1. A compound of the general formula (III); X is a direct bond, -0-, -S-, -S(0)-, -S(02)-, or -N(R6)-, wherein R2 is hydrogen or all

AMIDE DERIVATIVES AS GK ACTIVATORS
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Diabetes is characterised by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: Type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack β-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired β-cell function besides a range of other abnormalities.
Type 1 diabetic patients are currently treated with insulin, while the majority of type 2 diabetic patients are treated either with sulphonylureas that stimulate -cell function or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin. Among the agents applied to enhance tissue sensitivity towards insulin metformin is a representative example.
Even though sulphonylureas are widely used in the treatment of NIDDM this therapy is, in most instances, not satisfactory: In a large number of NIDDM patients sulphonylureas do not suffice to normalise blood sugar levels and the patients are, therefore, at high risk for acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulphonylureas and are thus gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the β-cells in NIDDM patients.
In normal subjects as well as in diabetic subjects, the liver produces glucose in order to avoid hypoglycaemia. This glucose production is derived either from the release of glucose from glycogen stores or from gluconeogenesis, which is a de novo intracellular synthesis of glucose. In type 2 diabetes, however, the regulation of hepatic glucose output is pooriy controlled and is increased, and may be doubled after an overnight fast. Moreover, in these patients there exists a strong con-elation between the increased fasting plasma glucose levels and the rate of hepatic glucose production. Similarly, hepatic glucose production will be increased in type 1 diabetes, if the disease is not property controlled by insulin treatment.

Since existing fomns of therapy of diabetes does not lead to sufficient glycaemic control and therefore are unsatisfactory, there is a great demand for novel therapeutic approaches.
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 occlusive heart disease is well known. The earliest stage in this sequence is the fonnation 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 macophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque fonns 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.
Epidemiological evidence has firmly established hyperiipidemia as a primary risk factor in causing cardiovascular disease (CVO) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Westem populations are now realized to be at particular high risk. Independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperiipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (or high blood pressure) is a condition, which occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such "essential" hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia, the relationship between these disorders has not been elucidated.

Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder.
It is known that hypertension can directly lead to heart failure, renal failure, and stroke (brain haemorrhaging). These conditions are capable of causing short-term death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can lead to long-term death.
The exact cause of essential hypertension is unknown, though a numt>er 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.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure, and brain haemorrhaging. However, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being reduced, the underlying cause of essential hypertension is not responding to this treatment.
Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries, while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviates hypertension.
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 occur in out-patient as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million patients undergoing non-cardiac

surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no drug therapy in this area, which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Another field for the present invention is obesity or appetite regulation.
Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world. Except for exercise, diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably cun-ently exist. However, due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity and/or means of appetite regulation.
The term obesity implies an excess of adipose tissue. In this context obesity is best viewed as any degree of excess adiposity that imparts a health risk. The cut off between nomnal and obese individuals can only be approximated, but the health risk imparted by the ot)esity is probably a continuum with increasing adiposity. The Framingham study demonstrated that a 20% excess over desirable weight clearly imparted a health risk (Mann GV N.Engl.J.Med 291. 226 (1974)). In the United States a National Institutes of Health consensus panel on obesity agreed that a 20% increase in relative weight or a body mass index (BMI = body weight in kilograms divided by the square of the height in meters) above the 85th percentile for young adults constitutes a health risk. By the use of these criteria 20 to 30 percent of adult men and 30 to 40 percent of adult women in the United States are obese. (NIH, Ann Intern Med 103,147 (1985)).
Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease, and certain types of cancer. In the industrialised western worid the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority.
When energy intake exceeds expenditure, the excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity.

The regulation of eating behaviour is incompletely understood. To some extent jppetite is controlled by discrete areas in the hypothalamus: a feeding centre in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety centre in the ventromedial lypothalamus (VMH). The cerebral cortex receives positive signals from the feeding centre hat stimulate eating, and the satiety centre modulates this process by sending inhibitory mpulses to the feeding centre. Several regulatory processes may influence these lypothalamic centres. The satiety centre may be activated by the increases in plasma jiucose and/or insulin that follow a meal. Meal-induced gastric distension is another possible nhibitory factor. Additionally the hypothalamic centres are sensitive to catecholamines, and jeta-adrenergic stimulation inhibits eating behaviour. Ultimately, the cerebral cortex controls ;ating behaviour, and impulses from the feeding centre to the cerebral cortex are only one nput. Psychological, social, and genetic factors also influence food intake.
At present a variety of techniques are available to effect initial weight loss. Jnfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is hat most obese patients eventually regain their weight. An effective means to establish 3nd/or sustain weight loss is the major challenge in the treatment of obesity today.
Glucokinase (GK) plays an essential role in blood glucose homeostasis. GK ::atalyses glucose phosphorylation, and is the rate-limiting reaction for glycolysis in lepatocytes 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 jiucose-responsive genes (Girard, J.et al., Annu Rev Nutr 17, 325-352 (1997)). In the fi-;ells, 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 night 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 issues that require glucose-sensing (mainly liver and pancreatic /ff-cells), and its So s for glucose, which is much higher (8-12 mM) than that of the other members of the hexokinase amily. Due to these kinetic characteristics, changes in serum glucose levels are paralleled jy changes in glucose metabolism in liver which in tum regulate the balance between tepatic glucose output and glucose consumption.
Activators of glucokinase may thus be useful for treating diseases where increasing :he activity of glucokinase is beneficial. Thus, there is a need for agents which activate glucokinase and increase glucokinase enzymatic activity. Such agents would be useful for :he treatment of type I diabetes and type II diabetes.

wo 00/58293, WO 01/44216, WO/0183465, WO/0183478. WO/0185706, and WO 01/85707, to Hoffman-La Roche, disclose compounds as glucokinase activators for treatment of type 2 diabetes.
SUMMARY OF THE INVENTION
This invention provides amide derivatives which are activators of glucokinase. The compounds of the present invention are useful as activators of glucokinase and thus are useful for the management, treatment, control and adjunct treatment of diseases where increasing the activity of glucokinase is beneficial. Such diseases include type I diabetes and type II diabetes. The present invention provides compounds as described ttelow, 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 provides the use of a compound according to the present invention for increasing the activity of glucokinase.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention 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 hyperglycemia.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention for 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 IGT.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention 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 Syndrome X.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention 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 2 diabetes.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention 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 the treatment of type 1 diabetes.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention for the treatment of dyslipidemia or 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 dyslipidemia or hyper¬lipidemia.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention 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 the treatment of hypertension.
The present invention provides the use of a compound according to the present invention or a phannaceutical composition according to the present invention 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 lowering of food intake.
The present invention provides the use of a compound according to the present invention or a phannaceutical composition according to the present invention for appetite regulation.
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 or a pharmaceutical composition according to the present invention for the treatment or prophylaxis of obesity.
The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment or prophylaxis of obesity.
The present invention provides the use of a compound according to the present invention or a phannaceutical composition according to the present invention 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 regulating feeding behaviour.
The present invention provides the use of a compound according to the present invention or a pharmaceutical composition according to the present invention for enhancing the secretion of enteroincretins. In one embodiment, said enteroincretin is GLP-1.
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. In one embodiment, said enteroincretin is GLP-1.
In one embodiment, use according to the present invention as described above is for a regimen, which comprises treatment with a further antidiabetic agent, such as a further antidiabetic agent selected from insulin or an insulin analogue, a sulphonylurea, a biguanide, a meglitinide, an insulin sensitizer, a thiazolidinedione insulin sensitizer, an a-glucosidase inhibitor, a glycogen phosphorylase inhibitor, and an agent acting on the ATP-dependent potassium channel of the pancreatic -cells.
In one embodiment, the use according to the present invention as described above is for a regimen, which comprises treatment with a further antihyperiipidemic agent, such as a further antihyperiipidemic agent selected from cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, and dextrothyroxine.
In one embodiment, the use according to the present invention as described above is for a regimen, which comprises treatment with a further antiobesity agent.
In one embodiment, the use according to the present invention as described above is for a regimen, which comprises treatment writh a further antihypertensive agent.
Other embodiments and aspects are as defined by the appended claims.
DEFINITIONS
In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning:
The term "optionally substituted" as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. When the group in question are substituted with more than one substituent the substituent may be the same or different.
The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.
The temn "perhaiomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.

The use of prefixes of this structure: C,-y-alkyl, Cx-y-alkenyl, Cx.y-alkynyl, Cx.y-cycloalkyl or Cx-y-cycloalkyl-Cx.y-alkenyl designates radical of the designated type having from X to y carbon atoms.
The term "alkyl" as used herein, alone or in combination, refers to a straight or branched chain saturated monovalent hydrocarbon radical having from one to ten carbon atoms, for example Ci.8-alkyl. Typical Ci-alkyl groups include, but are not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "Ci-a!kyl" as used herein also includes secondary CWalkyl and tertiary C4-alkyl.
The term "alkylene" as used herein, alone or in combination, refers to a straight or branched chain saturated divalent hydrocarbon radical having from one to ten carbon atoms, for example Ci.B-alkylene. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, and the like.
The term" alkeny!" as used herein, alone or in combination, refers to a straight or branched chain monovalent hydrocarbon radical containing from two to ten cart)on atoms and at least one carbon-carbon double bond, for example Cz-alkenyl. Typical C2-8-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.
The term "alkenylene" as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon double bond, for example C(2)-alkenylene. Typical C(2.«)-alkenyiene groups include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.
The term "alkynyl" as used herein alone or in combination, refers to a straight or aranched hydrocarbon group containing from 2 to the specified number of carbon atoms and at least one triple carbon-carbon bond, for example C2.a-alkynyl. Typical C2..8-alkynyl groups nclude, but are not limited to, ethynyl, 1-propynyi, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, l-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
The term" alkynylene" as used herein alone or in combination, refers to a straight )r branched chain divalent hydrocarbon radical having from two to ten carbon atoms and at east one carbon-carbon triple bond, for example C2-8-alkynylene. Typical C2.«-alkynylene jroups include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

The term "cycloalkyi" as used herein, alone or in combination, refers to a non-aromatic carbocyclic monovalent hydrocarbon radical having from three to twelve carbon atoms, and optionally with one or more degrees of unsaturation, for example Cj-cycloalkyl. Such a ring may be optionally fused to one or more benzene rings or to one or more of other cycloalkyi ring(s). Typical Cs-cycloalky) groups include, but are not limited to, cyclopropyl, cydobutyl, cyclopentyl, cydohexyl, cycloheptyl, cyclooctyl and the like.
The term "cycloalkylene" as used herein, alone or in combination, refers to a non-aromatic carbocyclic divalent hydrocarbon radical having from three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, for example CaA-cydoalkyl-ene. Such a ring may be optionally fused to one or more benzene rings or to one or more of other cydoalkyi ring(s). Typical Cj-cydoalkylene groups include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyi, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cydohexyl-1,4-diyl, cycloheptyl-1,4-diyl, orcyclooctyl-1,5-diyl, and the like.
The term "heterocyclic" or the tern "heterocydyl" as used herein, alone or in combination, refers to a three to twelve membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N, for example C3.«-heterocyclyl. Such a ring may be optionally fused to one or more of another "heterocyclic" ring(s) or cydoalkyi ring(s). Typical C3.8-heterocyclyl groups include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyn-olidine, morpholine, piperazine, and the like.
The term "heterocydylene" as used herein, alone or in combination, refers to a three to twelve-membered heterocyclic ring diradical optionally having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, 0, 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 cydoalkyi rings. Examples of "heterocydylene" include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-dyil, and the like.
The temn "alkoxy" as used herein, alone or in combination, refers to the monovalent radical RO-, where R' is alkyl as defined above, for example C(i)-alkyl giving C(i.a)-alkoxy. Typical C(i)-alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, te/t-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The temn "alkylthio" as used herein, alone or in combination, refers to a straight or branched monovalent radical comprising an alkyl group as described above linked through a divalent sulphur atom having its free valence bond from the sulphur atom, for example Ci-

alkylthio. Typical Cie-aikylthio groups include, but are not limited to. methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.
The term "alkoxycarbonyl" as used herein refers to the monovalent radical R'OC(O)-, where R is alkyl as described above, for example Ci.e-alkoxycarbonyl. Typical C,-alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyi, isopropoxycarbonyi, n-butoxycarbonyi, sec-butoxycarbonyl, tertbutoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
The term "carbamoyl" as used herein refers to NH2C(0}-.
The temn "aryl" as used herein refers to a carbocyciic aromatic ring radical with for instance 6 to 8 member atoms, or to an aromatic ring system radical with for instance from 12 to 18 member atoms. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyciic systems.
The term "heteroaryl", as used herein, alone or in combination, refers to an aromatic ring radical with for instance 5 to 7 member atoms, or to an 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. furanyi, thienyl, thiophenyl, pyn-olyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl. oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyi, benzofuranyl, benzothiophenyl, indolyl, and indazolyl, and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
Examples of "aryl" and "heteroaryl" includes, but are not limited to phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophene (2-thienyl, 3-thienyl), fury! (2-furyl. 3-furyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin, fluorenyl, xanthenyl, isoindanyl. benzhydryl, acridinyl, thiazolyl, pynolyl (1-pyn-olyl, 2-pyn'Olyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl). imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl, 4-oxazoiyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl, isooxaz-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl, isothiaz-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl {2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl. 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl). benzo[b]furanyl (2-

benzo[b]furanyl, 3-benzo[b]furany!, 4-ben2o[b]furanyl, 5-ben2o[b]furany!, 6-benzo[b]furanyl. 7-benzo[blfuranyl), 2.3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl). 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-ben2o[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (benzo[b]thiophen-2-yl. benzo[b]thiophen-3-yi, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), 2,3-dihydro-benzo[b]thiophenyi (2,3-dihydro-benzo[b]thiophen-2-yl, 2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl, 2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiaphen-6-yl, 2,3-dihydro-benzo[b]thiophen-7-yl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyi, 5-indolyl, 6-indolyi, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-inda20lyl, 7-indazolyl), benzimidazoiyi (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxa2olyl), benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, S-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazoiyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl. 5H-dibenz[b,flazepine-3-yl, 5H-dibenz[b,flazepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]a2epine-1-yl, 10,11-dihydro-5H-dibenz[b,f|azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f|azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole (2-benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole, 6-benzo[1,3]dioxole, 7-benzo[1,3]dioxole), and tetrazoly! (5-tetrazolyl, N-tetrazolyl).
The present invention also relates to partly or fully saturated analogues of the ring systems mentioned above.
As used herein, the term "fused arylheterocyclyl" refers to an aryl group fused to a heterocydyl group, the two having two atoms in common, and wherein the aryl group is the point of substitution. Examples of" fused arylheterocyclyl" used herein include 4-(2,3-benzo-dioxin), 3,4-methylenedioxy-1-phenyl, and the like.
As used herein, the temri "fused heterocyclylaryl" refers to a heterocydyl group fused to an aryl group, the two having two atoms in common, and wherein the heterocydyl group is the point of substitution. Examples of" fused heterocyclylaryl" used herein include 2-(1,3-benzodioxole and the like.
As used herein, the temi "fused heteroarylheterocyciyi" refers to a heteroaryl group fused to an heterocydyl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of "fused heteroarylheterocydyl" used herein include 1,2,3,4-tetrahydro-beta-carboline and the like.

