl, aryl-d ⁇ -alkylene- or aryl.
• Embodiment A29 A compound according to embodiment A28, wherein R 2 is hydrogen or d ⁇ -alkyl.
• Embodiment A30 A compound according to embodiment A29, wherein R 2 is hydrogen.
• Embodiment A31 A compound according to any one of the embodiments A1 to A30, wherein R 3 is hydrogen or C ⁇ _ 6 -alkyl.
• Embodiment A32 A compound according to embodiment A31, wherein R 3 is hydrogen.
• Embodiment A33 A compound according to any one of the embodiments A1 to A22, wherein R 2 and R 3 , 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 Z is a direct bond, -O-, -NH-, -NHCH 2 -, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(CH 3 )CONH-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment A35 A compound according to embodiment A34, wherein
• Z is a direct bond, -O-, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)SO 2 -, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment A36 A compound according to embodiment A35, wherein Z is a direct bond, -NHC(O)-, or -NHS(O) 2 -.
• Embodiment A37 A compound according to embodiment A2, wherein A 1 is
• R 23 , R 24 , R 25 , and R 26 are hydrogen or as defined in embodiment A1.
• Embodiment A38 A compound according to embodiment A37, wherein R 23 , R 24 , R 25 , and R 26 independently of each other are selected from the group consisting of halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, N(R 4 R 5 )-C 1-6 -alkylene-Z-, R 6 -W 1 -Z-, R 6 -W 1 -N(R 4 )-Z-, R 6 -N(R 4 )-Z-, and R 6 -W 1 -C 1-6 -alkylene-Z-, wherein R 2 , R 3 , R 4 , R 5 , R 6 , Z, and W 1 are as defined in embodiment
• Embodiment A39 A compound according to embodiment A37 or A38, wherein
• R 4 , R 5 , and R 6 independently of each other are selected from the group consisting of hydrogen, aryl, d- ⁇ -alkyl, heteroaryl-d ⁇ -alkylene-, and aryl-C 1-6 -alkylene-.
• Embodiment A40 A compound according to embodiment A39, wherein R 4 , R 5 , and R 6 independently of each other are hydrogen or C 1-6 -alkyl.
• Embodiment A41 A compound according to embodiment A40, wherein R 4 , R 5 , and R 6 are hydrogen.
• Embodiment A42 A compound according to embodiment A37 or A38, wherein
• R 4 and R 5 is taken together to form a ring having the formula -(CH 2 ) r Q-(CH 2 ) k - bonded to the nitrogen atom to which R 4 and R 5 are attached, wherein j and k independently of each other is 1 , 2, 3, or 4;
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-, wherein
• R 9 and R 10 independently of each other are selected from the group consisting of hydrogen, aryl, d- ⁇ -alkyl, and arylalkyl-.
• Embodiment A43 A compound according to embodiment A42, wherein
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 9 and R 10 independently of each other are hydrogen or alkyl.
• Embodiment A44 A compound according to embodiment A43, wherein
• Q is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHSO 2 -, -SO 2 NH-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• Embodiment A45 A compound according to embodiment A44, wherein Q is a direct bond.
• Embodiment A46 A compound according to any one of the embodiments A37 to A45, wherein
• W 1 is a direct bond, -O-, -C(O)-, -NH-, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment A47 A compound according to embodiment A46 wherein
• W 1 is a direct bond, -O-, -C(O)-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)SO 2 -, -C(O)-O-, or -O-C(O)-.
• Embodiment A48 A compound according to embodiment A47, wherein W 1 is a direct bond, or -C(O)-O-.
• Embodiment A49 A compound according to embodiment A48, wherein W 1 is a direct bond.
• Embodiment A50 A compound according to embodiment A37, wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2) -OR 2 , -NR 2 R 3 , d- ⁇ -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, or heteroaryl-Z-, wherein
• R 2 , R 3 , and Z are as defined in embodiment A37.
• Embodiment A51 A compound according to embodiment A50, wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 2 , -NR 2 R 3 , C 1-e -alkyl-Z-, C 3 - ⁇ o-cycloalkyl-Z-, Cs-io-heterocyclyl-Z-, Qj-io-aryl-Z-, or
• R 2 , R 3 , and Z are as defined in embodiment A37.
• Embodiment A52 A compound according to embodiment A51, wherein at least one of R 23 , R 24 , R 25 , and R 26 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 , -NR 2 R 3 , d- ⁇ -alkyl-Z-, Cs-io-cycloalkyl-Z-, C 3 . ⁇ 0 -heterocyclyl-Z-, Cs-io-aryl-Z-, or
• R 2 , R 3 , and Z are as defined in embodiment A37.
• Embodiment A53 A compound according to any one of the embodiments A37 to A52, wherein Z is a direct bond, -O-, -NH-, -NHCH 2 -, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)CON(H)-, -N(CH 3 )CON(H)-, -N(H)SO 2 -, -SO 2 N(H)-, -C(O)-O-, -N(H)SO 2 N(H)-, or -O-C(O)-.
