MXPA06010261A - Substituted heteroaryl- and phenylsulfamoyl compounds - Google Patents

Abstract

The present invention is directed at substituted heteroaryl- and phenylsulfamoyl compounds, pharmaceutical compositions containing such compounds and the use of such compounds as peroxisome proliferator activator receptor (PPAR) agonists. PPAR alpha activators, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans. The compounds are also useful for the treatment of negative energy balance (NEB) and associated diseases in ruminants.

Description

SUBSTITUTE HETEROARIL- AND FENILSULFAMOILO COMPOUNDS BACKGROUND OF THE INVENTION The present invention relates to substituted heteroaryl- and phenylsulfamoyl compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds as agonists of the peroxisome proliferator activating receptor (PPAR). The present compounds are particularly useful as PPARa agonists and for treating atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, osteoporosis and Syndrome x (also known as metabolic syndrome) in mammals, including humans. The compounds are also useful for the treatment of negative energy balance (NEB) and associated diseases in ruminants. It is recognized that atherosclerosis, a disease of the arteries, is 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 of this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow due to the presence of lipid deposits that are found mainly in smooth muscle cells and in macrophages of the inner layer of the arteries and the aorta. In addition, it is postulated that most of the cholesterol found in fatty streaks, in turn, gives rise to the development of the "fibrous plaque", which consists of cumulative lipid-laden and inner packed smooth muscle cells. of extra-cellular lipids, collagen, elastin and proteoglycans. These cells plus the matrix form a fibrous layer that covers a deeper deposit of extracellular cellular debris and lipids. Lipids are mainly free cholesterol and esterified. The fibrous plaque forms slowly and probably calcifies and becomes necrotic over time, advancing to the "complicated lesion", which justifies arterial occlusion and the tendency to mural thrombosis and arterial muscle spasms that characterize advanced atherosclerosis. Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in the cause of cardiovascular disease (CVD) due to atherosclerosis. In recent years, the leaders of the medical profession have placed a renewed emphasis on the reduction of plasma cholesterol levels and low density of lipoprotein cholesterol in particular, as an essential step in the prevention of CVD. Now it is known that the upper limits of "normal" are significantly lower than those appreciated so far. As a result, it has become clear that large segments of Western populations are at particularly high risk. Additional independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension and being male. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part due to the existence of multiple independent risk factors in this population. The satisfactory treatment of hyperlipidemia in the general population and in diabetic subjects in particular, is therefore of exceptional medical importance.

Despite the recent discovery of insulin and its subsequent widespread use in the treatment of diabetes and the subsequent discovery and use of sulfonylureas, biguanides and thiazolidendiones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycaemic agents, the treatment of Diabetes could be improved. The use of insulin typically requires multiple daily doses. The determination of the best insulin dosage requires frequent estimates of sugar level in urine or blood. The administration of an excessive dose of insulin causes hypoglycaemia, with effects ranging from mild abnormalities in the level of blood glucose to coma, or even death. The treatment of non-insulin-dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, for example, thiazolidendiones, and in the most severe cases, insulin. However, clinically available hypoglycemic agents can have side effects that limit their use. In the case of insulin-dependent diabetes mellitus (Type I), insulin is usually the first route of therapy. In this way, although there are several anti-atherosclerosis and diabetes therapies, there is a need and continuous search in this field of technique for alternative therapies. In addition, the negative energy balance (NEB) is a problem that is frequently found in ruminants, particularly dairy cows. NEB can be experienced at any time during the life of the cows but is particularly prevalent during the transition period. The period of transition in ruminants is defined as the time period from late gestation to early lactation. This is sometimes defined as a period of 3 weeks before to three weeks after delivery, but has been extended to a period of 30 days before 70 days postpartum (JN Spain and WA Scheer, Tri-State Dairy Nutrition Conference, 2001, 13). The energy balance is defined as the energy intake minus the energy production and it is said that an animal is in negative energy balance if the energy intake is insufficient to meet the demands of maintenance and production (for example, milk) . A cow in NEB has to find the energy to face the deficit of its body reserves. In this way, the cows in NEB tend to lose body condition and live weight, so that cows that have more energy deficiency tend to lose the condition and weight with greater speed. It is important that the balance of energy and minerals and the general health of the cow be well managed in the transition period, since this interval is critically important for the subsequent health, production and profitability in dairy cows. Long-chain fatty acids (or non-esterified fatty acids, NEFA) are also mobilized from body fat. NEFAs, already elevated from approximately 7 days before calving, are a significant source of energy for the cow during the early postpartum period, and the higher the energy deficit, the higher the NEFA concentration in the blood. Some workers suggest that in the early breastfeeding period (see Bell earlier and references in that document) the breast uptake of NEFA explains some synthesis of milk fat.