As used herein, the term "fused heterocyclylheteroaryl" refers to a heterocyclyl jroup fused to an heteroaryl group, the two having two atoms in common, and wherein the leterocyclyi group is the point of substitution. Examples of "fused heterocyclylheteroaryl" jsed herein include 2-[1,3]-dioxolo[4,5-c]pyridine and the like.
As used herein, the term "fused arylcycloalkyl" refers to a aryl group fused to a ycloalkyl group, the two having two atoms in common, and wherein the aryl group is the toint of substitution. Examples of "fused cycloalkylaryl" used herein include 5-indanyi, 6-1,2,3,4-tetrahydronaphthyl), and the like.
As used herein, the tenn "fused cycloalkylaryl" refers to a cycloalkyi group fused to n aryl group, the two having two atoms in common, and wherein the cycloalkyi group is the oint of substitution Examples of "fused cycloalkylaryl" used herein include 1-indanyl, 2-idanyl, 1-(1,2,3,4-tetrahydronaphthyl), and the like.
As used herein, the term "fused heteroarylcycloalkyl" refers to a heteroaryl group ised to an cycloalkyi group, the two having two atoms in common, and wherein the Bteroaryl group is the point of substitution. Examples of "fused heteroarylcydoalkyr used srein include 5-aza-6-indanyl and the like.
As used herein, the term "fused cycloakylheteroaryl" refers to a cycloalkyi group sed to an heteroaryl group, the two having two atoms in common, and wherein the 'cloalkyl group is the point of substitution. Examples of "fused cycloalkylheteroaryl" used srein include 5-a2a-1-indanyl and the like.
The temn "arylene", as used herein, alone or in combination, refers to cart>ocyclic omatic ring diradical or to a aromatic ring system diradical. Examples of "arylene" include. It are not limited to, benzene-1,4-diy!. naphthalene-1,8-diyl, and the like.
The term "heteroarylene". as used herein, alone or in combination, refers to a five to ven membered aromatic ring diradical, or to a aromatic ring system diradical, containing e or more heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms, wherein N-ides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic bstitutions. Examples of "heteroarylene" used herein are furan-2,5-diyl, thiophene-2,4-diyl, J,4-oxadiazole-2,5-diyl, 1.3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazoie-2,5-diyl, 'idine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, d the like.
The term "alkylsulfanyl", as used herein, refers to the group RS-, where R is alkyl described above.
The term "alkylsulfenyl", as used herein, refers to the group RS(O)-, where R* is yl as described above.

The term "alkylsuifonyl", as used herein, refers to the group RS02-, where R Is alkyl as described above.
The term "acyl", as used herein, refers to the group RC(O)-, where R is alkyl, alkenyl, aikynyi, cycioalkyi, cydoalkenyi, or heterocyclyi as described above.
The term "aroyl", as used herein, refers to the group R*C(0)-, where R is aryl as described above.
The term "heteroaroyl", as used herein, refers to the group RaC(O)-, where R° is heteroaryl as described above.
The term "acyloxy", as used herein, refers to the group R°C(0)0-, where R' is alkyl, alkenyl, alkynyl, cycioalkyi, cycloalkenyl, or heterocyclyi as described above.
The term "aroyloxy", as used herein, refers to the group R*C(0}0-, where R is aryl as described above.
The term "heteroaroyloxy", as used herein, refers to the group RC(0)0-, where R is heteroaryl as described above.
Whenever the terms "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for "alkyl" and "aryl".
As used herein, the term "oxo" shall refer to the substituent =0.
As used herein, the term "mercapto" shall refer to the substituent -SH.
As used herein, the term "carboxy" shall refer to the substituent -COOH.
As used herein, the term "cyano" shall refer to the substituent -CN.
As used herein, the term "aminosulfonyl" shall refer to the substituent -SO2NH2.
As used herein, the term "sulfanyl" shall refer to the substituent -S-.
As used herein, the term "sulfenyl" shall refer to the substituent -S(0}-.
As used herein, the term "sulfonyl" shall refer to the substituent -S(0)r.
As used herein, the term "direct bond", where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a "direct bond".
The term "lower", as used herein, refers to an group having between one and six arbons, and may be indicated with the prefix Cx.6-- Lower alkyl may thus be indicated as Di-alkyl, while lower alkylene may be indicated as Cje-alkylene.
A radical such as Cx-y-cydoalkyi-Ca-b-alkenyl shall designate that the radical's point )f attachment is in part of the radical mentioned last.
As used herein, the term "optionally" means that the subsequently described !vent(s) may or may not occur, and includes both event(s) which occur and events that do lot occur.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless othenwise stated.
As used herein, the temns "contain" or "containing" can refer to in-line substitutions at any position along the above defined aikyi, alkenyl, alkynyl or cycloalkyi substituents with one or more of any of 0, S, SO, SO2, N, or N-aikyI, including, for example, -CHrO-CH2-, -CHz-SOrCHr, -CH2-NH-CH3 and so forth.
Certain of the above defined terms may occur more than once in the stmctural fomnulae, and upon such occunrence each term shall be defined independently of the other.
As used herein, the term "solvate" is a complex of variable stoichiometry fonned by a solute (in this invention, a compound of fonnula (I), (II), or (III)) and a solvent. Such solvents for the purpose of the present invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.
As used herein, the temn "biohydrolyzable ester" is an ester of a drug substance (in this invention, a compound of formula (I), (II), or (111)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transfonned to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters (e.g., C1-C4), lower acyloxyalkyi esters, lower alkoxyacyloxyalkyi esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
As used herein, the term "biohydrolyzable amide" is an amide of a drug substance (in this invention, a compound of general formula (I), (II), or (III)) 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) s biologically inactive but is readily converted in vivo by the subject to the biologically active arinciple. The advantage is that, for example, the biohydrolyzable amide is orally absorbed 'rom 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, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
As used herein, the temn "prodrug" includes biohydrolyzable amides and )iohydrolyzab!e esters and also encompasses a) compounds in which the biohydrolyzable unctionality in such a prodrug is encompassed in the compound of formula (I): for example, he lactam fomned by a carboxylic group in R and an amine in R*, and b) compounds which

may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I). Examples of these functional groups include, but are not limited to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, and the like.
The term "pharmacologically effective amount" or shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, animal or human that is being sought by a researcher or dinician. This amount can be a therapeutically effective amount. The tenri "therapeutically effective amounr 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.
The term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The temi is intended to include the full spectrum of treatments for a given disorder from wich 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, 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.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides carboxamide or sulfonamide activator of glucokinase having a heteroatom in the alpha, beta, or gamma position relative to the carboxamide or sulfonamide, respectively.


L' is -(CH2)„-C(R*)(R°)m-Y-, or a direti uond, wherein n is an integer of from 1 to 6,
R and R'° independently of each other are selected from alkyl, or cycloalkyi, optionally substituted by one or more substituents R*, R, and R\ or from aryl optionally substituted by one or more substituents R, R*\ R' and R'', m is an integer of 0 to 1, and
Y is a direct bond, -O- or -N(R)-. wherein
R' is hydrogen or alkyl, which may optionally be substituted with one or more substituents R, R, and R; or
X is alkylene, which may optionally be substituted with one or more substituents R*, R, and R, or a direct bond, and L is -0-, or -N(R')-, wherein
R* is hydrogen or alkyl, which may optionally be substituted with one or more substituents R R, and R; or
A is >C(R)-, wherein R is hydrogen or alkyl, optionally substituted with one or more substituents R'\ R and R", and
X is -0-, -S-, -S(0)-, -S(02)-, or -N(R')-, wherein
R* is as defined above, and L is -(CHzln-Y-, or a direct bond, wherein n is an integer of from 1 to 6, and
Y is a direct bond. 0, or -N(R)-, wherein
R is as defined above;
or
X is alkylene, which may optionally be substituted with one or more substituents R,
R, and R, or a direct bond, and
L is -0-, or -N(R°)-, wherein
R* is as defined above; R and R independently of each other are selected from alkyl, alkenyl, alkynyl, cycloalkyi, and heterocyclyl, optionally substituted with one or more substituents R**, R, and R; or from aryl, heteroaryl, fused heterocyclylaryl, fused heteroarylheterocydyl, fused heterocydyl-heteroaryl, fused arylcydoalkyl, fused cycloalkylaryl, fused heteroarylcycloalkyi, and fused cydoalkylheteroaryl, optionally substituted with one or more substituents R"", R**, R*®, and

or
R' and R may be taken together with the atoms to which they are attached to fornn a
cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents R, R,
and R*. and optionally fused to a heteroaryl or aryl ring, optionally substituted with one or
more substituents R**, R', R*®, and R*
or, when A is >C(R)-, then
R and R may be taken together with the atoms to which they are attached to form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents R, R, and R*, and optionally fused to a heteroaryl or aryl ring, optionally substituted with one or more substituents R**, R**, R**, and R*; or
R and R may be taken together with the atoms to which they are attached to form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents R, R, and R, and optionally fused to a heteroaryl or aryl ring, optionally substituted with one or more substituents R**, R**, R, and R"';
R* is hydrogen or alkyl, optionally substituted with one or more substituents R, R, and R*;
and
R is aryl or heteroaryl, optionally substituted with one or more substituents R**, R**, R*, and
wherein
D16 017 D18 D1B D20 D21 D22 O23 D*- D25 D2B rj? D2B O DO. D31 O32 D33 O* DS O36 r\ ,r\ ,r\ , T\ ,r\ ,r\ ,r\ ,r\ ,r\ ,r\ ,r\ ,r\ T\ r\ ,1A ,r\ ,r\ ,r\ ,r\ ,r\ ,r\ ,
R', R, and R independently of each other are selected from
-CHF2. -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(0)2CF3, -SCF3, -OR, -NRR -SR", -NR"S(0)2R, -S(0)2NR=R, -S(0)NR*'R, -S(0)R' -S(0)2R", -C(0)NRR -OC(0)NRR", -NR"C(0)R, -CH2C(0)NRR -OCH2C(0)NR=2R= -CH20R= -CH2NR"R' -OC(0)R' -C(0)R5and -C(0)OR"; C2-6-alkenyl and C2-alkynyl, which may optionally be substituted with one or more substituents selected from -CN, -CF3, -OCF3, -OR", -NRR" and C,uch as those described in the foregoing.
The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of fonnula (I) along with methods for the )reparation of compounds of formula (I). The compounds can be prepared readily according o the following reaction Schemes (in which all variables are as defined before, unless so ipecified) using readily available starting materials, reagents and conventional synthesis arocedures. In these reactions, it is also possible to make use of variants which are ;hemselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

Abbreviations
Abbreviations used in the Schemes and Examples are as follows:
j = days
3 = grams
h = hours
Hz = hertz
kD = kiloDalton
L = liters
M = molar
mbar = millibar
mg = milligrams
min = minutes
ml = milliliters
mM = millimolar
mmol = millimoles
mol = moles
N = nomnal
ppm = parts per million
psi = pounds per square inch
APCI = atmospheric pressure chemical ionization
ESI = electrospray ionization
i.v. = intravenous
m/z = mass to charge ratio

mp = melting point
MS = mass spectrometry
NIVIR = nuclear magnetic resonance spectroscopy
p.o. = per oral
Rf = relative TLC mobility
rt = room temperature
s.c. = subcutaneous
TLC = thin layer chromatography
tr = retention time
BOP = (1-benzotriazolyloxy)tris{dimethylamino)phosphonium hexafluorophosphate
DCM = dichloromethane
DIEA = diisopropylethylamine
DMF = N, N-dimethylfomnamide
DMPU = 1,3-dimethypropylene urea
DMSO = dimethylsulfoxide
EDC =1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
ether = diethyl ether
EtOAc = ethyl acetate
HMPA = hexamethylphosphoric triamide
HOBt =1-hydroxybenzotriazole
LAH = lithium aluminum hydride
LDA = lithium diisopropylamide
MeOH = methanol
NMM = N-methylmorphoiine, 4-methylmorpholine
TEA = triethylamine
TFA = trifluoroacefic acid
THF = tetrahydrofuran
THP = tetrahydropyranyl
TTF = fluoro-N,N,N'-tetramethylformamidinium hexafluorophosphate
Reaction schemes
Unless othenwise specified, the variables in the Schemes are as defined for formula (I).
Scheme 1 describes the preparation of compounds of formula (I).