• Embodiment A54 A compound according to embodiment A53, wherein Z is a direct bond, -O-, -S-, -SO 2 -, -C(O)NH-, -NHC(O)-, -N(H)SO 2 -, -C(O)-O-,
• Embodiment A55 A compound according to embodiment A54, wherein Z is a direct bond, -NHC(O)-, or-NHS(O) 2 .
• Embodiment A56 A compound according to embodiment A52, wherein at least one of R 23 , R 24 , R 25 , and R 28 is halogen, -C(O)OR 2 , -CN, -NO 2 , -OR 2 ,
• R 2 , and R 3 are as defined in embodiment A37.
• Embodiment A57 A compound according to any one of the embodiments A37 to A56, wherein R 2 and R 3 independently of each other are hydrogen, C 1- ⁇ -alkyl, aryl-C 1-6 -alkylene-, heteroaryl-d- ⁇ -alkylene-, d- ⁇ -alkyl-arylene-, C ⁇ -alkyl-heteroarylene-, heteroaryl, or aryl.
• Embodiment A58 A compound according to embodiment A57, wherein
• R 2 and R 3 independently of each other, are hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkylene- or aryl.
• Embodiment A59 A compound according to embodiment A58, wherein R 2 is hydrogen or C 1-6 -alkyl.
• Embodiment A60 A compound according to embodiment A59, wherein R 2 is hydrogen.
• Embodiment A61 A compound according to any one of the embodiments A37 to A60, wherein
• R 3 is hydrogen or d- ⁇ -alkyl.
• Embodiment A62 A compound according to embodiment A61 , wherein R 3 is hydrogen.
• Embodiment A63 A compound according to any one of the embodiments A37 to ASO, wherein R 2 and R 3 , 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 at least one of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment A65 A compound according to embodiment A64, wherein at least two of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment A66 A compound according to embodiment A65, wherein R 23 and R 26 are hydrogen.
• Embodiment A67 A compound according to embodiment A65 or embodiment A66, wherein at least three of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment A68 A compound according to any one of the embodiments A37 to A67, wherein R 24 or R 25 is halogen.
• Embodiment A70 A compound according to any one of the embodiments A37 to A67, wherein R 24 or R 25 is C 1-6 -alkyl.
• Embodiment A71 A compound according to embodiment A68, wherein R 24 or R 25 is methyl.
• Embodiment A72 A compound according to any one of the embodiments A37 to A67, wherein
• R 24 is hydrogen.
• Embodiment A73 A compound according to any one of the embodiments A37 to A72, wherein
• R 25 is hydrogen
• Embodiment A74 A compound according to embodiment A37, wherein R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment A76 A compound according to embodiment A75, wherein
• Embodiment A77 A compound according to embodiment A75, wherein L 1 is -O-.
• Embodiment A78 A compound according to embodiment A75, wherein L 1 is -S-.
• Embodiment A79 A compound according to embodiment A75, wherein L 1 is a bond.
• Embodiment A81 A compound according to any one of the embodiments A1 to A76, wherein D is a direct bond or -O-; E is a direct bond or -O-; and R 11 and R 12 are as defined in embodiment A1.
• Embodiment A82 A compound according to embodiment A81 , wherein D is a direct bond.
• Embodiment A83 A compound according to embodiment A81 , wherein D is -O-.
• Embodiment A84 A compound according to any one of the embodiments A81 to A83, wherein E is a direct bond.
• Embodiment A85 A compound according to any one of the embodiments A81 to A83, wherein
• E is -O-.
• Embodiment A86 A compound according to any one of the embodiments A1 to A85, wherein R 11 is selected from hydrogen, C ⁇ -alkyl, aryl, carbamoyl, aryl-C 1-6 -alkylene-,
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, d- ⁇ -alkyl, or aryl-d- ⁇ -alkylene-; or
• R 13 and R 14 may be taken together to form a ring having the formula -(CH 2 )o-X-(CH 2 )p- bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein o and p are independently of each other are 1 , 2, 3, or 4; and X is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -CON(H)-, -NHC(O)-, -NHCON(H)-, -NHSO 2 -, -SO 2 N(H)-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 18 and R 17 are selected from hydrogen, aryl, heteroaryl, Ci-e-alkyl, C ⁇ - 6 -alkoxy, aryl-C ⁇ -8-alkylene-, heteroaryl-C ⁇ -alkylene-, C ⁇ -alkyl-arylene-, d_ ⁇ -alkyl-heteroarylene-, C ⁇ _ 6 -alkoxy-arylene-, C 1-6 -alkoxy-heteroarylene-, heteroarylaryl-Ci- ⁇ -alkoxy-, or R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, Ci-e-alkyl, or aryl-C 1-6 -alkylene-.