Circulating NEFAs are picked up by the liver and oxidized to carbon dioxide or ketone bodies, including 3-hydroxybutyrate, by mitochondria or reconverted by esterification into triglycerides and stored. In non-ruminant mammals it is believed that the entry of NEFA into mitochondria is controlled by the enzyme carnitine palmitoyltransferase (CPT-1), however, some studies have shown that in ruminants there is a small change in CPT-1 activity during the transition period (GN Douglas, JK Drackley, TR Overton, HG Bateman, J. Dairy Science, 1998, Suppl 1, 81, 295). In addition, the capacity of the ruminant liver to synthesize very low density lipoproteins to export the triglycerides from the liver is limited. Significantly, if uptake of NEFA by bovine liver becomes excessive, accumulation of ketone bodies can lead to ketosis and excessive storage of triglycerides can lead to a fatty liver. Fatty liver can lead to prolonged recovery from other disorders, increased incidence of health problems and development of "dropping cows" that die. In this way, fatty liver is a metabolic disease of ruminants, particularly dairy cows of high production, in the transition period that negatively impacts on disease resistance (abomasal displacement, lameness), immune function (mastitis, metritis ), reproductive function (oestrus, calving interval, fetal viability, ovarian cystis, metritis, retained placenta) and milk production (peak milk yield, milk yield at 305 days). Fatty liver has developed largely on the day after childbirth and precedes an induced (secondary) ketosis. It is usually the result of an increase in the esterification of NEFA absorbed from the blood together with the low capacity of the ruminant liver to secrete triglycerides as very low density lipoproteins. Improving the energy balance or treating the negative energy balance, will reduce the negative scope of the sequels. This is addressed by the compounds of the present invention. SUMMARY OF THE INVENTION The present invention relates to compounds of Formula I Formula I or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug, wherein Q is carbon; each R1 is independently hydrogen, halo, (C1-C5) alkyl optionally substituted with one or more halo or with (C1-C3) alkoxy, (C5) alkoxy optionally substituted with one to eleven halo, (C1-C5) alkylthio optionally substituted with one or more halo, or R1 together with the two adjacent carbon atoms forms a C5-C6 carbocyclic ring of five or six condensed members, fully saturated, partially unsaturated or fully unsaturated where each carbon in the carbon chain can be optionally replaced by a heteroatom selected from oxygen and sulfur; R2 is hydrogen or (C1-C5) alkyl optionally substituted with d-C3 alkoxy; X is -COOR4, -0- (CR32) -COOR4, -S- (CR32) -COOR4, -CH2- (CR5W) - COOR4, 1H-tetrazol-5-yl-E- or thiazolidinedione-5-yl-G -; where w is 0, 1 or 2; E is (CH2) r and r is 0, 1, 2 or 3 and G is (CH2) S or methylidene and s is 0 or 1; each R3 is independently hydrogen, (C1-C4) alkyl optionally substituted with one to nine halo or with (C1-C3) alkoxy optionally substituted with one or more halo, or R3 and the carbon to which it is attached form a carbocyclic ring of 3 , 4, 5 or 6 members; R 4 is H, (C 1 -C 4) alkyl; benzyl or p-nitrobenzyl each R5 is independently hydrogen, (C1-C4) alkyl optionally substituted with one to nine halo or with (C1-C3) alkoxy, (d-C4) alkoxy optionally substituted with one to nine halo, alkylthio (C1) -C4) optionally substituted with one to nine halo or with (C1-C3) alkoxy, or R5 and the carbon to which it is attached form a carbocyclic ring of 3, 4, 5 or 6 members in which any carbon in a ring of 5 or 6 members can be replaced by an oxygen atom; Ar 1 is phenyl or phenyl fused to a member selected from thiazolyl, furanyl, oxazolyl, pyridine, pyrimidine, phenyl or thienyl, where Ar 1 is optionally mono-, di- or tri-substituted independently with: halo, alkyl (C1-C3) optionally substituted with from one to nine halo or (C1-C3) alkoxy optionally substituted with one to nine halo or (C1-C3) alkylthio optionally substituted with one to nine halo; B is a bond, CO, (CY2) n, CYOH, CY = CY, -L- (CY2) n-, - (CY2) nL-, -L- (CY2) 2-L-, NY-OC-CONY -, -S02NY -, - NY-SO2- where each L is independently O, S, SO or SO2, each Y is independently hydrogen or (C1-C3) alkyl and n is 0, 1, 2 or 3; Ar2 is a bond, phenyl, phenoxybenzyl, phenoxyphenyl, benzyloxyphenyl, benzyloxybenzyl, pyrimidinyl, pyridinyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazole or phenyl fused to a ring selected from the group consisting of: phenyl, pyrimidinyl, thienyl, furanyl , pyrrolyl, thiazolyl, oxazolyl, pyrazolyl and imidazolyl; each J is independently hydrogen, hydroxy, halo, alkyl (Ci-Cß) optionally substituted with one to eleven halo, alkoxy (Ci-Cß) optionally substituted with one to eleven halo, alkylthio (Ci-Cs) pp-substituted with one a eleven halo, (C3-C7) cycloalkyl, (C3-C7) cycloalkoxy, (C3-C7) cycloalkylthio or phenyl optionally substituted with one to four substituents selected from the group consisting of: halo, (C1-C3) alkyl optionally substituted with one to five halo, (C1-C3) alkoxy optionally substituted with one to five halo, (C1-C3) alkylthio optionally substituted with one to five halo; each of p and q are independently 0,1, 2 or 3; and with the conditions: a) if Ar1 is phenyl, B is a bond, Ar2 is a bond or phenyl and X is -COOH, then q is different from 0 and J is different from hydrogen, halo, alkyl (Ci-Cs) or unsubstituted phenyl; b) if Ar1 is phenyl, B is not a bond, Ar2 is phenyl and X is -COOR4 then B binds Ar1 in position para to NR2; and c) if B is O, S, SO, NH, CO, CH2 or SO2 then R1 is not H.