supported (5) with TFA in a suitable solvent such as dichloromethane affords (I) where R* is H. (1) may be treated with the amine (4) to afford (5), and subsequently (1), in like manner. The acid (2) may be activated by treatment with a carbodiimide reagent such as EDC, or with a coupling agent such as TFFH, in a solvent such as DCM or DMF, in the presence of (4) to afford (5). (5) may be converted in like manner to (I). The carbamyl chloride (6) may be prepared by treatment of (4) with a reagent such as phosgene, diphosgene, or triphosgene in a solvent such as DCM in the presence of a tertiary amine base such as TEA. Treatment of (8) with (6) in the presence of a tertiary amine base such as TEA affords (5), and in like manner, (I). The chlorosulfonamide (7) may be prepared by treatment of (4) with sulfuryl chloride in the presence of a tertiary amine base such as TEA or DIEA. (7) may be treated with (8) in a suitable solvent such as DCM in the presence of a tertiary amine base such as TEA or DIEA to afford 5, and. in like manner to the previous, (I).
Scheme 2 describes the preparation of the compound of formula (2).


sodium hydride or potassium tert-butoxide to afford (11) where X is S, N(R®), or O, respectively. (11) may be deprotected with, for example, aqueous alkali where PG is methyl or ethyl, to afford (2). Where L is a direct bond, treatment of (9) with base such as LDA and an oxidizing agent such as a sulfonyl-oxaziridine reagent affords (10) where R is OH. Treatment of such with a reagent R-LG\ where LG is a nudeofugal group such as Br, CI, I, or sulfonate, and a base such as DBU or sodium hydride affords (11). Further, treatment of (12) with two equivalents of strong base such as LDA and a reagent R-S-LG, where LG is an arylsulfinate group or halogen, affords (2) where X is S.
Scheme 3 describes an altemate preparation of a compund of fonmula (2).


treated with an aldehyde R-CHO in the presence of a reducing agent such as sodium cyanoborohydride to afford (14). The amine (14) may be treated with a reagent LG-L-COO-PG, where LG is a nucleofugal group such as tosylate, iodide, or bromide, in the presence of an organic base such as potassium carbonate, in a solvent such as DMF, to afford (15). PG is a carboxyl protecting group such as allyl or methyl, or benzyl, which may be removed by hydrolysis in, for example, aqueous base to afford (2). The hydroxyester (16) may be treated with R- LG in the presence of a base such as DBU, DIEA, or sodium hydride, to afford (18) where X is O. Alternately, (16) may be treated with methanesulfonyl chloride, toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride to afford (17) where R' is an arylsulfonate or alkylsulfonate group. (17) may then be treated with R-XH, where X is 0, S, or N-R®, in the presence of a suitable base such as TEA, DIEA, NaH, DBU, potassium t-butoxide, or the like, to afford (18). (18) may be deprotected as described above to afford (2). Scheme 4 desaibes an alternate preparation of compounds of fomiula (I).


an acyl azide intermediate. The acyl azide intemnediate is heated at a temperature of from 25 to 100°C to afford the isocyanate (19), which may be treated with an amine (4) to afford (20). Mtemately, (19) may be hydrolyzed in weak aqueous acid or weak aqueous base to afford the amine (20). The amine (20) may be treated with an aldehyde or ketone embodying the R* group, in the presence of a reducing agent such as sodium triacetoxyborohydride, to afford (23). (23) may be treated with reagents (6) or (7) in manner analogous to Scheme 1 to afford

(24). The amine (20) may be treated with reagents (6) or (7) in like manner to afford (22). Where R is a solid support such as Wang Resin, (22) and (24) may be treated with TFA as in Scheme 1 to afford (I).
In the above schemes, TG''" represents an amino protecting group. The term "amino protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups (PG as used herein) such as benzyloxy-carbonyl, 4-phenylbenzyloxycarbonyI, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxy-carbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl, 1,1-diphenyleth-1-yioxycarbonyl, 1,1-diphenylprop-1-yloxy-carbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclo-hexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxy-carbonyl ("FMOC"), t-butoxycarbonyl ("BOC"), 2-(trimethylsily!)ethoxycarbonyl, allyloxy-carbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyt, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobomyloxycarbonyl, 1-piperidyioxycarbonyl and the like; the benzoylmethylsulfonyl group, the 2-(nitro)phenyl-sulfenyl group, the diphenyiphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the compound of fomnula (I) and can be removed at the desired point without disrupting the remainder of the molecule. Prefen'ed amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups refen-ed to by the above terms are described by J. W. Barton, "Protective Groups In Organic Chemistry", J. G. W. McOmie. Ed., Plenum Press, New York, N.Y.. 1973, Chapter 2, and T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7. The related term "protected amino" defines an amino group substituted with an amino-protecting group discussed above.In the above schemes, "PG" represents carboxyl protecting group. The term "carboxyl protecting group"

as used herein refers to substituents of the carboxyl group commonly employed to block or protect the -OH functionality while reacting other functional groups on the compound. Examples of such alcohol -protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the methyl group, the ethyl group, the allyl group, the trimethylsilylethoxymethyl group, the 2,2,2-trichloroethyl group, the benzyl group, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The choice of carboxyl protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the fomriulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, "Protective Groups In Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New Yori/l and dried in vacuo to afford the urea.
General Procedure O. Alkylation of Urea, or Carbamate, or Amide Nitrogen on Polymer Support
To the conesponding polymer supported urea, carbamate, or amide having a free NH group (1 eq) 0.117 g, 0.73 mmol) is added potassium /-butoxide (3-10 eq). The resin mixture is shaken for 1 h at 25°C and then alkyl halide or alkyl sulfonate 3-10 eq is added. After 16 h the polymer is then washed with three cycles of DMF/methanol/DCM and dried in vacuo to give the alkylated product.
General Procedure P. Cleavage from Solid Support
The polymer is treated with TFA solution (5-50% v/v/ in DOM, excess) at 25°C to cleave the product from the polymer support. Filtration and concentration in vacuo affords the product.
Genera! Procedure Q. Preparation of N,0-Dimethyl N-Hydroxycarboxamides
Carboxylic acid (1 eq) in DOM (0.02-2 M) is treated with N,0- dimethylhydroxyl amine hydrochloride (1 eq) and triethylamine (1 eq), DOC, EDC, or other carbodiimide reagent (1 eq) is added. After 1-24 hr, The solution is concentrated in vacuo and the residue is removed by filtration. Alternately, the mixture may be given an aqueous workup. The filtrate is concentrate in vacuo. The product is used directly or is purified by silica gel chromatography.
General Procedure R. Preparation of Ketones from N,0-Dimethyl N-Hydroxycarboxamides
Organolithium or organomagnesium reagent, whether prepared in situ or commercially obatined, is treated in THF or ether (0.02 -1 M) with N,0-dimethyl N-hydroxy-carboxamides (1 eq) at a temperature of from -20''C to 25°C. Once starting amide is consumed, the mixture is given an aqueous workup. Concentration in vacuo afforded the product ketone.

General Procedure S1. Preparation of Secondary alcohol from Ketone
The ketone (1 eq) in ethanol or methanol (0.02 - 2 M) treated with sodium borohydride (0.25 - 2 eq,) at 0°C - 25°C, followed by aqueous wori-N-1.3-thiazol-2-vl-acetamide

2-Cyclopentylthio-2-(3-chlorophenyl)acetic acid (351 mg, 65%) is prepared from 2-bromo-2-(3-clilorophenyl)acetic acid methyl ester (527 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (68 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3-chlorophenyl)-N-1,3-thiazol-2-yl-acetamide (63 mg, 72%). LCMS (m/z): 353 (M+H)*
H NMR (400 MHz, CDCI3): 6 1.48-1.60 (m, 4H). 1.68-1.76 (m, 2H), 1.94-2.04 (m, 2H), 3.06-3.14 (m, 1H), 4.74 (s, 1H), 7.04-7.05 (d, 1H), 7.27-7.29 (m. 3H), 7.42 (s, 1H), 7.49-7.50 (d, 1H), 10.88 (br.lH).
Example 57
2-Cvclopentvlsulfanvl-2-(3-chloroDhenvl)-N-pvridin-2-vl-acetamide


A solution of 2-cyclopentylthio-2-(3-chlorophenyl)acetic acid (68 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3-chlorophenyl)-N-pyridin-2-yl-acetamide (59 mg, 68%). LCMS (m/z): 347 (M+H)*
H NMR (400 MHz. CDCI3): 6 1.52-1.64 (m, 4H), 1.70-1.84 (m, 2H). 1.89-2.08 (m, 2H), 3.09-3.15 (m, 1H), 4.74 (s, 1H), 7.02-7.10 (m, 3H), 7.40-7.42 (m, 2H), 7.70-7.72 (m, 1H), 8.19 (d. 1H), 8.32-8.33 (m. 1H). 9.34 (br, 1H).
Example 58
2-Cvclopentvlsulfanvl-2-(4-chloro)phenvl-N-pvridin-2-vl-acetamide

2-Cyciopentylthio-2-(4-chlorophenyl)acetic acid (390 mg, 72%) is prepared from 2-bromo-2-(4-chlorophenyl)acetic acid methyl ester (528 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (68 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-chlorophenyl)-N-pyridin-2-yl-acetamide (62 mg, 72%).
LCMS(m/z):347(M+H)*
'H NMR (400 MHz, CDCI3): 6 1.52-1.63 (m, 4H), 1.72-1.85 (m, 2H), 1.89-2.10 (m, 2H), 3.09-3.16 (m, 1H), 4.72 (s, 1H), 7.02-7.09 (m, 3H), 7.42-7.44 (m, 2H), 7.71-7.73 (m, 1H). 8.19 (d, 1H). 8.31-8.32 (m, 1H). 9.25 (br, 1H).
Example 59
2-Cvclopentvlsulfanvl-2-(4-bromophenvl)-N-1.3-thiazol-2-vl-acetamtde


2-Cyclopentyithio-2-(4-bromophenyl)acetic acid (441 mg, 70%) is prepared from 2-bromo-2-(4-bromophenyi)acetic acid methyl ester (616 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (79 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-bromophenyl)-N-1,3-thiazol-2-yl-acetamide (71 mg, 72%). LCMS(m/z):398(M+H)'
'H NMR (400 MHz, CDCI3): 8 1.48-1.61 (m, 4H), 1.68-1.76 (m, 2H), 1.96-2.02 (m, 2H), 3.07-3.12 (m. 1H), 4.74 (s, 1H), 7.02 (d, 1H), 7.28-7.30 (dd, 1H), 7.37-7.44 (m, 1H), 7.49-7.52 (m, 1H), 7.52 (d, 1H), 7.59 (d, 1H), 10.65 (br. 1H).
Example 60
2-Cvclopentvlsulfanvl-2-(4-bromophenyl)-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(4-bromophenyl)acetic acid (79 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-bromophenyl)-N-pyridin-2-yl-acetamide (73 mg, 75%). LCMS (m/z): 392 (M+H)*
'H NMR (400 MHz, CDCI3): 6 1.50-1.64 (m, 4H), 1.69-1.83 (m, 2H), 1.87-2.10 (m, 2H), 3.09-3.17 (p, 1H), 4.65 (s, 1H), 7.05-7.08 (dd, 1H). 7.31-7.36 (dd, 2H), 7.45-7.48 (m, 2H), 7.68-7.72 (m, 1H), 8.18 (d, 1H), 8.29-8.30 (m, 1H), 9.23 (br, 1H).
Example 61
2-Cvciopentvlsulfanvl-2-(4-methoxvphenv!VN-1.3-thia2ol-2-vl-acetamide


2-Cyclopentylthio-2-(4-methoxyphenyl)acetic acid (319 mg, 60%) is prepared from 4-methoxymandelic acid methyl ester (392 mg, 2 mmol) and cydopentane thiol (245 mg, 2.4 mmol) following the general procedure D. A solution of this add (67 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 nnmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-methoxyphenyl)-N-1,3-thiazol-2-yl-acetamide (65 mg, 75%). LCMS (m/z): 349 (M+H)*
'H NMR (400 MHz, CDCI3): 5 1.46-1.63 (m, 4H), 1.68-1.78 (m, 2H), 1.93-2.06 (m, 2H), 3.06-3.13 (m, 1H), 3.78 (s, 3H), 4.75 (s, 1H), 6.84-6.88 (m, 2H), 7.00-7.02 (dd, 1H), 7.31-7.34 (m, 2H), 7.46-7.48 (dd, 1H), 10.41 (br, 1H).
Example 62
2-Cvclopentvlsulfanvl-2-(4-methoxvphenvl)-N-pvridin-2-yl-acetamide

A solution of 2-cyclopentylthio-2-(4-methoxyphenyl)acetic acid (67 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-methoxyphenyl)-N-pyridin-2-yl-acetamide (60 mg, 70%). LCMS (m/z): 343 (M+H)*
'H NMR (400 MHz, CDCI3): 6 1.50-1.66 (m, 4H), 1.69-1.81 (m, 2H), 1.86-2.07 (m, 2H). 3.09-3.16 (m, 1H), 3.77 (s. 3H), 4.67 (s, 1H). 6.85-6.87 (m, 2H), 7.03-7.04 (m, 1H), 7.25-7.38 (m, 2H), 7.66-7.71 (m, 1H), 8.20 (d, 1H), 8.28-8.30 (m, 1H). 9.14 (br. 1H).