• Embodiment A87 A compound according to embodiment A86, wherein
• R 11 is selected from hydrogen, Ci-e-alkyl, aryl, carbamoyl, aryl-C ⁇ _ ⁇ -alkylene-, C ⁇ - ⁇ -alkyl-NH-C(O)-, aryl-C ⁇ -alkylene-NH-C(O)-, C ⁇ -alkyl-SO 2 -, aryl-C ⁇ -e-alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, C ⁇ -e-alkyl-C(O)-, aryl-C ⁇ - ⁇ -alkylene-C(O)-, N(R 13 )(R 14 )-C ⁇ .e-alkylene-Y-, and R 15 -W 2 -C ⁇ _6-alkylene-Y-, wherein
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, Ci-e-alkyl, or aryl-d- ⁇ -alkylene-; or
• R 13 and R 14 may be taken together to form a ring having the formula -(CH 2 ) 0 -X-(CH 2 ) p - bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein o and p are independently of each other are 1 , 2, 3, or 4; and X is a direct bond, -CH 2 -, -O-, -S-, -S(O 2 )-, -C(O)-, -CON(H)-, -NHC(O)-, -NHCON(H)-, -NHSO 2 -, -SO 2 N(H)-, -C(O)-O-, -O-C(O)-, -NHSO 2 NH-,
• R 16 and R 17 are hydrogen; and R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, d- ⁇ -alkyl, or aryl-Ci-e-alkylene-.
• Embodiment A88 A compound according to embodiment A87, wherein R 11 is selected from hydrogen, C ⁇ _ ⁇ -alkyl, aryl, carbamoyl, aryl-Ci- ⁇ -alkylene-,
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl, Ci-e-alkyl, or aryl-Ci-e-alkylene-; or
• R 13 and R 14 may be taken together to form a ring having the formula -(CH 2 ) 0 -X-(CH 2 )p- bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein o and p are independently of each other are 1 , 2, 3, or 4; X is a direct bond; and R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, Ci- ⁇ -alkyl, or aryl-d- ⁇ -alkylene-.
• Embodiment A89 A compound according to embodiment A88, wherein
• R 11 is selected from hydrogen, Ci-e-alkyl, aryl, carbamoyl, aryl-C ⁇ _6-alkylene-, C ⁇ - ⁇ -alkyl-NH-C(O)-, aryl-C ⁇ -alkylene-NH-C(O)-, C ⁇ -alkyl-SO 2 -, aryl-C ⁇ - ⁇ -alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, d ⁇ -alkyl-C(O)-, aryl-C ⁇ -alkylene-C(O)-, N(R 13 )(R 14 )-Ci -6 -alkylene-Y-, and R 15 -W 2 -d. ⁇ -alkylene-Y-, wherein
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 independently of each other are selected from hydrogen, aryl,
• Ci- ⁇ -alkyl or aryl-C ⁇ _6-alkylene-
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, d- ⁇ -alkyl, or aryl-C 1-6 -alkylene-.
• Embodiment A90 A compound according to embodiment A89, wherein R 11 is selected from hydrogen, Ci-e-alkyl, aryl, carbamoyl, aryl-Ci-e-alkylene-, d- ⁇ -alkyl-NH-C(O)-, aryl-C ⁇ .
• Y and W 2 independently of each other are a direct bond, -CH 2 -, -SO;*-, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 are hydrogen
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, C 1 _ ⁇ -alkyl, or aryl-d-e-alkylene-.
• Embodiment A91 A compound according to embodiment A90, wherein R 11 is selected from hydrogen, Ci-e-alkyl, aryl, carbamoyl, aryl-Ci-e-alkylene-, d-e-alkyl-NH-C(O)-, aryl-C ⁇ -alkylene-NH-C(O)-, C ⁇ -alkyl-SO 2 -, aryl-C ⁇ -alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, C ⁇ -alkyl-C(O)-, aryl-C ⁇ - ⁇ -alkylene-C(O)-, N(R 13 )(R 14 )-C ⁇ -alkylene-Y-, and R 15 -W 2 -C ⁇ _e-alkylene-Y-, wherein
• Y is a direct bond
• W 2 is a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO 2 -, or -O-C(O)-;
• R 13 and R 14 are hydrogen; and R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, Ci-e-alkyl, or aryl-Ci-e-alkylene-.