The present application also relates to methods to treat dyslipidemia, obesity, overweight condition, hypertriglyceridemia, hyperlipidemia, hypoalphaloproteinemia, metabolic syndrome, diabetes mellitus (Type I and / or Type II), hyperinsulinemia, impaired glucose tolerance, insulin resistance , diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, thrombosis, peripheral vascular disease, cognitive dysfunction or congestive heart failure in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of any of claims 1-18, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug. The present application also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug and a pharmaceutically acceptable excipient, carrier or diluent. In addition, the present application relates to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug; a second compound, said second compound being a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of the gene expression of HMG-CoA reductase, an inhibitor of HMG-gene expression CoA synthase, an inhibitor of MTP / Apo B secretion, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, an inhibitor of squalene epoxidase, an inhibitor of squalene cyclase, an inhibitor of squalene epoxidase / squalene cyclase combined, a fibrate, niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor, a bile acid sequestrant or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug; and a pharmaceutically acceptable excipient, vehicle or diluent. In addition, the present invention relates to methods for treating atherosclerosis in a mammal comprising administering to a mammal in need of treatment thereof: a first compound, said first compound being a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug; and a second compound, said second compound being a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a HMG-CoA reductase gene expression inhibitor, a gene expression inhibitor of HMG-CoA synthase, an inhibitor of the secretion of MTP / Apo B, a CETP inhibitor, an inhibitor of the absorption of bile acids, an inhibitor of the absorption of. cholesterol, an inhibitor of cholesterol synthesis, an inhibitor of squalene synthetase, an inhibitor of squalene epoxidase, an inhibitor of squalene cyclase, a squalene epoxidase / squalene cyclase inhibitor combined, a fibrate, niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor, or a bile acid sequestrant where the amounts of the first and second compounds result in a therapeutic effect. In addition, the present application also relates to kits for achieving a therapeutic effect in a mammal comprising co-packaging a first therapeutic agent comprising a therapeutically effective amount of a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt. of said compound or prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG GoA reductase inhibitor, a CETP inhibitor, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, slow release niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and guidelines for the administration of said first and second agents to get the therapeutic effect eutychic Another aspect of the present invention is the use of a compound of formula I, in the manufacture of a medicament for the palliative, prophylactic or curative treatment of the negative energy balance in ruminants. Another aspect of the invention is the use of a compound of formula I, in the manufacture of a medicament for the palliative, prophylactic or curative treatment of the negative energy balance or a ruminant disease associated with the negative energy balance in ruminants, where it is prevented or relieves the excessive accumulation of triglycerides in the liver tissue and / or prevents or alleviates the excessive increase in the levels of non-esterified fatty acids in serum. Another aspect of the invention is that in which the ruminant disease associated with the negative energy balance in ruminants, as mentioned in the aspects of the invention herein, includes one or more diseases independently selected from fatty liver syndrome, dystocia, immune dysfunction, impaired immune function, poisoning, primary and secondary ketosis, fallen cows syndrome, indigestion, inappetence, retained placenta, displaced abomasum, mastitis (endo -) - metritis, infertility, low fertility and lameness, preferably fatty liver syndrome, primary ketosis, fallen cows syndrome, (endo -) - metritis and reduced fertility. Another aspect of the invention is the use of a compound of formula I, in the improvement of fertility, including decrease in the rates of return to service, normal oestrus cycle, better rates of conception and better fetal viability. Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of effective homeoresis to accommodate labor and lactogenesis. Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for improving or maintaining ruminant liver function and homeostatic signals during the transition period.

In one aspect of the invention, the compound of formula I is administered during the period of 30 days before delivery to 70 days after delivery. In another aspect of the invention, the compound of formula I is administered before delivery and, optionally, also at delivery. In still another aspect of the invention, the compound of formula I is administered after delivery. In still another aspect of the invention, the compound of formula I is administered at delivery. More preferably, the compound of formula I is administered during the period of 3 weeks before delivery to 3 weeks after delivery. In another aspect of the invention, the compound of formula I is administered up to three times during the first seven days after delivery. Preferably, the compound of formula I is administered once during the first 24 hours after delivery. In another aspect of the invention, the compound of formula I is administered before delivery and up to four times after delivery. In another aspect of the invention, the compound of formula I is administered at delivery and then up to four times after delivery. Another aspect of the invention is the use of the compound of formula I in the manufacture of a medicament for the palliative, prophylactic or curative treatment of the negative energy balance in ruminants and to increase the quality of the ruminant's milk and / or the performance of the milk. In a preferred aspect of the invention, the increase in milk quality is observed in a reduction of the levels of ketone bodies in the milk of the ruminant.

In another aspect of the invention, the peak milk yield is increased. Preferably, the ruminant is a cow or a sheep. In another aspect of the invention, a total increase in the yield of ruminant milk is obtained during the 305 days of the bovine lactation period. In another aspect of the invention, a total increase in the yield of ruminant milk is obtained during the first 60 days of the bovine lactation period. Preferably, the total increase in milk yield of the ruminant or the increase in the peak yield of milk or the increase in the quality of the milk is obtained from a dairy cow. In another aspect of the invention, the increase in the quality of the ruminant's milk and / or the milk yield is obtained after the administration of a compound of formula I to a healthy ruminant. In another aspect of the invention, a compound of formula I is provided, for use in veterinary medicine. The present application also relates to compounds having the Formula II Formula II or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or (C 1 -C 4) alkyl; Ar 1 is phenyl optionally mono-, di- or trisubstituted independently with: halo, (C 1 -C 3) alkyl optionally substituted with one to five halo or (C 1 -C 3) alkoxy optionally substituted with one to five halo or alkylthio (C 1 -) C3) optionally substituted with one to five halo; B is (CY2) n, O, S; -CH2S- or -CH2O and n is 1 or 2; Ar2 is phenyl or phenyl fused to a ring selected from the group consisting of; phenyl, pyrimidinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl and imidazolyl; each J is independently hydrogen, hydroxy; halo; alkyl (CrC8) optionally substituted with one to eleven halo; alkoxy (C-i-Cß) optionally substituted with one to eleven halo; alkylthio (C-i-Cs) optionally substituted with one to eleven halo; cycloalkyl (C3-C7); cycloalkoxy (C3-C7); cycloalkylthio (C3-C7); or phenyl optionally substituted with one or more: halo or (C 1 -C 3) alkyl optionally substituted with one to five halo or alkoxy (CrC) optionally substituted with one to five halo or (C 1 -C 3) alkylthio optionally substituted with one to five halo; and q is 0, 1, 20 3. It should be understood that both the above general description and the following detailed description are only illustrative and explanatory and do not restrict the invention, as claimed.

BRIEF DESCRIPTION OF THE FIGURE Figure 1 shows the levels of serum NEFA for the transition cows to which the compound Z was administered: 2-methyl-5- (4'-trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid (EXAMPLE 193), compared to the controls.