Example 63
2-Cvclopentvlsulfanvl-2-(3-cvanoDhenvl)-N-1, 3-thiazol-2-vl-acetamide

2-Cyclopentylthio-2-(3-cyanophenyl)acetic acid (323 mg, 62%) is prepared from 3-cyanomandelic acid methyl ester (382 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure D. A solution of this acid (65 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3-cyanophenyi)-N-1,3-thiazol-2-yl-acetamide (64 mg, 74%). LCMS (m/z): 344 (M+H)*
'H NMR (400 MHz, CDCI3): (51.48-1.61 (m, 4H), 1.68-1.78 (m, 2H), 1.91-2.20 (m, 2H), 3.05-3.12 (m, 1H), 4.81 (s, 1H), 7.07-7.08 (d, 1H), 7.45-7.47 (t, 1H), 7.50-7.51 (d, 1H), 7.58-7.60 (d, 1H), 7.68-7.70 (d, 1H), 7.76 (s, 1H), 11.28 (br, 1H).
Example 64
2-Cvclopentvlsulfanvl-2-(3-cvanoDhenvl)-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(3-cyanophenyl)acetic acid (65 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3-cyanophenyl)-N-pyridin-2-yl-acetamide (61 mg, 72%). LCMS (m/z): 338 (M+H)*
'H NMR (400 MHz, CDCI3): 6 1.51-1.62 (m, 4H), 1.73-1.80 (m, 2H), 1.92-2.08 (m, 2H), 3.09-3.17 (m. 1H), 4.71 (s. 1H), 7.08-7.11 (m, 2H), 7.43-7.47 (m, 1H), 7.57-7.60 (m, 1H), 7.68-7.75 (m, 3H), 8.19 (d, 1H), 8.30-8.32 (m, 1H). 9.44 (br. 1H).


Example 65
2-CvcloDentvlsulfanvl-2-(4-cvanophenvl)-N-1. 3-thiazol-2-vl-acetamide
2-Cyclopentylthio-2-(4-cyanophenyl)acetic acid (313 mg, 60%) is prepared from 4-cyanomandelic acid nnethyl ester (382 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure D. A solution of this acid (65 mg, 0.25 mmol) in THF is reacted with 2-aminothia2ole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-cyanophenyl)-N-1,3-thiazol-2-yl-acetamide (58 mg, 68%). LCMS(m/z):344(M+H)*
H NMR (400 MHz. CDCI3): 6 1.46-1.57 (m. 4H), 1.72-1.78 (m, 2H), 1.94-2.04 (m, 2H), 3.04-3.12 (m, 1H). 4.82 (s. 1H), 7.02-7.04 (m, 2H), 7.42-7.44 (m, 1H), 7.57 (d, 1H), 7.63-7.66 (dd, 1H). 7.80-7-84 (m, 1H), 8.21-8.22 (m. 1H), 10.41 (br, 1H).
Example 66
2-CvcloDentvlsulfanvl-2-(4-cvanoDhenvl)-N-pvridin-2-vl-acetamide

A solution of 2-(cyclopentylthio)-2-(4-cyanophenyl)acetic acid (65 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-cyanophenyl)-N-pyridin-2-yl-acetamide (67 mg, 80%). LCMS (m/z); 338 (M+H)*
'H NMR (400 MHz, CDCI3): 6 1.54-1.61 (m, 4H), 1.70-1.76 (m. 2H), 1.88-2.06 (m, 2H), 3.09-3.16 (m, 1H), 4.72 (s, 1H), 7.07-7.10 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 1H), 7.69-7.74 (m. 1H). 8.16 (d, 1H), 8.29-8.31 (m, 1H). 9.32 (br, 1H).

Example 67
2-Cvclopentvlsulfanvl-2-(4-nitroDhenvl)-N-1. 3-thiazol-2-vl-acetamide


H O N-

2-Cyclopentylthio-2-(4-nitrophenyl)acetic acid (270 mg, 48%) is prepared from 2-bromo-2-(4-nitrophenyl)acetic acid methyl ester (548 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (70 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-nitrophenyl)-N-1,3-thiazol-2-yl-acetamide (67 mg, 74%). LCMS(/n/2):364(M+H)*
'H NMR (400 MHz, CDCI3): (J 1.26 (m, 4H), 1.40 (m, 2H), 1.66 (m, 2H), 3.44 (m, 1H), 4.87 (s, 1H), 7.03 (d, 1H), 7.42 (m, 2H), 7.64 (d, 1H), 8.18 (m, 2H), and 11.2 (br. 1H).
Example 68
2-Cvdopentvlsuifanvl-2-(4-nitrophenvl)-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(4-nitrophenyi)acetic acid (70 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-nitrophenyl)-N-pyridin-2-yl-acetamide (63 mg, 70%). LCMS(m/z): 358(M+H)*.


Example 69
2-Cvclopentvlsulfanvl-2-(4-methvlsulfonvl)phenvl-N-1.3-thiazol-2-yl-acetamide

M 1 H
3 o
0" "0 v-i 0 N-

2-Cyclopentyittiic>-2-(4-methyisulfonylphenyl)acetic acid (471 mg, 75%) is prepared from 2-bromo-2-(4-methylsulfonylphenyl)acetic acid methyl ester (614 mg, 2 mmol) and cydopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (79 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-methylsulfonylphenyl)-N-1,3-thiazol-2-yl-acetamide (84 mg, 85%). LCMS(m/z):397(M+H)*
H NMR (400 MHz, CDCI3): 6 1.59 (m, 4H), 1.75 (m, 2H), 2.04 (m, 2H), 3.04 (s, 3H), 3.13 (m, 1H). 4.83 (s, 1H), 7.04 (d, 1H), 7.49 (d, 1H). 7.62 (m, 2H), 7.93 (m. 2H), 10.31 (br, 1H).
Example 70
2-Cvclopentylsulfanvl-2-f4-methvlsulfonvlphenvi)-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(4-methylsulfonylphenyl)acetic acid (79 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-methylsulfonylphenyl)-N-pyridin-2-yl-acetamide (80 mg, 82%). LCMS (m/z): 391 (M+H)*
H NMR (400 MHz, CDCI3): 6 1.58 (m, 4H), 1.75 (m, 2H), 2.03 (m. 2H), 3.03 (s, 3H), 3.14 (m, 1H), 4.76 (s. 1H), 7.08 (m, 1H), 7.66 (m, 2H), 7.70 (m, 1H), 7.91 (m, 2H), 8.17 (d, 1H), 8.32 (m, 1H),9.32(br, 1H).


Example 71
2-Cvclopentvlsulfanyl-2-(4-trifluoromethv)Dhenvl-N-1, 3-thiazol-2-vl-acetamide
2-Cyclopentylthio-2-(4-trifluoromethylphenyl)acetic acid (413 mg, 68%) is prepared om 2-bromo-2-(4-trifluoromethylphenyl)acetic acid methyl ester (594 mg, 2 mmol) and /clopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this cid (76 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following le general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-trifluoromethylphenyl)-N-1,3-iiazol-2-yl-acetamide (82 mg. 85%). CMS(m/z):387(M+H)*
NMR (400 MHz. CDCI3): 6 1.50-1.62 (m, 4H), 1.71-1.80 (m, 2H), 1.96-2.08 (m, 2H). 3.06-16 (m. 1H), 4.82 (s, 1H), 7.03-7.048 (d, 1H), 7.48-7.49 (d, 1H), 7.53-7.55 (d, 2H), 7.6-7.62 I, 2H). 10.51 (br, 1H).
xample 72
■Cvclopentvlsulfanvl-2-f4-trifluoromethvphenvl-N-pvridin-2-vl-acetamide

A solution of 2-cydopentylthio-2-(4-trifluoromethylphenyl)acetic acid (76 mg, 0.25 mol) in THF is reacted with 2-aminopyridine (57 mg. 0.6 mmol) following the general ocedure E to obtain 2-cyclopentylsuifanyl-2-(4-trifluoromethylphenyl)-N-pyridin-2-yl-»tamide (76 mg, 80%). :MS(m/z):381 (M+H)*

'H NMR (400 MHz, CDCI3): rf 1.57-1.65 (m, 4H), 1.70-1.81 (m, 2H), 1.93-2.05 (m, 2H), 3.11-3.17 (m, 1H), 4.75 (s, 1H), 7.06-7.10 (m, 1H), 7.24-7.25 (m, 1H), 7.56-7.61' (m, 3H), 7.69-7.74 (m. 1H), 8.19 (d, 1H). 8.29-8.31 (m. 1H), 9.34 (br, 1H).
Example 73
2-Cvclopentvlsuifanvl-2-(3-trifluoromethoxvphenvl)-N-1. 3-thiazol-2-vl-acetamide

2-Cyclopentylthio-2-(3-trifluoromethoxyphenyl)acetic acid (416 mg, 65%) is prepared from 2-bromo-2-(3-trifluoromethoxyphenyi)acetic acid methyl ester (626 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (80 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cydopentylsulfanyl-2-(3-trifluoromethoxylphenyl)-N-1,3-thiazol-2-yl-acetamide (78 mg, 78%). LCMS(n7/z):403(M+H)*
'H NMR (400 MHz, CDCI3): 6 1.61 (m. 4H), 1.75 (m, 2H), 2.02 (m, 2H), 3.13 (m, 1H). 4.77 (s, 1H), 7.03 (d, 1H), 7.18 (m. 1H). 7.27 (d, 1H), 7.33-7.40 (m, 2H), 7.47 (d. 1H), 10.25 (br, 1H).
Example 74
2-Cvclopentvlsulfanvl-2-(3-trifluoromethoxvphenvl>-N-pvridin-2-vl-acetamide


A solution of 2-cyclopentylthio-2-(3-trifluoromethoxyphenyl)acetic acid (80 mg, 0.25 mmol) in THF is reacted witli 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3-trifluoromethoxyphenyl)-N-pyridin-2-yl-acetamide (TTP-00176052) (71 mg, 72%). LCMS(m/z):397(M+H)*
H NMR (400 MHz, CDCI3): 6 1.58 (m, 4H), 1.73 (m. 2H), 2.03 (m, 2H), 3.14 (m, 1H), 4.70 (s, 1H), 7.05-7.10 (m. 1H), 7.15 (m, 1H), 7.31 (d. 1H), 7.36 (m, 2H). 7.71 (m, 1H), 8.19 (d, 1H), 8.31 (m, 1H), and 9.25 (br, 1H).
Example 75
2-Cvclopentvlsulfanvl-2-(4-trifluoromethoxvphenvl)-N-1. 3-thiazol-2-vl-acetamide

F' O
2-Cyclopentylthio-2-(4-trifluoromethoxyphenyl)acetic acid (448 mg, 70%) is prepared from 2-bromo-2-(4-trifluoromethoxylphenyl)acetic acid methyl ester (626 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (80 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-trifluoromethoxylphenyl)-N-1,3-thia2ol-2-yl-acetamide (85 mg, 85%). LCMS(/n/z):403(M+H)*
'H NMR (400 MHz, CDCI3): 6 1.55 (m, 4H), 1.74 (m, 2H). 2.01 (m, 2H). 3.11 (m, 1H), 4.79 (s. 1H). 7.03 (d, 1H), 7.26 (m, 2H), 7.47 (m, 3H), 10.87 (br. 1H).

Example 76
2-Cyclopentvlsulfanvl-2-(4-trifluoromethoxvphenvl)-N-Dvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(4-trifluoromethoxyphenyl)acetic acid (80 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentyisulfanyl-2-(4-trifluoromethoxyphenyl)-N-pyridin-2-yl-acetamide (79 mg, 80%). LCMS(m/z):397(M+H)*
H NMR (400 MHz, CDCI3): S 1.58 (m, 4H), 1.74 (m, 2H), 2.04 (m, 2H). 3.15 (m, 1H), 4.70 (s, 1H), 7.08 (m, 1H). 7.18 (dd, 2H), 7.47 (dd, 2H), 7.71 (m, 1H), 8.19 (d, 1H), 8.31 (m, 1H), 9.25 (br.lH).
Example 77
2-Cvclopentvlsulfanvl-2-(4-phenvl)phenvl-N-1. 3-thiazol-2-vl-acetamide

'-
2-Cyciopentylthio-2-(4-phenyl)phenylacetic acid (406 mg, 65%) is prepared from 2-bromo-biphenylacetic acid methyl ester (610 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (78 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cydopentylsulfanyl-2-(4-phenyl)phenyl-N-1,3-thiazol-2-yl-acetamide (69 mg, 70%). LCMS (m/z): 395 (M+H)*

'H NMR (400 MHz, CDCI3): rf 1.47-1.66 (m, 4H). 1.72-1.81 (m, 2H). 1.99-2.21 (m, 2H), 3.10-3.22 (p. 1H), 4.83 (s, 1H), 6.99-7.01 (m, 1H), 7.41-7.58 (m, 6H), 7.63-7.65 (m, 1H), 7.67-7.77 (m, 1H), 8.03 (d, 1H), 8.56 (d, 1H), 10.42 (br. 1H).
Example 78
2-Cvclopentvlsulfanvl-2-(4-Dhenvl)phenvl-N-pvridin-2-vl-acetamide

"-
A solution of 2-cyclopentylthio-2-(4-phenyl)phenylacetic acid (78 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-phenyl)phenyl-N-pyridin-2-yl-acetamide (76 mg, 78%). LCMS(m/z):389(M+H)*
H NMR (400 MHz, CDCI3): 6 1.53-1.62 (m, 4H), 1.71-1.78 (m, 2H), 2.01-2.12 (m, 2H), 3.08-3.20 (p, 1H), 4.92 (s, 1H), 7.13-7.17 (m, 1H), 7.25-7.58 (m, 6H), 7.61-7.67 (m. 1H), 7.71-7.75 (m, IN), 7.82-7.86 (m, 1H), 8.29-8.31 (m, 1H), 8.33-8.36 (m, 1H), 8.46-8.48 (d, 1H), 10.39 (br. 1H).
Example 79
2-Cvclopentvlsulfanvi-2-(4-phenoxvDhenvl>-N-1. 3-thiazol-2-vl-acetamide