• Embodiment A92 A compound according to embodiment A90, wherein
• R 11 is selected from hydrogen, Ci-e-alkyl, aryl, carbamoyl, aryl-Ci- ⁇ -alkylene-, C ⁇ . ⁇ -alkyl-NH-C(O)-, aryl-C ⁇ -alkylene-NH-C(O)-, d- ⁇ -alkyl-SO 2 -, aryl-C ⁇ - ⁇ -alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, C ⁇ -alkyl-C(O)-, aryl-C ⁇ - ⁇ -alkylene-C(O)-, N(R 13 )(R 14 )-C ⁇ -e-alkylene-Y-, and R 15 -W 2 -C ⁇ -alkylene-Y-, wherein
• Y is a direct bond, -CH 2 -, -SO 2 -, -N(H)CO-, -N(H)SO r , or -O-C(O)-;
• W 2 is a direct bond;
• R 13 and R 14 are hydrogen; and
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, Ci-e-alkyl, or
• Embodiment A93 A compound according to any one of the embodiments A90 to A92, wherein R 11 is selected from hydrogen, Ci-e-alkyl, aryl, carbamoyl, aryl-Ci-e-alkylene-,
• R 15 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyi, d- ⁇ -alkyl, or aryl-Ci-e-alkylene-.
• Embodiment A94 A compound according to embodiment A93, wherein
• R 11 is selected from hydrogen, C ⁇ _6-alkyl, aryl, carbamoyl, aryl-C ⁇ _6-alkylene-, C ⁇ . ⁇ -alkyl-NH-C(O)-, aryl-C ⁇ -alkylene-NH-C(O)-, C ⁇ . 6 -alkyl-SO 2 -, aryl-C ⁇ . 6 -alkylene-SO 2 -, aryl-SO 2 -, SO 2 -, C ⁇ - ⁇ -alkyl-C(O)-, aryl-d.e-alkylene-C(O)-, and NH 2 -C ⁇ -e-alkylene-.
• Embodiment A95 A compound according to embodiment A94, wherein R 11 is hydrogen or Ci- ⁇ -alkyl.
• Embodiment A96 A compound according to embodiment A95, wherein R 11 is hydrogen.
• Embodiment A97 A compound according to any one of the embodiments A1 to A96, wherein R 12 is hydrogen or Ci-e-alkyl.
• Embodiment A98 A compound according to embodiment A97, wherein R 12 is hydrogen.
• Embodiment A99 A compound according to any one of the embodiments A1 to A98, wherein G 1 is Ci-e-alkyl, C 2 ⁇ -alkenyl, C 2 _ ⁇ -alkynyl, cycloalkyl or heterocyclyi, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 , Cs-io-cycloalkyl and Ci-e-alkyl, wherein R 18 and R 19 are as defined in embodiment A1.
• Embodiment A100 A compound according to embodiment A99, wherein
• G 1 is Ci- ⁇ -alkyl, C 2 - ⁇ -alkenyl, C 2 - ⁇ -alkynyl, cycloalkyl or heterocyclyi, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 and C ⁇ -alkyl, wherein R 18 and R 19 are as defined in embodiment A1.
• Embodiment A101 A compound according to embodiment A99, wherein
• G 1 is Ci-e-alkyl, C 2 _e-alkenyl, C 2 - ⁇ -alkynyl, C 3 . 10 -cycloalkyl or C 3 . 10 -heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 , dno-cycloalkyl and Ci-e-alkyl, wherein R 18 and R 19 are as defined in embodiment A1.
• Embodiment A102 A compound according to embodiment A100 or embodiment A101, wherein
• G 1 is d- ⁇ -alkyl, C 2 _e-alkenyl, C 2 ⁇ -alkynyl, C 3 _ ⁇ 0 -cycloalkyl or C 3 - ⁇ 0 -heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 and Ci-e-alkyl, wherein
• R 18 and R 19 are as defined in embodiment A1.
• Embodiment A103 A compound according to any one of the embodiments A99 to A102, wherein
• G 1 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,
• Embodiment A104 A compound according to embodiment A103 wherein
• G 1 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
• G 1 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
• G 1 is selected from the group consisting of isobutyl, cyclopentyl, and piperidyl.
• Embodiment A107 A compound according to embodiment A105 wherein G 1 is isobutyl.
• Embodiment A108 A compound according to embodiment A105 wherein G 1 is cyclopentyl.
• Embodiment A109 A compound according to embodiment A105 wherein G 1 is piperidyl.
• Embodiment A110 A compound according to any one of the embodiments A99 to A102, wherein R 18 and R 19 , independently of each other, are hydrogen, Ci-e-alkyl, heteroaryl-C ⁇ . ⁇ -alkylene-, aryl-Ci- ⁇ -alkylene-, d- ⁇ -alkyl-heteroarylene-, heteroaryl, or aryl.
• Embodiment A111 A compound according to embodiment A110, wherein R 18 and R 19 , independently of each other, are hydrogen, C ⁇ _ 6 -alkyl, d-io-heteroaryl-Ci- ⁇ -alkylene-, d-io-aryl-d- ⁇ -alkylene-, Ci- ⁇ -alkyl-d-io-arylene-,
• Embodiment A112 A compound according to embodiment A111 , wherein R 18 and R 19 , independently of each other, are hydrogen or Ci- ⁇ -alkyl.
• Embodiment A113 A compound according to embodiment A112, wherein R 18 is hydrogen.
• Embodiment A114 A compound according to embodiment A112 or A113, wherein R 19 is hydrogen.