DETAILED DESCRIPTION OF THE INVENTION The present invention can be more easily understood by reference to the following detailed description of illustrative embodiments of the invention and the examples included therein. Before describing the present compounds, compositions and methods, it will be understood that this invention is not limited to specific synthetic manufacturing processes which can of course vary. It will also be understood that the terminology used in this document is for the sole purpose of describing particular embodiments and is not intended to be limiting. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids which are used to prepare pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as hydrochloride salts, hydrobromide, hydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, citrate acid, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-? b / s- (2-hydroxy-3-naphthoate)). The invention also relates to base addition salts of the compounds of the present invention. The chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of those compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or addition salts of water-soluble amines such as N-methylglucamine- (meglumine), and the lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines. The usual specialist chemist will recognize that certain compounds of this invention will contain one or more atoms that may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All those isomers and mixtures thereof are included in this invention. Also included are hydrates and solvates of the compounds of this invention. When the compounds of the present invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the R and S designations refer respectively to each stereogenic center in ascending numerical order (1, 2, 3, etc.). ) according to the conventional IUPAC numbering schemes for each molecule. When the compounds of the present invention possess one or more stereogenic centers and the stereochemistry is not given in the name or in the structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form. The compounds of this invention may contain olefin-type double bonds. When such bonds are present, the compounds of the invention exist in the form of cis and trans configurations and mixtures thereof. The term "cis" refers to the orientation of two substituents one with respect to the other and to the plane of the ring (both "up" or both "down"). Analogously, the term "trans" refers to the orientation of two substituents with respect to each other and to the plane of the ring (the substituents being on opposite sides of the ring). Alpha and Beta refer to the orientation of a substituent with respect to the plane of the ring. Beta is above the plane of the ring and Alpha is below the plane of the ring. This invention also includes isotopically-labeled compounds, which are identical to those described by Formulas I and II, except for the fact that one or more atoms are replaced by one or more atoms having an atomic mass or specific mass numbers. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 180, 17O, 18F and 36CI respectively. The compounds of the present invention, prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in tissue distribution assays of the drug and / or substrate. The isotopes tritium (ie, 3H) and carbon-14 (ie, 14C) are particularly preferred for their ease of preparation and detectability. In addition, replacement with heavier isotopes such as deuterium (i.e., 2H), can produce certain therapeutic advantages resulting from increased metabolic stability, for example increase of half-life in vivo or reduction of dosage requirements, and therefore , may be preferred in some circumstances. The isotopically-labeled compounds of this invention and prodrugs thereof can generally be prepared by performing the procedures described in the schemes and / or Examples shown below, substituting an isotopically-labeled reagent for an isotopically-readily available reagent. In this specification and the claims that follow, reference will be made to a number of terms that will be defined to have the following meanings: The term "treat" or "treatment" as used herein includes preventive treatment (e.g. , prophylactic) and palliative. As used herein, "therapeutically effective amount of a compound" means an amount that is effective to show therapeutic or biological activity at the site (s) of activity in a mammalian subject, without undue adverse side effects (such as undue toxicity, irritation or allergic response), in proportion to a reasonable benefit / risk ratio, when used as in the present invention. The term "cerebrovascular disease", as used herein, is selected, but not limited, from the group consisting of ischemic (eg, transient) attacks, ischemic (transient) stroke, acute stroke, cerebral apoplexy, hemorrhagic stroke, post-stroke neurological deficits, first stroke, recurrent stroke, reduced recovery time after a stroke, and provision of thrombolytic therapy for stroke. Preferred patient populations include patients with or without stroke or pre-existing coronary heart disease. The term "coronary artery disease", as used herein, is selected, but without limitation, from the group consisting of atherosclerotic plaque (e.g., prevention, regression, stabilization), vulnerable plaque (e.g., prevention, regression, stabilization), vulnerable plaque area (reduction), arterial calcification (eg, calcified aortic stenosis), increased coronary artery calcium level, dysfunctional vascular reactivity, vasodilation disorders, coronary artery spasm, myocardial infarction first, re- myocardial infarction, ischemic cardiomyopathy, stent restenosis, PTCA restenosis, arterial restenosis, restenosis by coronary bypass graft, vascular bypass restenosis, decreased time of routine exercise, angina / chest pain, unstable angina pectoris, dyspnea on exertion, decreased capacity for exercise, ischemia (reduce time to), silent ischemia (reduce time to), increased severity and frequency of ischemic symptoms, reperfusion after thrombolytic therapy for acute myocardial infarction. The term "hypertension", as used herein, is selected, but not limited, from the group consisting of lipid disorders with hypertension, systolic hypertension, and diastolic hypertension. The term "ventricular dysfunction", as used herein, is selected, but without limitation, from the group consisting of systolic dysfunction, diastolic dysfunction, heart failure, congestive heart failure, dilated cardiomyopathy, diopatic dilated cardiomyopathy, and undilated cardiomyopathy. . The term "cardiac arrhythmia," as used herein, is selected, but not limited, to the group consisting of atrial arrhythmias, supraventricular aminotrans, ventricular arrhythmias, and sudden death syndrome. The term "pulmonary vascular disease", as used herein, is selected, but not limited, from the group consisting of pulmonary hypertension, peripheral artery block and pulmonary embolism. The term "peripheral vascular disease", as used herein, is selected, but not limited, from the group consisting of peripheral vascular disease and claudication. The term "vascular hemostatic disease", as used herein, is selected, but not limited, to the group consisting of deep vein thrombosis, vaso-occlusive complications of sickle cell anemia, varicose veins, pulmonary embolus, seizures transient ischemic events, embolic events, including stroke, in patients with mechanical heart valves, embolic events, including stroke, in patients with right or left ventricular assist devices, embolic events, including stroke, in patients with intra-aortic balloon pump support , embolic events, including stroke, in patients with artificial hearts, embolic events, including stroke, in patients with cardiomyopathy, embolic events, including stroke, in patients with atrial fibrillation or atrial flutter.