2-Cyclopentylthio-2-(4-phenoxyphenyl)acetic acid (459 mg, 70%) is prepared from 2-bromo-(4-phenoxyphenyl)acetic acid methyl ester (642 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (82 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general

procedure E to obtain 2-cyclopentylsulfanyl-2-(4-phenoxyphenyl)-N-l,3-thiazol-2-yl-
acetamide (81 mg, 79%).
LCMS(m/z):411 (M+H)*
H NMR (400 MHz. CDCI3): 6 1.60 (m, 4H), 1.75 (m, 2H), 2.05 (m, 2H), 3.15 (m, 1H). 4.72 (s,
1H), 6.95-7.12 (m, 5H), 7.34 (t, 1H), 7.41 (d, 2H), 7.73 (t, 1H), 8.24 (d, 1H), 8.30 (dd, 1H),
and 9.39 (br.lH).
Example 80
2-Cvclopentvlsulfanvl-2-f4-phenoxvphenvl)-N-pyridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(4-phenoxyphenyl)acetic acid (82 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(4-phenoxyphenyl)-N-pyridin-2-yl-acetamide (79 mg, 78%). LCMS(m/z):405(M+H)*
H NMR (400 MHz, CDCI3): 6 1.53-1.56 (m, 4H), 1.72 (m, 2H), 1.98 (m, 2H), 3.16 (m. 1H), 4.81 (s, 1H), 6.99 (m, 4H), 7.14 (m, 2H). 7.29-7.44 (m, 4H), 7.49 (t, 1H). 7.56 (d, 1H), 8.00 (dd,1H), and 10.93 (br,1H).
Example 81
2-Cvclopentvlsulfanvl-2-(3.4-difluorophenvl)-N-1.3-thiazol-2-vl-acetamide


H O N

2-Cyclopentylthio-2-(3,4-difluorophenyl)aceticacid (316 mg, 58%) is prepared from 2-bromo-2-(3,4-difluorophenyl)acetic acid methyl ester (530 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (68 mg.

0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general
procedure E to obtain 2-cyclopentylsulfanyl-2-(3,4-difluorophenyl)-N-1,3-thiazol-2-yl-
acetamide (66 mg, 75%).
LCMS (m/z): 355 (M+H)*
'H NMR (400 MHz, CDCI3): 6 1.50-1.55 (m, 4H), 1.70-1.74 (m, 2H), 1.87-2.02 (m, 2H), 3.03-
3.09 (m, 1H). 4,74 (d, 1H), 7.06-7.18 (m, 1H), 7.28-7.34 (m, 1H), 7.70-7.74 (m, 1H), 8.19 (d,
IN), 8.29-8,31 (m, 1H), 9.28 (br, 1H).
Example 82
2-Cvclopentvlsulfanvl-2-f3.4-difluorophenvl)-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(3,4-difluorophenyl)acetic acid (68 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 nng, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3,4-difluorophenyl)-N-pyridin-2-yl-acetamide (61 mg, 70%). LCMS(m/z): 349(M+H)*
'H NMR (400 MHz, CDCI3): 6 1.50-1.62 (m, 4H). 1.69-1.80 (m, 2H), 1.87-2.08 (m, 2H), 3.09-3.16 (m, 1H), 4.69 (s, 1H), 7,01-7.08 (m, 3H), 7.42-7.44 (m, 1H), 7.72-7.74 (m. 1H), 8.19 (d, 1H), 8.30-8.32 (m, 1H), 9.88 (br. 1H).
Example 83
2-Cvclopentvlsulfanvl-2-(3.5-difluorophenvlVN-1.3-thiazol-2-vl-acetamide


2-Cydopentylthio-2-(3,5-difluorophenyl)acetic acid (326 mg, 60%) is prepared from 2-bromo-2-(3,5-difiuorophenyl)acetic acid methyl ester (530 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (68 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cydopentylsulfanyl-2-(3,5-difluorophenyl)-N-1,3-thiazol-2-yl-acetamide (62 mg, 70%). LCMS (m/z): 355 (M+H)*
H NMR (400 MHz, CDCU): 6 1.48-1.55 (m, 4H), 1.71-1.75 (m, 2H), 1.87-2.05 (m, 2H). 3.04-3.09 (m, 1H), 4.75 (d, 1H), 7.08-7.16 (m, 1H), 7.26-7.32 (m, 1H), 7.71-7.74 (m, 1H), 8.19 (d. 1H), 8.29-8.32 (m, 1H), 9.66 (br, 1H).
Example 84
2-Cvclopentvlsulfanvl-2-(3, 5-difluorophenvl>-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-(3,5-difluorophenyl)acetic acid (68 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3,5-difluorophenyl)-N-pyridin-2-yl-acetamide (66 mg, 76%). LCMS(m/z):349(M+H)*.
Example 85
2-Cvciopentvisuifanvl-2-{3.4-(methvlenedioxv)phenvlVN-1. 3-thiazoi-2-vl-acetamide


2-Cyclopenty!thio-2-{3,4-(methylenedioxy)phenyl}acetic acid (336 mg, 60%) is prepared from 3,4-(methylenedioxy)mandelic acid methyl ester (420 mg, 2 mmol) and cydopentane thiol (245 mg, 2.4 mmol) following the general procedure D. A solution of this acid (70 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-{3,4-(methylenedioxy)phenyl}-N-1,3-thiazol-2-yl-acetamide (59 mg, 65%). LCMS(m/z):363(M+H)*
H NMR (400 MHz, CDCI3): 6 1.46-1.61 (m. 4H), 1.68-1.79 (m, 2H), 1.92-2.34 (m, 2H), 3.05-3.12 (m, 1H), 4.71 (s, 3H), 5.94-5.95 (m. 2H), 6.74 (d, 1H), 6.84 (d, 1H), 6.94 (s, 1H), 7.02 ( d, 1H), 7.49 (d,1H). 10.61 (br, 1H).
Example 86
2-Cvclopentvisulfanvl-2-(3.4-(methvlenedioxv)phenvl>-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-{3,4-(methylenedioxy)phenyl}acetic acid (70 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-{3,4-(methylenedioxy)phenyl}-N-pyridin-2-yl-acetamide (53 mg, 60%). LCMS (m/z): 357 (M+H)*
'H NMR (400 MHz, CDCI3): rf 1.48-1.62 (m, 4H), 1.67-1.78 (m. 2H). 1.92-2.08 (m. 2H). 3.06-3.14 (m, 1H). 4.62 (s, 3H), 5.93 (d, 2H). 6.74 (d, 1H). 6.87 (d. 1H), 6.95 (s, 1H), 7.02-7.06 (m. 1H), 7.67-7.71 (t, 1H), 8.19 (d, 1H), 8.28 (d. 1H), 9.17 (s, 1H).

Example 87
2-Cvclopentvlsulfanvl-2-r3.5-bis(trifluoromethvl)phenvl]-N-1. 3-thiazol-2-vl-acetamide

2-Cyclopentylthio-2-[3.5-bis(trifluoromethyl)phenyl]acetic acid (521 mg, 70%) is prepared from 2-bromo-2-[3,5-bis(trifluoromethyl)phenyl]acetic acid methyl ester (730 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (93 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyi-2-[3,5-bis(trifluoro-methyl)phenyl]-N-1,3-thiazol-2-yl-acetamide (93 mg, 82%). LCMS (m/z): 455 (M+H)*
H NMR (400 MHz, CDCI3): S 1.51-1.64 (m, 4H), 1.69-1.78 (m, 2H), 1.92-2.00 (m, 2H), 3.14-3.22 (p, 1H), 4.91 (s, 1H). 7.48 (t, 1H), 7.61 (t. 1H), 7.72 (d, 1H), 7.80 (br, 1H), 8.8.10 (s, 1H). 11.12(br, 1H).
Example 88
2-Cvclopentvlsulfanvl-2-r3.5-bis(trifluoromethvl)phenvl1-N-pvridin-2-vl-acetamide

A solution of 2-cyclopentylthio-2-[3,5-bis(trifluoromethyl)phenyl]acetic acid (93 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyi-2-[3,5-bis(trifluoromethyl)phenyl]-N-pyridin-2-yl-acetamide (90 mg, 80%). LCMS(m/z):449(M+H)*

'H NMR (400 MHz, CDCI3): rf 1.52-1.60 (m, 4H), 1.64-1.78 (m, 2H), 1.92-1.99 (m, 2H), 3.26-3.32 (m, 1H). 4.92 (s, 1H), 7.48 (t. 1H), 7.61 (t, 1H), 7.69 (s, 1H), 7.75 (d. 1H). 8.10 (s, 1H), 8.12 (d, 1H), 8.21- 8.33 (dd, 1H), 11.12 (br, 1H).
Example 89
2-Cvclopentvlsulfanvl-2-f3-ch!oro-4-methoxv)phenvl-N-1. 3-thiazol-2-vi-acetamide

2-Cyclopentylthio-2-(3-chloro-4-methoxyphenyl)acetic acid (421 mg, 70%) is prepared from 2-bromo-2-(3-chloro-4-methoxyphenyl)acetic acid methyl ester (588 mg, 2 mmol) and cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (75 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3-chloro-4-methoxyphenyl)-N-1,3-thiazDl-2-yi-acetamide (77 mg, 80%) LCMS(m/z):383(M+H)*
H NMR (400 MHz, CDCI3): 6 1.60 (m, 4H), 1.75 (m, 2H), 2.03 (m, 2H), 3.12 (m, 1H), 3.90 (s, 3H). 4.70 (s, 1H), 6.89 (m, 1H), 7.00 (dd, 1H), 7.29 (m, 1H). 7.31 (dd. 1H), 7.45 (dd, 1H), 9.96(br. 1H).
Example 90
2-Cvclopentvlsulfanvl-2-(3.4-dichloro-phenyl>-N-thiazol-2-vl-acetamide

2-(Cyclopentylthio)-2-(3,4-dichloro phenyl) acetic acid (458 mg, 75%) is prepared from 2-bromo-2-(3,4-dichloro phenyl) acetic acid methyl ester (594 mg, 2 mmol) and

cyclopentane thiol (245 mg, 2.4 mmol) following the general procedure C. A solution of this acid (76 mg. 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (87 mg, 90%). LCMS(m/z):387(M+H)*
'H NMR (400 MHz, CDCI3): 6 1.48-1.62 (m, 4H), 1.71-1.80 (m, 2H), 1.96-2.05 (m, 2H). 3.08-3.15 (m. 1H), 4.71 (s. 1H), 7.03-7.04 (dd, 1H), 7.24-7,26 (m, 1H), 7.41 (d, 1H), 7.47 (d. 1H). 7.51 (d,1H) 10.25 (br.lH).
Example 91
N-(5-Bromo-1.3-thiazol-2-vl)-2-(cvclopentvlthio)-2-(3.4-dichlorophenvnacetamide


O N—

A solution of 2-(Cyclopentylthio)-2-(3,4-dichloro phenyl) acetic acid (76 mg, 0.25 mmol) in THF is reacted with 2-amino-5-bromo-thiazole (107 mg, 0.6 mmol) following the general procedure E to obtain N-(5-bromo-1,3-thiazol-2-yl)-2-(cyclopentylthio)-2-(3,4-di-chlorophenyl)acetamide (93 mg, 80%). LCMS467(m/z):(M + 2H)*
Example 92
2-Cvclopentvlsulfanvl-2-(3,4-dichlorophenyl)-N-F(4-methoxvcarbonylmethvl)-1,3-thiazol-2-vl1-acetamide


A solution of 2-cyclopentylthio-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF is reacted with methyl-2-amino-4-thiazoleacetate (103 mg, 0.6 mmol) following ttie general procedure E to obtain 2-Cyclopentylsulfanyl-2-(3,4-dichlorophenyl)-N-[(4-methoxy-carbonylmethyl)-1, 3-thiazol-2-yi]-acetamide (86 mg, 75%). LCMS(m/z):459(M+H)*
'H NMR (400 MHz, CDCI3): -N-pvridinvl-2-vl-acetamide

A solution of 2-(cyclopentylthio)-2-(3,4-dichloro phenyl) acetic acid (76 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentyisulfanyl-2-(3,4-dichloro-phenyl)-N-pyrJdinyl-2-yl-acet-amide (84 mg, 88%). LCMS (m/z); 381 (M+H)
H NMR (400 MHz, CDCI3): 6 1.52-1.61 (m, 4H), 1.67-1.81 (m, 2H), 1.89-2.10 (m, 2H), 3.08-3.17 (m, 1H), 4.72 (s, 1H). 7.03-7.08 (m, 3H), 7.41-7.42 (m, 1H). 7.73-7.75 (m. 1H), 8.19 (d, 1H), 8.31-8.32 (m, 1H). 9.66 (br, 1H).