• Embodiment A115 A compound according to embodiment A100 or embodiment A102, wherein
• R 18 and R 19 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
• G 1 is alkyl or cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 , -NR 18 R 19 and
• Ci-e-alkyl, or G 1 is aryl optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein R 18 , R 19 , R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A117 A compound according to embodiment A116, wherein G 1 is C ⁇ - ⁇ -alkyl or d-urcycloalkyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 ,
• G 1 is C 3 .i 0 -aryl optionally substituted with one or more substituents R 40 , R 41 , and
• Embodiment A118 A compound according to embodiment A117, wherein
• G 1 is d- ⁇ -alkyl or C 3 _ 10 -cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of -CN, -CF 3 , -OCF 3 , -OR 18 ,
• G 1 is phenyl optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein R 18 , R 19 , R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A119. A compound according to embodiment A116, A117, or A118, wherein R 18 and R 19 , independently of each other, are hydrogen, Ci-e-alkyl, heteroaryl-d- ⁇ -alkylene-, aryl-Ci-e-alkylene-, C ⁇ _ ⁇ -alkyl-arylene-, Ci ⁇ -alkyl-heteroarylene-, heteroaryl, or aryl.
• Embodiment A120 A compound according to embodiment A119, wherein R 18 and R 19 , independently of each other, are hydrogen, Ci-e-alkyl, d-io-heteroaryl-Ci- ⁇ -alkylene-, C3- ⁇ o-aryl-C ⁇ _ 6 -alkylene-, d-e-alkyl-Oj- K rheteroarylene-, C 3 . ⁇ 0 -heteroaryl, or d-io-aryl.
• Embodiment A121 A compound according to embodiment A120, wherein R 18 and R 19 , independently of each other, are hydrogen or Ci-e-alkyl.
• Embodiment A122 A compound according to embodiment A121 , wherein R 18 is hydrogen.
• Embodiment A123 A compound according to embodiment A121 or A122, wherein R 19 is hydrogen.
• Embodiment A124 A compound according to embodiment A116 or embodiment A117, wherein
• R 18 and R 19 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
• R 40 , R 41 , and R 42 independently of each other are halogen, -CN, -NO 2 , d- ⁇ -alkyl, -CHF 2 , -CF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR 54 S(O) 2 R 55 , -OC(O)NR 54 R 55 ,
• R 54 and R 55 independently of each other are hydrogen, Ci-e-alkyl, Ci-6-alkyl-arylene-, Ci- ⁇ -alkyl-heteroarylene-, aryl-Ci-e-alkylene-, heteroaryl-C ⁇ _6-alkylene-, heteroaryl, or aryl; or
• R 54 and R 55 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 R 40 , R 41 , and R 42 independently of each other are halogen, -CN, d-e-alkyl, -CF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR 54 S(O) 2 R 55 , -SfC R 54 , -SfOfcR 54 . -CHzdOJOR 54 , -CHzOR 54 , -CHzNR ⁇ R 55 , and -C ⁇ OR 54 ; wherein
• R 54 and R 55 independently of each other are hydrogen, Ci- ⁇ -alkyl, aryl-Ci-e-alkylene-, heteroaryl-d-e-alkylene-, heteroaryl, or aryl; or
• R 54 and R 55 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 R 40 , R 41 , and R 42 independently of each other are halogen, or -OR 54 wherein
• R 54 is hydrogen, Ci-e-alkyl, Ci ⁇ -alkyl-heteroarylene-, aryl-C ⁇ _ 6 -alkylene-, heteroaryl-C ⁇ -alkylene-, heteroaryl, or aryl.
• Embodiment A128 A compound according to embodiment A126, wherein
• R 54 and R 55 independently of each other are hydrogen, or Ci-e-alkyl, C ⁇ .6-alkyl-C3. ⁇ o-arylene-, d-e-alkyl-Qj-io-heteroarylene-, Cj-io-aryl-d-e-alkylene-, Qj-io-heteroaryl-d- ⁇ -alkylene-, d- 10 -heteroaryl, or Qj-io-aryl.
• Embodiment A129 A compound according to embodiment A128, wherein R 54 and R 55 independently of each other are hydrogen or C ⁇ _ 6 -alkyl.
• Embodiment A130 A compound according to embodiment A129, wherein R 54 is hydrogen.
• Embodiment A131 A compound according to embodiment A129 or embodiment A130, wherein
• R 55 is hydrogen.
• Embodiment A132 A compound according to embodiment A127 wherein
• R 54 is methyl
• Embodiment A133 A compound according to any one of the embodiments A1 to A98, wherein
• G 1 is aryl or heteroaryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A134 A compound according to embodiment A133, wherein
• G 1 is Qj-io-aryl or C 3 . 10 -heteroaryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A135. A compound according to embodiment A133, wherein G 1 is aryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A136 A compound according to embodiment A135, wherein
• G 1 is C 3 . 10 -aryl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein
• R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A137. A compound according to embodiment A136, wherein
• G 1 is phenyl, optionally substituted with one or more substituents R 40 , R 41 , and R 42 , wherein R 40 , R 41 , and R 42 are as defined in embodiment A1.