The term "diabetes", as used herein, refers to any of several diabetogenic states including type I diabetes, type II diabetes, Syndrome X, metabolic syndrome, lipid disorders associated with insulin resistance, impaired tolerance to glucose, non-insulin dependent diabetes, microvascular diabetic complications, reduced nerve conduction velocity, reduction or loss of vision, diabetic retinopathy, increased risk of amputation, decreased renal function, renal failure, resistance syndrome to insulin, pluri-metabolic syndrome, central adiposity (visceral) (upper body), diabetic dyslipidemia, decreased insulin sensitivity, retinopathy / diabetic neuropathy, nephropathy / micro and macro angiopathy and diabetic micro / macroalbuminuria, diabetic cardiomyopathy, diabetic gastroparesis , obesity, increased glycosylation of hemoglobin (includes HbA1C), better control of glucose, impaired renal function (dialysis, final stage) and liver function (mild, moderate and severe). The terms "inflammatory disease, autoimmune disorders and other systemic diseases", as used herein, are selected, but not limited to, among the group consisting of multiple sclerosis, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, irritable bowel disease , Crohn's disease, colitis, vasculitis, lupus erythematosus, sarcoidosis, amyloidosis, apoptosis and disorders of complementary systems. The term "cognitive dysfunction", as used herein, is selected, but not limited, from the group consisting of dementia secondary to atherosclerosis, transient cerebral ischemic attacks, neurodegeneration (including Parkinson's, Huntington's disease, amyloid deposition and sclerosis). lateral amyotrophic), neuronal deficiency and delayed onset or progression of Alzheimer's disease. The "transition period" means from 30 days before delivery to 70 days after delivery. The term "treat", "treat" or "treatment" as used herein includes prophylactic, palliative and curative treatment. "Negative energy balance" as used in this document means that energy through food does not meet the maintenance and production (milk) requirements. The term "cow" as used herein includes heifer and primiparous and multiparous cows. "Healthy ruminant" means that the ruminant does not show signs of the following indications: fatty liver syndrome, dystocia, immune dysfunction, impaired immune function, poisoning, primary and secondary ketosis, fallen cows syndrome, indigestion, inappetence, placenta retained, displaced abomasum, mastitis, (endo -) - metritis, infertility, low fertility and / or lameness. "Quality" of the milk as used herein refers to milk levels of proteins, fats, lactose, somatic cells and ketone bodies. An increase in the quality of the milk is obtained with an increase in the content of fats, proteins or lactose, or with a decrease in the levels of somatic cells or the levels of ketone bodies; An increase in milk yield means an increase in the milk solids content, milk fats or milk proteins, as well as, or instead, an increase in the volume of milk produced. "Excessive accumulation of triglycerides" as used herein means a higher triglyceride content than the physiological 10% w / w in liver tissue. "Excessive increase in the levels of unesterified fatty s in serum" as used herein means levels of non-esterified fatty s of more than 800 μmol / L in serum. Unless otherwise specified, "antepartum" means from 3 weeks before the birth until the day of delivery. Unless otherwise specified, "postpartum" means from the moment the newborn is "expelled" from the uterus to 6 weeks after it is expelled from the uterus. "At birth" means 24 hours after the newborn is expelled from the uterus. "Periparturient" means the period from the beginning of the prepartum period until the end of the postpartum period. "Metabolic syndrome", also known as "Syndrome X", refers to a common clinical disorder that is defined as the presence of increased insulin levels along with other disorders including visceral obesity, hyperlipidemia, dyslipidemia, hyperglycemia, hypertension and potentially hyperuricemia, and renal dysfunction.