Example 96
2-Cvclopentvlsulfanvl-2-(3.4-dichloro-phenvl)-N-pvrimidin-2-vl-acetamide
A solution of 2-(cyclopentylthio)-2-(3,4-dichloro phenyl) acetic acid (76 mg, 0.25 mmol) in THF is reacted with 2-aminapyrimidine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-pyrimidin-2-yl-acet-amide (81 mg, 85%). LCMS (m/z): 382 (M+H)*
'H NMR (400 MHz. CDCI3): 6 1.53-1.57 (m, 4 H), 1.70-1.75 (m, 2H), 1.99-2.04 (m, 2 H). 3.11-3.18 (m, 1H), 4.72 (s. 1H), 7.07-7.09 (t, 1H), 7.39, (s. 1H), 7.48 (t, 1H), 7.64 (s, 1H), 8.11-8.13 (dd, 1H), 8.65 (d. 1H). 9.82 (br, 1H).
Example 97
2-Cvclohexvlsulfanvl-2-(3.4-dichloroDhenvl)-N-1. 3-thiazol-2-vl-acetamide

2-Cyclohexylthio-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is prepared from 2-bromo-2-(3.4-dichlorophenyl)acetic acid methyl ester (594 mg, 2 mmol) and cyclohexane thiol (278 mg, 2.4 mmol) following the general procedure C. A solution of this acid (76 mg, 0.25 mmol) in THF is reacted with 2-aminothia20le (60 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclohexylsulfanyl-2-(3,4-dichlorophenyl)-N-1.3-thiazol-2-yl-acetamide (72 mg, 72 %). LCMS (m/z): 401 (M + H)*

'H NMR (400 MHz. CDCI3): 6 0.84-0.87 (m, 1H), 1.09-1.41 (m, 4H). 1.48-2.02 (m. 4H), 2.65-2.78 (m. 1H), 4.87 (s, 1H), 6.98-7.04 (dd. 1H). 7.33-7.35 (dd. 1H), 7.41-7.48 (m. 2H), 7.62-7.67(dd. 1H). 11.64 (br.lH).
Example 98
2-Cvclohexvlsulfanvl-2-(3.4-dichlorophenvlVN-pvridin-2-vl-acetamide

A solution of 2-cyclohexylthio-2-(3,4-dichlorophenyl)acetic acid (76 mg. 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-cyclohexylsulfanyl-2-(3,4-dichlorophenyl)-N-pyridin-2-yl-acetamide (TTP-00176116 (69 mg. 70%). LCMS(m/z):395{M+H)*
'H NMR (400 MHz. CDCI3): 6 0.81-0.89 (m. 1H), 1.24-1.47 (m. 4H). 1.60-2.11 (m, 4H). 2.74-2.81 (m. 1H). 4.66 (s. 1H), 7.06-7.10 (m. 1H), 7.26-7.33 (m, IN). 7.37-7.41 (dd, 2H). 7.53 (d. 1H). 7.69-7.74 (m. 1H), 8.17 (d. 1H). 8.31-8.32 (dd, 1H), 9.34 (br. 1H).
Example 99
2-lsopropvlsulfanvl-2-(3.4-dichlorophenvl)-N-1. 3-thiazol-2-vl-acetamide CH,
H3C-


N
Cl

S

CI
2-lsopropyllthio-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is prepared from 2-bromo-2-(3,4-dichlorophenyl)acetic acid methyl ester (594 mg. 2 mmol) and isopropane thiol (183 mg, 2.4 mmol) following the general procedure C. A solution of this acid (76 mg. 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg. 0.6 mmol) following the general

procedure E to obtain 2-isopropylsulfanyl-2-(3,4-dichlorophenyl)-N-1,3-thiazol-2-yl-acetamide
(TTP-00176084 (67 mg, 74%).
LCMS(/77/z);361(M+H)*
H NMR (400 MHz, CDCI3): S 1.24-1.27 (dd, 6H), 2.91-3.10 (m, 1H), 4.77 (s. 1H), 7.01-7.03
(m, 1H), 7.25-7.29 (m, 1H), 7.37-7.41 (m, 1H), 7.51-7.55 (m, 1H). 7.97-7.99 (dd, 1H). 11.24
(br, 1H).
Example 100
2-isopropvisulfanvl-2-(3.4-dichlorophenvl)-N-pvridin-2-vl-acetamide CH,
H3C-


Cl

O

'""1

CI
A solution of 2-isopropylthio-2-(3,4-dichlorophenyl)acetic acid (76 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-isopropylsulfanyl-2-(3,4-dichlorophenyl)-N-pyridin-2-yl-acetamide (64 mg, 72%). LCMS(m/z):355(M + H)*
H NMR (400 MHz, CDCI3): 5 1.30-1.33 (dd, 6H), 2.97-3.05 (m, 1H), 4.66 (s. 1H), 7.06-7.09 (m, 1H), 7.26-7.29 (m. 1H). 7.40 (d, 1H), 7.53 (d, 1H), 7.68-7.73 (m, 1H), 8.17 (d, 1H), 8.29-8.31 (m,1H), 9.31 (br, 1H).
Example 101
2-AHvlsulfanvl-2-(3.4-dichiorophenvl)-N-1,3-thiazol-2-vl-acetamide HjC


CI

H
1>

CI
2-Allylthio-2-(3,4-dichlorophenyl)acetic acid (458 mg, 75%) is prepared from 2-3romo-2-(3,4-dichiorophenyl)acetic acid methyl ester (594 mg, 2 mmol) and allyl thiol (178

mg, 2.4 mmol) following the general procedure C. A solution of this acid (76 mg, 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure E to obtain 2-allylsulfanyl-2-(3,4-dichlorophenyl)-N-1,3-thia2ol-2-yl-acetamide (72 mg. 80%). LCMS (m/z): 359 (M+H)*
'H NMR (400 MHz, CDCI3): S 3.09-3.25 (m, 2H), 2.91-3.10 (m, 1H), 4.66 (s, 1H), 5.05-5.16 (m, 2H), 5.73-5.82 (m, 1H), 7.05-7.07 (m, 1H), 7.24-7.27 (dd, 1H), 7.38-7.44 (dd, 1H), 7.52 (d, 1H). 7.94-7.97 (dd, 1H), 11.78 (br, 1H).
Example 102
2-(3,4-Dichlorophenvl)-2-(isobutvlthio)-N-pvridin-2-vlacetamide

2-(2-Methylpropanethio)-2-(3,4-dichloro phenyl) acetic acid (457 mg, 78%) is prepared from 2-bromo-2-(3,4-dichloro phenyl) acetic acid methyl ester (594 mmol, 2 mmol) and 2-methylpropanethiol (216 mg, 2.4 mmol) following the general procedure C. A solution of this acid (73 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-(3,4-dichlorophenyl)-2-(isobutylthio)-N-pyridin-2-ylacetamide (69 mg, 88%). LCMS(m/z):369(M+H)*
H NMR (400 MHz, CDCI3): 6 0.96-1.01 (dd. 7H), 1.82-1.89 (m, 1H), 2.49-2.51 (m, 2H), 5.3 (s, 1H), 7.08-7.09 (m. 1H), 7.26-7.29 (m, 1H), 7.41 (d, 1H), 7.54 (d, 1H), 7.69-7.73 (m. 1H), 8.17 (d, 1H). 8.30-8.32 (m, 1H) 9.19 (br, 1H).


Example 103
2-f3.4-Dichlorophenvl)-2-(isobutvlthio)-N-1.3-thiazol-2-vlacetamide
A solution of 2-(2-methylpropanethio}-2-(3,4-dichioro phenyl) acetic acid (73 mg 0.25 mmol) in THF is reacted with 2-aminothiazole (60 mg, 06 mmol) following the general procedure E to obtain 2-(3,4-dichloropheny!)-2-(isobutylthio)-N-1,3-thiazol-2-ylacetamide (72 mg, 90%).
LCMS (m/z): 375 (M+H)*
'H NMR (400 MHz, CDCI3): 6 0.94 (d, 6H), 1.76 (m, 1H), 2.44 (m, 2H), 4.67 (s, 1H), 7.06 (d, 1H), 7.30 (d, 1H), 7.41 (d, 1H). 7.48 (d, 1H), 7.55 (s, 1H). 11.54 (br, 1H).
Example 104
2-(3,4-DichloroDhenvlV2-K2-furvlmethvl)thiol-N-pvridin-2-vlacetamide

2-(2-Furanylmethylthio)-2-(3.4-dichloro phenyl) acetic acid (482 mg, 76%) is prepared from 2-bromo-2-(3,4-dichloro phenyl) acetic acid methyl ester (594 mg, 2 mmol) and 2-furanylmethylthiol (274 mg, 2.4 mmol) following the general procedure C. A solution of this acid (79 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-(3,4-dichlorophenyl)-2-[(2-furylmethy!)thio]-N-pyridin-2-ylacetamide (80 mg, 82%). LCMS (m/z): 393 (M+H)*

'H NMR (400 MHz, CDCI3): 6 3.78 (dd. 2H), 4.56 (s, 1H). 6.24 (dd, 2H), 7.07 (t, 1H), 7.24 (d, 1H), 7.30 (d. 1H). 7.39 (d, 1H), 7.49 (s, 1H), 7.70 (dd. 1H), 8.15 (d, 1H), 8.26 (dd, 1H), 9.14 (br.lH).
Example 105
2-(3,4-Dichlorophenvl)-2-r(2-furvlmethvl)thiol-N-1.3-thiazol-2-vlacetamide

CI

o

il'

CI
A solution of 2-(2-furanylmethylthio)-2-(3,4-dichloro phenyl) acetic acid (79 mg 0.25 mmol) in THF is reacted with 2-aminothiazoie (60 mg, 0.62 mmol) following the general procedure E to obtain 2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-1.3-thiazol-2-ylacet-amide (85 mg, 85%). LCMS(m/z):399(M+H)*
'H NMR (400 MHz. CDCI3): 6 3.78 (dd, 2H). 4.67 (s, 1H), 6.14 (s, 1H), 6.23 (s, 1H). 7.02 (d. 1H). 7.24 (m, 2H). 7.37 (m, 2H). 7.49 (s, 1H), 11.41 (br. 1H).
Example 106
2-(4-Methvlthio)-2-Dhenvl-N-pvridin-2-ylacetamide H3C



V

2-(4-Methylphenylthio)-2-phenylacetic acid (310 mg, 60%) is prepared from a-bromophenylacetic acid methyl ester (458 mg. 2 mmol) and 4-methylthiophenol (298 mg. 2.4 mmol) following the general procedure C. A solution of this acid (65 mg, 0.25 mmol) in THF

is reacted with 2-aminopyridine (57 mg, 0.6 mmol) following the general procedure E to obtain 2-(4-methylphenylthio)-2-phenyl-N-pyridin-2-ylacetamide (61 mg, 72%). LCMS(/r7/z):335(M+H)*.
Example 107
2-(3.4-Dichlorophenvl)-2-r(2-furvlmethvnthio1-N-pvridin-2-vlacetamide C\-

2-(4-Chlorophenlythio)-2-(3,4-dichlorophenyl)acetic acid (542 g, 78%) is prepared from 2-bromo-2-(3,4-dichlorophenyl)acetic acid methyl ester (594 mg, 2 mmol), 4-chloro-benzenethiol (347mg, 2.4 mmol) following the general procedure C. A solution of this acid (87g, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-(3,4-dichlorophenyl)-2-[(2-furylmethyl)thio]-N-pyridin-2-yl-acetamide (85 mg, 80%). LCMS(m/z):423(M+H)*
'H NMR (400 MHz, CDCI3): tf 4.88 (s, 1H), 7.06-7.10 (m, 1H), 7.24-7.27 (m, 3H), 7.31-7.34 (m. 2H), 7.42 (d, 1H), 7.51 (d, 1H), 7.69-7.73 (m, 1H), 8.13 (d, 1H), 8.27-8.29 (dd, 1H). 8.98 (br, 1H).
Example 108
2-r(4-Fluorophenvl)thio1-N-pvridin-2-vl-2-f4-(trifluoromethvl)phenvnacetamide F.

2-(4-Fluorophenlythio)-2-(4-trifluoromethylphenyl)acetic acid (760 mg, 92%) is prepared from 2-hydroxy-2-(4-trifluoromethyl phenyl)acetic acid methyl ester (860 mg, 2.5

mmol) and 4-fluorobenzenethiol (308 mg, 2.4 mmol) following the general procedure D. A solution of this acid (165 mg, 0.50 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-[(4-fluorophenyl)thio]-N-pyridin-2-yl-2-[4-(trifluoromethyl)phenyl]acetamide (0.12 g, 59%) as a solid. LCMS(m/z):408(M+2H)*
Example 109
2-f(4-Fluorophenvl)thio1-N-1.3-thia2oi-2-vl-2-r4-(trifluoromethvl)phenvnacetamide


H
II \\ }

A solution of 2-(4-fluorophenlythio)-2-(4-trifluoromethyl phenyl) acetic acid (165 mg, ).50 mmol) in THF is reacted with 2-aminothiazole (500 mg, 0.5 mmol) following the general srocedure E to obtain 2-[(4-fluorophenyl)thio]-N-1,3-thiazol-2-yl-2-[4-(trifluoromethyl)phenyl]-jcetamide (93 mg, 45%) as a solid. -CMS (m/z): 414 (M+2H)*
Example 110
?-r(4-Methvlphenvl)thio]-N-1.3-thiazol-2-vl-2-f4-ftrifluoromethvnDhenvl1acetamide

A solution of 2-(4-methylphenlythio)-2-(4-trifluoromethylphenyl)acetic acid (160 mg, .50 mmol) in THF is reacted with 2-aminothiazole (0.50 g, 0.50 mmol) following the general rocedure E to obtain 2-[(4-methylphenyl)thio]-N-1,3-thia2ol-2-yl-2-[4-(trifluoromethyl)pheny!]-cetamide (94 mg, 45%). CMS (m/z): 410 (M+2H)*

Example 111
2-f4-FluoroDhenvl)-2-[(4-fluorophenvl)thio1-N-Dvridin-2-viacetamide F.