• Embodiment A138 A compound according to any one of the embodiments A133 to A137, wherein
• R 40 , R 41 , and R 42 independently of each other are halogen, -CN, -NO 2 , d- ⁇ -alkyt, -CHF 2 , -CF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR ⁇ S ⁇ R 55 ,
• R 54 and R 55 independently of each other are hydrogen, Ci-e-alkyl, C ⁇ . 6 -alkyl-arylene-, d- ⁇ -alkyl-heteroarylene-, aryl-Ci-e-alkylene-, heteroaryl-C ⁇ -alkylene-, heteroaryl, or aryl; or
• R 54 and R 55 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 R 40 , R 41 , and R 42 independently of each other are halogen, -CN, Ci-e-alkyl, -CF 3 , -OR 54 , -NR ⁇ R 55 , -SR 54 , -NR ⁇ SfOkR 55 , -S ⁇ JR 54 , -SfO ⁇ R 54 , -CH 2 C(O)OR 54 , -CHzOR 54 , -CHzNR ⁇ R 55 , and -C ⁇ JOR 54 ; wherein
• R 54 and R 55 independently of each other are hydrogen, Ci- ⁇ -alkyl, C ⁇ .6-alkyl-arylene-, d- ⁇ -alkyl-heteroarylene-, aryl-Ci-e-alkylene-, heteroaryl-Ci-e-alkylene-, heteroaryl, or aryl; or R 54 and R 55 , 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 R 40 , R 41 , and R 42 independently of each other are halogen, or -OR 54 wherein
• R 54 is hydrogen, Ci-e-alkyl, d- ⁇ -alkyl-heteroarylene-, aryl-Ci-e-alkylene-, heteroaryl-C ⁇ _ ⁇ -alkylene-, heteroaryl, or aryl.
• Embodiment A141 A compound according to any one of the embodiments A138 to A139, wherein
• R 54 and R 55 independently of each other are hydrogen, or d- ⁇ -alkyl, d-e-alkyl-d-io-arylene-, d-e-alkyl-d-irj-heteroarylene-, Cs-uraryl-d- ⁇ -alkylene-, Qj-io-heteroaryl-Ci-e-alkylene-, C 3 _ 10 -heteroaryl, or Cs-io-aryl.
• Embodiment A142 A compound according to embodiment A141 , wherein R 54 and R 55 independently of each other are hydrogen or Ci- ⁇ -alkyl.
• Embodiment A143 A compound according to embodiment A142, wherein R 54 is hydrogen.
• Embodiment A144 A compound according to embodiment A142 or embodiment A143, wherein
• R 55 is hydrogen.
• Embodiment A145 A compound according to embodiment A140 wherein
• R 54 is methyl
• Embodiment A146 A compound according to embodiment A135, wherein G 1 is
• R 56 , R 57 , R 58 , R 59 , and R 60 are hydrogen or halogen, -CN, -NO 2 , Ci- ⁇ -alkyl. -CHFz, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 61 , -NR 6 R 62 , -SR 61 , -NR 61 S(O) 2 R 62 , -S(O) 2 NR 61 R 62 , -S(O)NR 61 R 62 , -S(O)R 61 , -S(O) 2 R 61 , -C(O)NR 61 R 62 , -OC(O)NR 61 R 62 , -NR 61 C(O)R 62 , -CH
• R 61 and R 62 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 R 56 , R57J R58I R 59 ) and R ⁇ o independently of each other are halogen, -CN, -NO 2 , Ci-e-alkyl, -CHF 2 , -CF 3 , -OR 61 , -NR 61 R 62 , -SR 61 , -NR 61 S(O) 2 R 62 ,
• R 61 and R 62 independently of each other are hydrogen, C ⁇ _ 6 -alkyl, d- 6 -alkyl-arylene-, C ⁇ -alkyl-heteroarylene-, aryl-Ci-e-alkylene-, heteroaryl-Ci- 6 -alkylene-, heteroaryl, or aryl; or
• R 61 and R 62 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 R 56 or R 57 is -OR 61 .
• Embodiment A149 A compound according to embodiment A148 wherein R 61 is methyl.
• Embodiment A150 A compound according to embodiment A147, wherein R 61 and R 62 independently of each other are hydrogen, or C ⁇ _6-alkyl,
• Embodiment A151 A compound according to embodiment A150, wherein R 61 and R 62 independently of each other are hydrogen or Ci-e-alkyl.
• Embodiment A152 A compound according to embodiment A151 , wherein R 61 is hydrogen.
• Embodiment A153 A compound according to embodiment A151 or embodiment A152, wherein
• R 62 is hydrogen.