By "pharmaceutically acceptable" it is meant that a carrier, diluent, excipients and / or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. "Compounds", when used herein, include any pharmaceutically acceptable derivative or variant, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric, and other mixtures. of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms and prodrugs. By "tautomers" are meant chemical compounds that may exist in two or more forms of different structure (isomers) in equilibrium, the forms differing, normally, in the position of a hydrogen atom. Various types of tautomería can be produced, including keto-enol tautomería, ring-chain and ring-ring. The term "prodrug" refers to compounds that are drug precursors that after administration release the drug in vivo by some chemical or physiological method (for example, a prodrug that is brought to physiological pH or through enzymatic action becomes in the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming moieties of the compounds of the present invention include, but are not limited to, those having a carboxyl moiety in which the free hydrogen is replaced by alkyl (CrC4). ), (C2-C) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl which has from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di- N, N-alkylamino (C? -C2) -alkyl (C2-C3) (such as? -dimethylaminoethyl), carbamoyl-alkyl (C2), N, N-di-al quil (CrC2) carbamoyl-alkyl (C? -C2) and piperidino-, pyrrolidino- or morpholino-alkyl (C2-C3). The following paragraphs describe illustrative ring (s) for the generic descriptions of rings contained in this document. Illustrative five to six membered aromatic rings optionally having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl. Carbocyclic rings of five to eight partially saturated, fully saturated or fully unsaturated members optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other illustrative five membered carbocyclic rings include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazole, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1,2, 5- oxadiazolyl, 1,4-oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2, 3,5-oxatriazolyl, 3 7-1,2,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl and 1, 3-oxathioliol. Other illustrative six membered carbocyclic rings include 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3-triazinyl, 1,4-triazinyl, 1,2,3-triazinyl, , 3,5-trityanil, 4 - / - 1, 2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1 , 2-oxazinyl, 4A / -1, 4-oxazinium, 1, 2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6- oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl. Other illustrative seven member rings include azepinyl, oxepinyl and thiepinyl. Other illustrative eight member carbocyclic rings include cyclooctyl, cyclooctenyl and cyclooctadienyl. Illustrative bicyclic rings consisting of two rings of five or six condensed partially saturated, fully saturated or fully unsaturated, taken independently, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen include indolizinyl, indolyl, isoindolyl , 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyran (3,4-b) piployl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl , benzimidazolyl, benzothiazolyl, purinyl, 4 ^ -quinolizinyl, quinolinyl, isoquinolinyl, cinnoiinyl, phthalazinyl, quinazolinyl, quinoxajinil, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrid ( 3,4-b) -pyridinyl, pyrido (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2A / -1, 3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H- 2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1, 2-benzoxazinyl and 4H-1,4-benzoxazinyl. The content of carbon atoms of various hydrocarbon-containing residues is indicated by a prefix designating the minimum and maximum number of carbon atoms in the remainder, ie the prefix C-Cj denotes a remainder of the integer "i" to the whole number "j" of carbon atoms, inclusive. Thus, for example, C 1 -C 3 alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, and all isomeric forms and linear and branched forms thereof. By "aryl" is meant an optionally substituted six-membered aromatic ring, including polyaromatic rings. Examples of aryl include phenyl, naphthyl and biphenyl. "Heteroaryl" as used herein means an optionally substituted five- or six-membered aromatic ring, including polyaromatic rings in which the appropriate carbon atoms are substituted with nitrogen, sulfur or oxygen. Examples of heteroaryl include pyridine, pyrimidine, thiazole, oxazole, quinoline, quinazoline, benzothiazole and benzoxazole. By "halo" or "halogen" is meant chlorine, bromine, iodine or fluoro. By "alkyl" is meant a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Examples of such alkyl groups (assuming that the indicated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, -methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. This term also includes a saturated hydrocarbon (straight or branched chain) in which a hydrogen atom is removed from each of the terminal carbons. "Alkenyl" indicated herein may be linear or branched, and may also be cyclic (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) or bicyclic groups or contain cyclic groups. They contain 1-3 carbon-carbon double bonds, which can be cis or trans. By "alkoxy" is meant a straight chain saturated alkyl or a branched chain saturated alkyl linked through an oxy. Examples of such alkoxy groups (assuming that the indicated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isocyhoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy. It will be understood that if a carbocyclic or heterocyclic moiety can be linked or otherwise bound to an indicated substrate through different ring atoms without indicating a specific binding point, then all possible points are contemplated, through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so on. The term "HMG CoA reductase inhibitor" is selected, but not limited, from the group consisting of lovastatin, simvastatin, pravastatin, fluindostatin, velostatin, dihydrocompactin, compactin, fluvastatin, atorvastatin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin, cerivastatin , rosuvastatin, pitavastatin, mevastatin or rivastatin or a pharmaceutically acceptable salt thereof. The term "antihypertensive agent" is selected, but not limited, from a calcium channel blocker (including, but not limited to, verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, manidipine, cylindydine, lercanidipine, and felodipine), an ACE inhibitor (including, but not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, trandolapril, ramipril, zestril, zofenopril, cilaapril, temocapril, espirapril, moexipril, delapril, imidapril, ramipril, terazosin, urapidine, indoramin, amolsulalol and alfuzosin), an A-II antagonist (including, but not limited to, losarían, jrbesartan, telmisartan and valsartan), a diuretic (including, but without limitation, amiloride and bendroflumetiazide), a beta-adrenergic receptor blocker (such as carvedilol) or an alpha-adreceptor blocker nérgico (including, but without limitation, doxazosin, prazosin and trimazosin) or a pharmaceutically acceptable salt of such compounds. In one embodiment of the present invention, p is 1 or 2 and R1 is attached to Q.

In another embodiment of the present invention, Ar1 is: In another embodiment of the present invention, Ar2 is In another embodiment of the present invention,. Ar 1 is phenyl or phenyl fused to oxazolyl or thiazolyl; and Ar2 is phenyl or phenyl fused to a ring selected from the group consisting of: phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl and imidazolyl. In. Another embodiment of the present invention, halo is fluoro.

In another embodiment of the present invention, B is a bond or -L- (CY2) n- or - (CY2) nL-, and L is O or S, and n is 0, 1 or 2. In another embodiment of the present invention, X is -COOR4; B is a link; Ar 1 is phenyl or phenyl fused to oxazolyl or thiazolyl; and Ar2 is phenyl or phenyl fused to a ring selected from the group consisting of: phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl and imidazolyl. In another embodiment of the present invention, X is -COOR4; B is -L- (CY2) n- or - (CY2) n-L-, and L is O or S, and n is 0, 1 or 2; Ar 1 is phenyl or phenyl fused to oxazolyl or thiazolyl; and Ar2 is phenol or phenyl fused to a ring selected from the group consisting of: phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl and imidazolyl. In another embodiment of the present invention, In another embodiment of the present invention, q is 1 or 2 and each J is independently halo, (C 1 -C 3) alkyl optionally substituted with one to three halo, or (C 1 -C 3) alkoxy optionally substituted with one to three halo. In another embodiment of the present invention, p is 1 and R 4 is H or alkyl (d-Cs). In another embodiment of the present invention, L is S and n is 1. In another embodiment of the present invention, the compound of formula I is selected from the group consisting of: 2-methyl-5- [4- (5-methyl -benzooxazol-2-yl) -phenylsulfamoyl] benzoic acid; 5- [4- (5-Chloro-benzooxazol-2-yl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2-Methyl-5- [4- (4-trifluoromethyl-benzylsulfanyl) -phenylsulfamoyl] -benzoic acid; - [4- (4-Fer-butyl-benzylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2-Ethyl-5- [4- (5-methyl-benzooxazol-2-yl) -phenesulfamoyl] -benzoic acid; 5- [4- (4-Ethyl-benzylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 5- [4- (3,4-Difluoro-benzylsulfanyl) -phenylsulphamoyl] -2-methylbenzoic acid; 5- [4- (3,4-Dimethyl-benzylsulfanyl) -phenylsulfamoyl-2-methyl-benzoic acid; 5- [4- (5,7-difluoro-benzothiazol-2-ylmethylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2,3-Dimethyl-5- (4, -trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid; 2-Ethyl-5- [4- (4-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoyl] -benzoic acid; 2-Ethyl-5- (4'-trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid; 2-Isopropyl-5- [2- (4-trifluoromethoxy-pheny] -benzooxazol-5-ylsulfamoyl] -benzoic acid; and 2-Methyl-5- (4, -trifluoromethoxy-b-phenyl-4-ylsulfamoyl) -benzoic acid; or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug. In another embodiment of the present invention, the compound of formula I is selected from the group consisting of: 2-ethyl-5- [4- (6-methyl-benzothiazol-2-yl) -phenylsulfamoyl] -benzoic acid; 2-Methyl-5- (4, -trifluoromethyl-biphenyl-4-ylsulfamoyl) -benzoic acid; 2-Isopropyl-5- [propyl- (4, -trifluoromethoxy-biphenyl-4-yl) -sulfamoyl] -benzoic acid; 2-Methyl-5 - [(4'-propoxy-biphenyl-4-yl) -propyl-sulfamoyl] -benzoic acid; 2-Methyl-5- (4'-propoxy-biphenyl-4-ylsulfamoyl) -benzoic acid; 2-Ethyl-5- [4- (4-trifluoromethoxy-benzyl-fluoyl) -phenylsulfamoyl] -benzoic acid; 5- (4'-tert-Butyl-biphenyl-4-ylsulfamoyl) -2-methyl-benzoic acid; 5- [4- (4-Chloro-benzylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2-Methyl-5- [4- (3-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoyl] -benzoic acid; 2-Methyl-5- [2- (4-trifluoromethyl-phene) -benzooxazol-5-ylsulfamoyl] -benzoic acid; 2-Methyl-5- [4- (5-phenyl-be? Zooxazol-2-yl) -phenylsulfamoyl] -benzoic acid; and 2-isopropyl-5- [4- (5-methyl-benzooxazol-2-yl) -phenylsulfamoyl] -benzoic acid; or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug. In an embodiment of the methods of the present invention, atherosclerosis is treated. In one embodiment of the methods of the present invention, peripheral vascular disease is treated..