2-(4-Fluorophenlythio}-2-(4-fluorophenyl)acetic acid (400 mg, 75%) is prepared from 2-hydroxy-2-(4-fluorophenyi)acetic acid methyl ester (368 mg, 2 mmol) and 4-fluorobenzene-thioi (307 mg, 2.4mmol) following the general procedure D. A solution of this add (66 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-(4-fluorophenyl)-2-[(4-fluorophenyl)thio]-N-pyridin-2-ylacetamide (73 mg, 82%).
LCMS(m/z):357(M + H)*
H NMR (400 MHz, CDCI3): «J4.91 (s, 1H), 6.95-7.08 (m, 5H), 7.37-7.42 (m, 4H), 7.70 (m, 1H), 8.15 (d, 1H), 8.27 (d, 1H), 8.94 (br, 1H).
Example 112
2-(4-BromoDhenvl)-2-r(4-fluoroDhenvnthio1-N-Pvridin-2-vlacetamide

2-(4-Fluorophenlythio)-2-(4-bromophenyl) acetic acid (593 mg, 87%) is prepared from 2-hydroxy-2-(4-bromophenyl) acetic acid methyl ester (490 mg, 2 mmol) and 4-fluoro-benzenethiol (307 mg, 2.4 mmol) following the general procedure D. A solution of this add (85 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-(4-bromophenyl)-2-[(4-fluorophenyl)thio]-N-pyridin-2-ylacet-amide (88 mg, 85%). LCMS (m/z): 419 (M +2 H)*


Example 113
2-(4-Bromophenvl)-2-r(4-methvlphenvl)thio1-N-pvridin-2-viacetamide
2-(4-Methylphenlythio)-2-(4-bromophenyl)acetic acid (559 mg, 83%) is prepared from 2-hydroxy-2-(4-bromophenyl) acetic acid methyl ester (490 mg, 2 mmol) and 4-methyl-benzenethiol (298 mg, 2.4 mmol) following the general procedure D. A solution of this acid (84 mg, 0.25 mmol) in THF is reacted with 2-aminopyridine (56 mg, 0.6 mmol) following the general procedure E to obtain 2-(4-bromophenyl)-2-[(4-methylphenyl)thio]-N-pyridin-2-yiacet-amide (85 mg, 82%). LCMS(/77/z):414(M+H)*
H NMR (400 MHz, CDCI3): 6 2.29 (s. 3H), 4.90 (s, 1H), 7.05 (dd, 1H), 7.08 (d, 2H), 7.31 (d, 4H). 7.46 (d. 2H), 7.68 (t. 1H), 8.14 (d. 1H). 8.28 (d, 1H). 9.11 (br, 1H).
Example 114
N-f 1 -(4-Chlorophenvl)cvclODentvl1-N'-1.3-thia2ol-2-vlurea

Following general procedure H, 1-(4-chlorophenyl)-1-cydopentanecarboxylic acid (112 mg, 0. 5 mmol) is transformed into the con-esponding acid chloride, which in tum gave the 1-(4-chlorophenyl)-1-cyclopentyl isocyanate. This isocyanate is reacted with 2-amino-thiazole (100 mg, 1.0 mmol) to obtain N-[1-(4-chlorophenyl)cyclopentyl]-N'-1.3-thiazol-2-ylurea(115mg, 72%). LCMS (m/z): 322 (M + H)"
'H NMR (400 MHz, CDCI3): 61.83 (m, 4H). 2.04 (m, 2H), 2.30 (m, 2H), 6.78 (d, 1H), 7.25-7.36(m,5H), 10.00 (br.2H).

Example 115
N-f1-(4-Chlorophenvl)cvclopentvn-N'-Pvridin-2-vlurea
cpA-O
\\ A H H N
Following general procedure H, 1-(4-chlorophenyl}-1-cyclopentanecarboxylic acid (112 mg, 0. 5 mmol) is transfomied into the con-esponding acid chloride, which in tum gave the 1-(4-chlorophenyl)-1-cyclopentyl isocyanate. This isocyanate is reacted with 2-amino-oyridine (94 mg, 1.0 mmol) to obtain N-[1-(4-chlorophenyl)cyclopentyl]-N'-pyridin-2-ylurea [108mg,68%). LCMS(m/z):316(M+Hr
'H NMR (400 MHz, CDCI3): 6 1.80-1.92 (m, 4H), 2.02-2.09 (m, 2H), 2.36-2.40 (m, 2H), 6.32 ;d, 1H), 6.83 (dd, 1H), 7.25 (m, 2H), 7.41 (m, 2H), 7.49 (m, 1H). 8.12 (d, 1H), 8.87 (br, IN), 3.94(br, 1H).
Example 116
Nl-[1 -(4-Chlorophenvl)cvclohexvn-N'-1.3-thiazol-2-vlurea


H H N

Following general procedure H, 1-{4-chlorophenyl)-1-cyclohexanecarboxylic acid 119 mg, 0. 5 mmol) is transfomied into the corresponding acid chloride, which in tum gave he 1-(4-chlorophenyl)-1-cyciohexyl isocyanate. This isocyanate is reacted with 2-amino-tiiazole (100 mg, 1.0 mmol) to obtain N-{1-(4-chlorophenyl)cyclohexyl]-N'-1,3-thiazol-2-1urea(104mg, 62%). .CMS (m/z): 336 (M+H)*
H NMR (400 MHz, CDCI3): 6 1.28 (m, 1H), 1.57-1.76 (m, 7H), 2.26 (d, 2H), 6.80 (d, 1H), .24-7.34 (m, 5H), 10.00 (br, 2H).

Example 117
N-[1-(4-Chlorophenvi)cvclohexvil-N'-pvridin-2-vlurea

Following general pnacedure H, 1-(4-chlorophenyi)-1-cyclohexanecarboxyiic acid (119 mg, 0. 5 mmol) is transformed into the corresponding acid chloride, which in turn gave the 1-(4-chlorophenyl)-1-cyclohexyl isocyanate. This isocyanate is reacted with 2-amino-pyridine (94 mg, 1.0 mmol) to obtain N-[1-(4-chlorophenyI)cydohexyl]-N'-pyridin-2-ylurea (106mg,65%). LCMS(m/z):330(M+H)*
H NMR (400 MHz, CDCI3): 8 1.27 (m, 1H), 1.67-1.80 (m, 7H), 2.38 (m, 2H), 6.30 (br, 1H), 6.87 (m, 1H), 7.25-7.41 (m, 4H). 7.51 (d, 1H), 8.17 (s, 1H), 8.40 (br, 1H), 10.09 (br. 1H).

Example 118
1-f3-Benzvloxvphenv!)-1-/-butvl-3-(thiazol-2-vl)urea

'v
T H CH,

1-(3-Benzyloxypheny!)-1-/-butyl-3-(thiazol-2-yl)urea (27 mg, 70.9%) is prepared from (3-benzyloxyphenyl)-;-butyl amine (25 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS (m/z): 382 (M+H)*
'H NMR (400 MHz. CDCI3): 6 1.00 (d, 6H), 2.21 (d, 2H), 2.36 (s, 2H), 3.02 (m, 1H), 6.84 (d, 1H), 7.09 (m, 2H). 7.16 (t, 1H), 7.24 (s, 1H), 7.25 (m, 4H), 7.57 (d, 1H). 7.96 (d, 1H), 8.23 (br, 1H).


Example 119
1-f3,4-Dichlorophenvl)-1-i-butvl-3-fthiazol-2-vnurea
1-(3,4-Dichlorophenyi)-1-hbutyl-3-(thiazol-2-y!)urea (24 mg, 70%) is prepared from ;3,4-dichlorophenyl)-/-butyl amine (20 mg, 0.1 mmol) following the general procedure X to afford the title compound. -CMS (m/z): 344 (M+H)"
H NMR (400 MHz, CDCI3): J 0.97 (d, 6H), 1.85 (m, 1H), 3.59 (d, 2H), 7.16 (s, 1H), 7.28 (d, 2H), 7.42 (dd, IN), 7.56 (d, 1H), 8.80 (br, 1H).
Example 120
I -(4-Fluorophenvl)-1 -n-Dentvl-3-(thiazol-2-vl)urea
H3C.
H
1-(4-Fluorophenyl)-1-n-pentyl-3-(thlazol-2-yl)urea (24 mg, 74.9%) is prepared from 4-fluorophenyl) n-pentyl amine (18 mg, 0.1 mmol) following the general procedure X to ifford the title compound. .CMS(m/z):308(M+H)*
H NMR (400 MHz, CDCI3): 6 0.87 (t, 3H), 1.30 (m 4H), 1.58 (m, 2H), 3.71 (t, 2H). 6.87 d.lH), 7.24 (m, 4H), 7.29 (d, 1H), 7.60 (br, 1H).

Example 121
1-f3.4-Methvlenedioxvbenzvi)-1-f3.4-dichlorobenzvl)-3-(thiazol-2-vl)urea


H

1-(3,4-Methylenedioxybenzyl)-1-(3,4-dichlorobenzyl)-3-(thiazol-2-yl)urea (29 mg, 66.5%) is prepared from N-(3,4-methylenedioxybenzyl)-N-(3,4-dichlorobenzyl) amine (30 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):436(M+H)*
H NMR (400 MHz, CDCI3): d4.43 (s, 2H), 4.53 (s, 2H). 5.96 (s, 2H), 6.76 (d. 1H), 6.84 (s, 1H), 7.19 (s, 1H), 7.31 (d, 2H), 7.40 (d, 2H), 8.38 (d, 1H), 9.73 (br, 1H).

Example 122
1-(4-Fluorophenvl)-1-cvclopentvl-3-(thiazol-2-vl)urea

(XX."


1-(4-Fluoroyphenyl)-1-cyclopentyl-3-(thiazol-2-yi)urea (19 mg, 62.2%) is prepared from 4-fluorophenyl cyclopentyl amine (18 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):306(M+H)*
H NMR (400 MHz, CDCI3): 6 1.25 (m, 4H), 1.55 (m, 2H), 1.96 (m, 2H). 4.85 (p, 1H), 6.85 (d. 1H), 7.19 (m, 2H), 7.25 (m, 2H), 7.67 (br, 1H), 8.18 (d. 1H).

Example 123
1-(3,4-Dichloroben2vl)-1-[ethvl-(2-thiophenen-3-(thiazol-2-vibrea

1-(3.4-Dichlorobenzy!)-1-[2-(2-thienyl)ethyl]-3-(thia2ol-2-yl)urea (33 mg. 80.3%) is prepared from 3,4-dichlorobenzyl [2-(2-thienyl)ethyl] amine (28 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):412(M+H)*
'H NMR (400 MHz, CDCI3): tf 3.10 (t. 2H), 3.62 (t, 2H), 4.45 (s, 2H), 6.84 (dd, 2H), 6.94 (m, 1H), 7.15 (t, 1H), 7.29 (d, 1H), 7.38 (s, IN), 7.40 (m, 1H), 8.02 (d, 1H), 9.74 (br, IN).
Example 124
1-(3,4-Dichlorobenzvl)-1-/-butvl-3-(thiazol-2-v!)urea CH.,

1-(3,4-Dichlorobenzyl)-1-/-butyl-3-(thiazol-2-yl)urea (26 mg, 72.2%) is prepared from 3,4-dichlorobenzyl butyl amine (23 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):358(M+H)'
H NMR (400 MHz, CDCI3): 6 0.92 (d, 6H), 2.03 (m, 1H), 3.11 (d, 2H), 4.59 (s, 2H), 6.88 (d, 1H), 7.08 (dd, 1H). 7.32 (m, 2H), 7.41 (d, 1H), 8.66 (br, 1H).

Example 125
1 -(4-FluoroDhenvlV1 -cvclohexvlmethvl-3-fthiazol-2-vl)urea

1-(4-Fluorophenyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea (20 mg, 60%) is prepared from cyclohexylmethyl 4-fluorophenyl amine (21 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):334(M+H)*
H NMR (400 MHz. CDCI3): rf 1.06 (m, 2H), 1.17 (m, 4H), 1.52 (m, 1H), 1.71 (m, 4H), 3.59 (d, 2H), 6.86 (d. 1H), 7.18 (d. 1H), 7.24-7.31 (m, 4H), 7.64 (br. 1H).
Example 126
1 -(3-Chloropheneth vl>-1 -i-butvl-3-(thiazol-2-vl )urea
H3C

CH,

I H

<<

1-(3-Chlorophenethyl)-1-/-butyl-3-(thiazol-2-yi)urea (22 mg, 65.3%) is prepared from (3-chlorophenethyl) /-butyl amine (20 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):338(M+H)*
'H NMR (400 MHz, CDCI3): S 0.92 (d, 6H), 1.99 (m, 1H), 2.90 (t, 2H), 3.02 (d, 2H). 3.56 (t, 2H), 6.87 (d. 1H), 7.11 (s. 1H), 7.21 (d. 2H), 7.23 (s. 1H), 7.34 (d, 1H). 8.31 (br, 1H).

Example 127
1 -(2-Ethoxvbenzvl)-1 -i-Butvl-3-(thia20l-2-vnurea CH3
I H
1-(2-Ethoxyphenyl)-1-/-butyl-3-(thiazol-2-yl)urea (23 mg, 69%) is prepared from (2-ethoxypheny!) (-butyl amine (20 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):320(M+H)*
'H NMR (400 MHz. CDCI3): 6 0.94 (d. 6H), 1.48 (t, 3H), 2.11 (m, 1H). 3.28 (d, 2H), 4.17 (q, 2H), 4.53 (s. 2H). 6.83 (d, 1H). 6.92 (dd. 1H). 7.20 (d. 1H), 7.23 (s. 1H). 7.31 (m. 2H). 8.76 (br. 1H).
Example 128
1-(4-Fluorophenvl)-1(4-tetrahvdrothiopvranvl)-3-fthiazol-2-vl)urea

F 1-(4-Fluorophenyl)-1-(4-tetrahydrothiapyranyl)-3-(thiazol-2-yl)urea (25 mg. 73.7%) is prepared from 4-fluorophenyi 4-tetrahydrothiapyranyl amine (21 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):338(M+H)*
H NMR (400 MHz, CDCI3): 6 1.49 (m. 2H). 2.20 (d, 2H), 2.65 (d. 2H), 2.84 (2H), 4.51 (m. 1H), 6.86 (d, 1H), 7.19 (d, 2H), 7.21 (d, 1H), 7.25 (d. 2H), 7.46 (br, 1H).