• Embodiment A154 A compound according to any one of the embodiments A146 to A153, wherein at least one of R 56 , R 57 , R 58 , R 59 , and R 60 are hydrogen.
• Embodiment A155 A compound according to embodiment A154, wherein at least two of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment A156 A compound according to embodiment A155, wherein at least three of R 23 , R 24 , R 25 , and R 26 are hydrogen.
• Embodiment A157 A compound according to any one of the embodiments A1 to A156, wherein
• L 2 is a direct bond, d- ⁇ -alkylene, C 2 -e-alkenylene, C 2- ⁇ -alkynylene, -N-R 20 -, -d.e-alkylene-N(R 20 )-, -C 2-6 -alkenylene-N(R 20 )-, or -C 2 ⁇ -alkynylene-N(R 20 )-, wherein R 20 is as defined in embodiment A1.
• Embodiment A158 A compound according to any one of the embodiments A1 to A153, wherein
• L 2 is -N-R 20 -, -alkylene-N(R 20 )-, -alkenylene-N(R 20 )-, or -alkynylene-N(R 20 )-, wherein R 20 is as defined in embodiment A1.
• Embodiment A159 A compound according to embodiment A157 or embodiment A158, wherein
• L 2 is -N-R 20 -, -d- ⁇ -alkylene-N R 20 )-, -d- ⁇ -alkenylene-NfR 20 )-, or -C 2 - 6 -alkynylene-N(R 20 )-, wherein
• R 20 is as defined in embodiment A1.
• Embodiment A160 A compound according to embodiment A159, wherein L 2 is -N-R 20 -, wherein
• R 20 is as defined in embodiment A1.
• Embodiment A161 A compound according to embodiment A157, wherein L 2 is a direct bond.
• Embodiment A162 A compound according to any one of the embodiments A1 to A160, wherein
• R 20 is hydrogen, or
• R 20 is Ci-e-alkyl, C 2 ⁇ -alkenyl, C 2 -e-alkynyl, Qj-io-cycloalkyl-W 3 -, Cs-io-heterocyclyl-W 3 -, d-io-aryl-W 3 -, or C- M o-heteroaryl-W 3 -, optionally substituted with one or more substituents R 30 , R 31 , and R 32 wherein
• W 3 , R 30 , R 31 , and R 32 are as defined in embodiment A1.
• Embodiment A163 A compound according to embodiment A162, wherein W 3 is alkylene.
• Embodiment A164 A compound according to embodiment A163, wherein W 3 is C 2-6 -alkylene.
• Embodiment A165 A compound according to embodiment A162, wherein W 3 is a direct bond.
• Embodiment A166 A compound according to any one of the embodiments A1 to A160, wherein
• R 20 is hydrogen, Ci-e-alkyl, C 2-e -alkenyl, or C 2 - ⁇ -alkynyl, optionally substituted with one or more substituents R 30 , R 31 , and R 32 wherein
• R 30 , R 31 , and R 32 are as defined in embodiment A1.
• Embodiment A167 A compound according to any one of the embodiments A162 to A166, wherein
• R 20 is hydrogen, or
• R 20 is Ci-e-alkyl, d ⁇ -alkenyl, or Ci- ⁇ -alkynyl, optionally substituted with one or more substituents R 30 , R 31 , and R 32 wherein R 30 , R 31 , and R 32 are as defined in embodiment A1.
• Embodiment A168 A compound according to any one of the embodiments A1 to A167, wherein
• R 30 , R 31 , and R 32 independently of each other are selected from -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3l -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 52 , -NR ⁇ R 53 , -SRs 2 , -NR 52 S(0) 2 R 63 . -SfOfeNR ⁇ R 83 , -S(O)NR 5 R 53 , -S(O)R 52 , -S(O) 2 R 52 , -dOJNR R 53 ,
• Embodiment A169 A compound according to embodiment A168, wherein R 52 and R 53 , 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
• R 52 and R 53 independently of each other are hydrogen, C ⁇ - ⁇ -alkyl, aryl-Ci- ⁇ -alkylene- heteroaryl-C ⁇ -alkylene- heteroaryl, or aryl.
• Embodiment A171 A compound according to embodiment A170, wherein R 52 and R 53 independently of each other are hydrogen, Ci-e-alkyl, aryl-d- ⁇ -alkylene-or aryl.
• Embodiment A172 A compound according to embodiment A171, wherein R 52 and R 53 independently of each other are hydrogen or C ⁇ _6-alkyl.
• Embodiment A173. A compound according to embodiment A172, wherein R 52 is hydrogen.
• Embodiment A174 A compound according to embodiment A172 or embodiment A173, wherein
• R 53 is hydrogen
• Embodiment A175. A compound according to embodiment A167, wherein R 20 is hydrogen.
• Embodiment A176 A compound according to any one of the embodiments A1 to A175, wherein
• L 3 is -C(O)-, -C(O)-C(O)- or -C(O)CH 2 C(O)-.