In one embodiment of the methods of the present invention, dyslipidemia is treated. In one embodiment of the methods of the present invention, diabetes is treated. In one embodiment of the methods of the present invention, hypoalphalipoproteinemia is treated. In one embodiment of the methods of the present invention, hypercholesterolemia is treated. In one embodiment of the methods of the present invention, hypertriglyceridemia is treated. In one embodiment of the methods of the present invention, obesity is treated. In one embodiment of the methods of the present invention, osteoporosis is treated. In one embodiment of the methods of the present invention, the metabolic syndrome is treated. In another embodiment of the present invention, the pharmaceutical composition is for the treatment of atherosclerosis in a mammal comprising an amount for treating atherosclerosis of a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or a prodrug and a pharmaceutically acceptable excipient, vehicle or diluent. In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the second compound is an HMG-CoA reductase inhibitor or a CETP inhibitor.

In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the second compound is rosuvastatin, rivastatin, pitavastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or cerivastatin or a prodrug of said compound or a pharmaceutically salt acceptable of said compound or prodrug. In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the second compound is ethyl ester of [2f?, 4SJ-4 - [(3,5-?> / S-trifluoromethyl) ethyl ester. -benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the composition further comprises an inhibitor of cholesterol absorption. In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the co-steric absorption inhibitor is ezetimibe. In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the composition further comprises an antihypertensive agent. In an embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, said antihypertensive agent is a calcium channel blocker, an inhibitor of ACE, an A-II antagonist, a diuretic, a beta-adrenergic receptor blocker, or an alpha-adrenergic receptor blocker. In one embodiment of the compositions, methods and kits of the pharmaceutical combination of the present invention, the antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine. , nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, manidipine, cilinidipine, le? idipine, felodipine or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug. In another embodiment of the present invention, the compound of formula II is: 4- (5-Chloro-benzooxazol-2-yl) -phenylamine; 4- (4-Trifluoromethyl-benzylsulfanyl) -phenylamine; 4- (4-tert-Butyl-benzylsulfanyl) -phenylamine; 4- (4-Ethyl-benzylsulfanyl) -phenylamine; 4- (3,4-Difluoro-benzylsulfanyl) -phenylamine; 4- (3,4-Dimethyl-benzylsulfanyl) -phenylamine; 4- (5,7-Difluoro-benzothiazol-2-ylmethylsulfanyl) -phenylamine; 4, -Trifluoromethoxy-biphenyl-4-ylamine; 4- (4-Trifluoromethoxy-benzylsulfanyl) -phenylamine; or 4-Trifluoromethoxy-phenyl) -benzooxazol-5-ylamine; or a pharmaceutically acceptable salt thereof. In general, the compounds of this invention can be manufactured by methods that include procedures analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain methods for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other procedures can be described in the experimental section.