Example 129
1-f3.4-Dichlorobenzvl)-1-cvclohexvlmethvl-3-(thiazol-2-vl)urea


H

1-(3,4-Dichlorobenzyl)-1-cyclohexylmethyl-3-(thiazol-2-yl)urea (30 mg, 75.6%) is prepared from N-(3,4-dichlorobenzyl)-N-(cydohexylmethyl)amine (26 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS {miz): 398 (M+ H)*
H NMR (400 MHz. CDCI3): rf 0.92 (m. 2H), 1.16-1.23 (m, 3H), 1.69-1.74 (m, 6H), 3.11 (d, 2H), 4.58 (s, 2H), 6.88 (d, 1H), 7.10 (d. 1H). 7.30 (d, 2H), 7.32 (s, 1H), 8.58 (br, 1H).
Example 130
1 -(3-Methvlpvridine)-1 -(cvclohexvlmethvl)-3-(thiazol-2-vl)urea


H

-N

1-(3-Pyridinylmethyl)-1-cyclohexyimethyl-3-(thiazol-2-yl)urea (26 mg, 78.8 %) is prepared from N-(3-pyridinylmethyl)-N-(cyclohexylmethyt)amine (20 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS (m/z): 331 (M+H)*
'H NMR (400 MHz, CDCI3): 6 1.25 (m, 4H), 1.56 (m, 6H), 1.74 (m, 1H), 2.17 (d, 2H), 4.63 (s, 2H), 6.88 (d, 1H), 6.93 (d, 1H), 7.29 (s, 1H), 7.34 (d, 1H), 7.66 (d, 1H), 8.54 (d, 1H). 9.45 (br, 1H).

Example 131
1-(2-Ethoxvbenzvl)-1-cvclohexvlmethvl-3-(thiazol-2-vi)urea

1-(2-Etlioxybenzyl)-1-cyclohexyimethyl-3-(thiazol-2-yl)urea (29 mg, 77.7 %) is prepared from N-(2-ethoxybenzyl)-N-(cyclohexylmethyl)amine (24 mg, 0.1 mmol) following the general procedure X to afford the title compound. LCMS(m/z):374(M+H)*
H NMR (400 MHz, CDCI3): 90% CH3CN 40min., 20ml/min., Rt=35min Solvent A=water, ;olvent B=CH3CN, solvent C=0.5% TFA/water). iPLC-MS (Method B): m/z = 447 (M+1); Rt = 4.92 min

The above [2-(3-cyclohexyl-2-(4-methoxyphenoxy)propionylamino)thiazol-4-yl]acetic acid ethyl ester (0.05 g, 0.11 mmol) was dissolved in EtOH (5 ml), NaOH (IN, 1 ml) was added and the reaction-mixture was standing 2 hours. The solvent was evaporated in vacuo, water (5 ml) was added and pH was adjusted with IN HCI to acidic. The resulting precipitation was filtered, washed with water and dried in a vacuum-owen to give the title compound.
'H-NMR (DMSO-de): Selected data 612.51 (s, 1H); 12.41(s, 1H); 6.98 (s, 1H); 6.84 (s. 4H): 4.85 (m, 1H); 3.67 (s, 3H); 3.60 (s, 2H); HPLC-MS (Method B): m/z = 419 (M+1); R, = 4.74 min
Example 141
1 -Cvclopentvlmethvl-1 -f3,4-dichloro-phenyl)-3-thiazol-2-vl-urea

CI
CI
3,4-Dichloroaniline (16.1 g, 100 mmol) is dissolved in dry THF (200 ml) in a round-bottomed flask, and then cyclopenthylcarboxyaldehyde (9.81 g, 100 mmol) is added to the solution and stirred for 10 min at rL Molecular sieves (4 g, 4 A°) is added to the reaction mixture followed by addition of sodium triacetoxyborohydride (21.1 g, 200 mmol) and the mixture stirred at 25°C for 12 h. The reaction mixture is then filtered through silica gel, washed with saturated sodium bicarbonate (200 ml) and extracted with ethyl acetate (3x200 ml). The organic extracts are combined, dried (sodium sulfate), filtered, and condensed in vacuo to give N-cyclopenthylmethyl-3,4-dichloroaniline (23. 8 g, 98.7%) as an oil (LC-MS: m/z = 245 (M+1), R, = 2.92 min).
W-cyclopentylmethyl-3,4-dichloroaniline (1.21 g, 5.00 mmol) is dissolved in dry DCM (25 ml) and triethylamine (1.4 ml, 10.0 mmol) is added to the solution. Then triphosgene (2.97 g, 10.0 mmol) is added at -20°C and resulting mixture is stirred and allowed to warm up to 25°C within 3 h. On warming to rt., 2-aminothiazole (0.50 g, 5.0 mmol) is added to the reaction mixture and stirred for 12 h. Followed by TLC and LC-MS, upon consumption of

starting material, the mixture is washed with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts are combined, dried (sodium sulfate), filtered, and condensed in vacuo to give 1-cyclopentyl-1-(3,4-dichloro-phenyl)-3-thiazol-2-yl-urea (1.42 g, 76.5%) as a pale yellow solid.
LC-MS:m/z371 (M+1)*
Example 142
1 -Cyclopentyl-I -(3.4-dichloro-phenvl)-3-thiazol-2-vl-urea

CI
Sodium triacetoxyborohydride (5.3 g, 25.0 mmol) is added batchwise to a stirred solution of 3,4-dichloroaniline (1.62 g, 10.0 mmol), cyclopentanone (1.80 ml, 20.0 mmol) and acetic acid (3.4 ml, 60.0 mmol) in 75 ml 1,2-dichloroethane. The resulting suspension is stirred for 48 h at 25°C. The reaction mixture is given an aqueous workup with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts are dried and concentrated in vacuo to give N-cydopentyl-3,4-dichloroaniline which is used without further purification.
Carbonyldiimidazole (178 mg, 1.1 mmol) is added to a THF solution of N-cyclopentyl-3,4-dichloroaniline (230 mg, 1.0 mmol). The mixture is stirred for 1 h at 25°C, after which time 2-aminothiazole (100 mg, 1.0 mmol) is added. The reaction is then stirred for 16 h at 25°C The reaction mixture is concentrated and residue purified by silica gel chromatography to afford 1-cyclopentyl-1-(3,4-dichloro-phenyl)-3-thiazol-2-yl-urea as a solid (30 mg. 10% yield).
LC-MS:m/z379(M+1)*


Example 143
1 -(3,4-Dichloro-phenv!)-1 -propvl-3-thiazol-2-vl-urea CH,
CI
2-Aminothiazole (5.0 g, 50.0 mmol) is dissolved in DCE (20 ml), then solid supported 2-(4-formyl-3-methoxyphenoxy) ethyl polystyrene (6.9 g, 10.0 mmol, loading: 1.46 mmol/g) Is added to the solution and stin-ed for 30 min. Acetic acid (2.1 ml, 5.0 mmol) is added to the mixture followed by addition of sodium triacetoxyborohydride (10.56 g, 50.0 mmol). The resin mixture is shaken at rt for 16 h, then washed with three cycles of DMF/methanol/DCM. Then the resin is dried in vacuo to give solid-supported 2-aminothia-zole.
The coaesponding above solid-supported starting material 2-amino thiazoyl-A/-2-(3-methoxybenzyloxy)ethyl polystyrene (5.0 g, 7.3 mmol) is treated with triphosgene (5.30 g, 17. 8 mmol) In the presence of DCM (25 ml) and diisopropylethylamine (7.63 ml, 43.8 mmol). The product on solid support is then washed with DCM. Then the resin is dried in vacuo to give corresponding carbamyl chloride N [2-(3-methoxybenzyloxy)ethyl polystyrene-2-amino thiazoyi chloride.
The corresponding carbamyl chloride resin (1.0 g, 1.46 mmol) is treated with 3,4-di-chloroaniline (1.17 g, 7.30 mmol) in the presence of DCE (25 ml) and diisopropylethylamine (2.54 ml, 14.6 mmol). The product on solid support is then washed with three cycles of DMF/methanol/DCM, dried in vacuo to give con-esponding urea N [2-(3-methoxybenzyloxy) ethyl polystyrene-2-amino thiazoyl-A/'-3,4-dichlorophenyl urea.
To the corresponding urea (A/ [2-(3-methoxybenzyloxy) ethyl polystyrene-2-amino thiazoyl-3,4-dichlorophenyl urea) (0.117 g. 0.73 mmol) is added potassium /-butoxide (3.65 ml, 3.65 mmol, 1M solution in THF). The resin mixture is shaken for 1 h at rt, and then 1-bromopropane (0.332 ml, 3.65 mmol) is added to the resin mixture and shaken for 16 h. The product on solid support is then washed with three cycles of DMF/methanol/DCM, dried in vacuo to give corresponding propylated urea N [2-(3-methoxybenzyloxy) ethyl polystyrene-2-amino thiazoyi, A/'-(3,4-dichlon3phenyl)-W- propyl urea.

The corresponding above urea is then treated with TFA (5 ml, 5% DCM solution) to cleave the solid support to give the title compound 1-{3,4-dichloro-phenyl)-1-propyl-3-thiazol-2-yl-urea (0.163 g, 67.9%) as a pale yellow solid.
LC-MS:m/z331 (M+1)*

BIOLOGICAL ASSAY
Glucokinase Activity Assay (I)
Glucokinase activity is assayed spectrometrically coupled to glucose 6-phosphate dehydrogenase to detemnine compound activation of glucokinase. The final assay contains 50 mM Hepes, pH 7.1, 50 mM KCI, 5 mM MgCb, 2 mM dithiothreitol, 0.6 mM NADP, 1 mM ATP, 0.195 pM G-6-P dehydrogenase (from Sigma), 15 nM recombinant human glucokinase. The glucokinase is human liver glucokinase N-temiinally truncated with an N-terminal His-tag
((His)8-VEQILA Q466) and is expressed in E.coli as a soluble protein with enzymatic
activity comparable to liver extracted GK. This glucokinase is minor splice variant from human liver (Proc. Natl. Acad. Sci. U.S.A. 88,7294-7297 (1991). As stated, the gene is
truncated N-terminally and with a His-tag {(His8)- VEQILA Q466), according to standard
procedures. The truncated fonn represents both GK variants from liver and the pancreatic glucokinase, the amino acid sequence being fully conserved downstream of the first 15 amino acids N-terminally. The protein is expressed as a soluble protein in E.coli BL21 DE3 under control of the T7 promoter. The enzymatic activity of the His-tagged, N-tenninaily truncated recombinant glucokinase is comparable to liver extracted GK. Purification of His-tagged Human Glucokinase (hGK) is performed as follows: E. coli cell pellet from 50 ml culture is resuspended in 5 ml extraction buffer A (25 mM HEPES, pH 8.0,1 mM MgCla, 150 mM NaCI, 2 mM Mercaptoethanol) with addition of 0.25 mg/mi lysozyme and 50 pg/ml sodium azide. After 5 minutes at room temperature 5 ml of extraction buffer B (1.5 M NaCI, 100 mM CaCl2,100 mM MgCl2, 0.02 mg/ml DNase 1, Protease inhibitor tablet: 1 tablet pr. 20 ml buffer) is added. The extract is then centrifugated at 15.000 g for 30 minutes. The resulting supernatant is loaded on a 1 ml Metal Chelate Affinity Chromatography (MCAC) Column charged with Ni*. The column is washed with 2 volumes buffer A containing 20 mM imidazole and the bound his-tagged hGK is subsequently eluted using a 20 minute gradient of 20 to 500 mM imididazol in buffer A. Fractions are examined using SOS-gel electrophoresis, and fractions containing hGK (MW: 52 KDa) are pooled. Finally a gelfiltration step is used for final polishing and buffer exhange. hGK containing fractions are loaded onto a Superdex 75 (16/60) gelfiltration column and eluted with Buffer B (25 mM HEPES, pH 8.0, 1 mM MgCl2,150 mM NaCI, 1 mM Dithiothreitol). The purified hGK is examined by SDS-gel electrophoresis and MALDI mass spectrometry and finally 20 % glycerol is added before freezing. The yield from 50 ml E. coli culture is generally approximately 2-3 mg hGK with a purity >90%,

The compound to be tested is added into the well in final 2.5% DMSO concentration in an amount sufficient to give a desired concentration of compound, for instance 50 pM. The reaction starts after glucose is added to a final concentration of 2 mM. The assay uses a 96-well UV plate and the final assay volume used is 200 pl/well. The plate is incubated at 25°C for 5 min and kinetics is measured at 340 nm in SpectraMax every 30 seconds for 5 minutes. Results for each compound are expressed as the fold activation of the glucokinase activity compared to the activation of the glucokinase enzyme in an assay without compound after having been subtracted from a "blank", which is without glucokinase enzyme and without compound. The compounds in each of the Examples exhibits activation of glucokinase in this assay. A compound, which at a concentration of at or below 30 pM gives 1.3- fold higher glucokinase activity than the result from the assay without compound, is deemed to be an activator of glucokinase.
While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the present invention. For example, effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for glucokinase-deficiency mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention.

WE CLAIM :
1. A compound of the general formula (III);

X is a direct bond, -0-, -S-, -S(0)-, -S(02)-, or -N(R6)-, wherein
R2 is hydrogen or all