• Embodiment A177 A compound according to embodiment A176 wherein L 3 is -C(O)-.
• Embodiment A178 A compound according to embodiment A176 wherein L 3 is -C(O)-C(O)-.
• Embodiment A179 A compound according to embodiment A176 wherein L 3 is -C(O)CH 2 C(O)-.
• Embodiment A180 A compound according to any one of the embodiments A1 to A179, wherein
• R 1 is hydrogen, or
• R 1 is Ci-e-alkyl, C 2 ⁇ -alkenyl, C 2 -e-alkynyl, C 3 - ⁇ o-cycloalkyl-W 4 -, C 3 - ⁇ o-heterocyclyl-W 4 -, d-io-aryl-W 4 -, or d- 10 -heteroaryl-W 4 -, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• W 4 , R 33 , R 34 , and R 35 are as defined in embodiment A1.
• Embodiment A181. A compound according to embodiment A180, wherein W 4 is alkylene.
• Embodiment A182 A compound according to embodiment A181 , wherein W 4 is d-e-alkylene.
• Embodiment A183 A compound according to embodiment A180, wherein W 4 is a direct bond.
• Embodiment A184 A compound according to any one of the embodiments A1 to A176, wherein
• R 1 is hydrogen, Ci-e-alkyl, C 2 ⁇ -alkenyl, or C 2- ⁇ -alkynyl, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• R 33 , R 34 , and R 35 are as defined in embodiment A1.
• Embodiment A185 A compound according to any one of the embodiments A180 to A184, wherein
• R 1 is hydrogen, Ci-e-alkyl, C 2 _ ⁇ -alkenyl, or C 2 ⁇ -alkynyl, optionally substituted with one or more substituents R 33 , R 34 , and R 35 , wherein
• R 33 , R 34 , and R 35 are as defined in embodiment A1.
• Embodiment A186 A compound according to embodiment A185, wherein R 1 is hydrogen or Ci-e-alkyl optionally substituted with one or more substituents R 33 ,
• R 33 , R 34 , and R 35 are as defined in embodiment A1.
• Embodiment A187. A compound according to any one of the embodiments A1 to A186, wherein
• R 33 , R 34 , and R 35 independently of each other are selected from -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -OR 52 , -NR ⁇ R 53 , -SRs 2 , -NR ⁇ SfOkR 53 , -S OkNR R 53 , -S(O)NR 52 R 53 , -S(O)R 52 , -S(O) 2 R 52 , -CfOJNR ⁇ R 53 ,
• Embodiment A188 A compound according to embodiment A186, wherein R 52 and R 53 , 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 R 52 and R 53 independently of each other are hydrogen, Ci-e-alkyl, heteroaryl-d-e-alkylene- heteroaryl, or aryl.
• Embodiment A190 A compound according to embodiment A189, wherein R 52 and R 53 independently of each other are hydrogen, Ci-e-alkyl, aryl-d- ⁇ -alkylene-or aryl.
• Embodiment A191 A compound according to embodiment A190, wherein R 52 and R 53 independently of each other are hydrogen or Ci-e-alkyl.
• Embodiment A192 A compound according to embodiment A191 , wherein R 52 is hydrogen.
• Embodiment A193 A compound according to embodiment A191 or embodiment A192, wherein
• R 53 is hydrogen
• Embodiment A194. A compound according to embodiment A186, wherein R 1 is hydrogen.
• Embodiment A195. A compound according to any one of the embodiments A1 to A194, wherein
• G 2 is heteroaryl, fused heterocyclylheteroaryl, or fused cycloalkylheteroaryl, optionally substituted with one or more substituents R 43 , R 44 , and R 45 , wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G 2 with
• R 43 , R 44 , and R 45 are as defined in embodiment A1.
• Embodiment A196 A compound according to embodiment A195, wherein
• G 2 is fused cycloalkylheteroaryl optionally substituted with one or more substituents R 43 , R 44 , and R 45 , wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G 2 with -N(R 1 )-, and wherein
• R 43 , R 44 , and R 45 are as defined in embodiment A1.
• Embodiment A197 A compound according to embodiment A196 wherein G 2 is fused cycloalkylthiazolyl optionally substituted with one or more substituents
• R 43 , R 44 , and R 45 are as defined in embodiment A1.
• Embodiment A198 A compound according to embodiment A197, wherein G 2 is fused cycloalkylthiazolyl optionally substituted with -COOH
• Embodiment A199 A compound according to embodiment A195, wherein
• G 2 is heteroaryl optionally substituted with one or more substituents R 43 , R 44 , and R 45 , wherein said heteroaryl group posesses a nitrogen atom adjacent to the atom joining G 2 with -N(R 1 )-, and wherein R 43 , R 44 , and R 45 are as defined in embodiment A1.
• Embodiment A200 A compound according to embodiment A199, wherein
• G 2 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 R 43 , R 44 , and R 45 , wherein

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