The Reaction Schemes described in this document are intended to provide a general description of the methodology employed in the preparation of many of the given Examples. However, it will be evident from the detailed descriptions given in the Experimental section that the preparation modes employed extend beyond the general procedures described in this document. In particular, it is noted that the compounds prepared according to these Schemes may be modified further to provide new Examples within the scope of this invention. For example, an ester functionality can be further reacted using procedures well known to those skilled in the art to give another ester, an amide, an acid, a carbinol or a ketone. As an initial indication, in the preparation of the compounds of the present invention, it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of the remote functionality (eg, primary amine, secondary amine, carboxyl in intermediates). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparative procedures and can be readily determined by a person skilled in the art. The use of such protection / deprotection procedures is also within the knowledge of the person skilled in the art. For a general description of protecting groups and their use see TW Greene, Protective Groups in Organic Svnthesis, John Wiley and Sons, New York, 1991. For example, in the reaction schemes shown below, certain compounds contain primary amines or functionalities of carboxylic acid, which can interfere with reactions elsewhere in the molecule if left unprotected. Accordingly, such functionalities can be protected by an appropriate protecting group, which can be removed at a later stage. Suitable protecting groups for the protection of amine and carboxylic acid include those protecting groups normally used in peptide synthesis (such as N-α-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyleneoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) they are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering another functionality of the compound. Scheme 1 1d According to Reaction Scheme 1, the compounds of formula 1d, which are compounds of formula I wherein x is -COOR 4, R 2 is H, R (optionally present) is halo, alkyl, alkoxy or alkylthio and R 1, B , Ar2, J, p and q5 are as described above prepared by procedures well known in the art. For example, the treatment of benzoic acid or ester 1a (which are commercially available or known in the literature or can be prepared according to procedures familiar to those skilled in the art) with chlorosulfonic acid (halo is chlorine) at temperatures between approximately 90 and 110 ° C, preferably 100 ° C, for a period of about 15 min to 3 h, preferably 2.5 h for the acid and 15 min for the ester, leads to the halogenated sulfonyl 1b. The reaction of the sulfonyl chloride 1b with appropriately substituted anilines 1e (the preparation of the anilines 1e is described in Schemes 4, 5, 6, 7 and 8) to form the sulfanilides 1c can be carried out under well-known reaction conditions for the specialists in the technique. For example, the reaction of the sulfonyl chloride 1b and an aniline 1e can be carried out in an inert solvent such as tetrahydrofuran, dimethylformamide or a mixture of acetone and water, in the presence of a base such as pyridine, potassium carbonate or sodium carbonate, at temperatures between 20 ° C and 65 ° C, preferably at room temperature for a period of about 10 to 36 h, preferably about 20 h. If 1b is a chlorosulfonylbenzoic ester (R 4 = CH 3), it may be preferred to carry out the reaction in an organic solvent such as tetrahydrofuran in the presence of an amine base such as pyridine and triethylamine. The ester product 1c can be converted to the benzoic acid 1d by hydrolysis with an alkali metal hydroxide, preferably sodium hydroxide, in a mixture of an alcohol, preferably mephanol, and water at a temperature of about 50 to 100 ° C preferably at room temperature. reflux, during a period of approximately 2 to 30 h. Scheme 2 2d According to Reaction Scheme 2, the desired compounds of Formula I where x is -COOR4, R2 is H, B is a bond, Ar2 is phenyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio, and R1, J, p and q are as described above, they are prepared by reacting a halogenated sulfonyl (where halo is chloro) 1 b and 4-haloaniline 2a (where halo is bromo or iodo) in an inert solvent such as teirahydrofuran or a solvent mixture such as acetone and water, in the presence of an amine base such as pyridine / triethylamine or an inorganic base such as potassium carbonate or sodium carbonate, at a temperature of about 20 ° C to 50 ° C, preferably at room temperature, during a a period of about 20 h to form the halogenated sulfanilide 2b. The reaction of the halogenated sulfanilide 2b in a solvent such as tetrahydrofuran, dioxane, dimethoxyethane or dioxane / water with an appropriately substituted benzeneboronic acid derivative 2c under palladium catalysis in the presence of a base such as potassium carbonate, cesium carbonate or sodium carbonate , at temperatures between 80 ° C and 110 ° C, preferably at reflux, for 6-30 h, preferably 20 h, using procedures known to those skilled in the art, leads to bifenylsulfanilide 2d. Additional palladium catalysts, phosphine ligands, solvents, bases and reaction temperatures that can be used are illustrated in Chemical Reviews 102, 1359 (2002). For example, the reaction of bromosulfanilide as halogenated sulfanilide 2b with an arylboronic acid 2c in the presence of a catalytic amount of dichloro [1, -bis (diphenylphosphino) ferrocene] palladium (II) adduct of dichloromethane and 1,1'-bis (diphenylphosphide) No) ferrocene, with potassium carbonate as the base and aqueous dioxane as the solvent, produces 2-biphenylanilide. As shown in Scheme 1, the ester group of compound 2d (X, -COOR4) can be converted to an acid group by basic hydrolysis. Scheme 3 According to Reaction Scheme 3, the desired compounds of Formula I where x is -COOR4, R2 is alkyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio, and R1, R2, B, Ar2, J, p and q are as described above, they are prepared by treating a sulfanilide 1c with an appropriate halogenated alkyl (where halo is bromine or iodine) 3a or with an alkyl sulfonate in the presence of an alkali metal carbonate such as potassium carbonate, sodium carbonate or cesium carbonate. an inert solvent such as acetone or dimethylformamide at temperatures between 60 ° C and 80 ° C, preferably acetone at reflux temperature to produce the n-alkylsulfanilide ester 3b. The / 7-alkylsulfanilide 3b ester can be converted to the acid 3c by basic hydrolysis such as under the reaction conditions illustrated previously in Scheme 1, Schemes 4, 5, 6, 7 and 8 describe the preparation of anilines 1e, used in the synthesis shown in Scheme 1. Alternatively, the anilines 1e of Scheme 1 are commercially available or are known in the literature or can be prepared according to procedures well known in the art. Scheme 4 Compounds of Formula I where R2 is hydrogen, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is a bond, Ar2 is a phenyl ring fused to a midazole, oxazole or thiazole ring (D is N, O or S) and J and q are as described above, can be prepared by 4a and 4b (Scheme 4) or by similar synthetic routes familiar to those skilled in the art. In Scheme 4a, a derivative of 2-aminophenol, 2-aminothiophenol or 2-aminoaniline 4a is heated with an appropriately substituted 4-aminobenzoic acid 4b in polyphosphoric acid to between about 170 ° C and 200 ° C for 4-10 h, preferably at 190 ° C for 6 h, to yield the corresponding 4-benzoxazol-2-yl-phenylamine, 4-benzothiazol-2-yl-phenylamine or 4-benzimidazol-2-yl-phenylamine derivatives 1 e4. As an alternative, as summarized in Scheme 4b, the acylation of a 2-aminophenol derivative, 2-aminoiiophenol or 2-aminoaniline 4a with 4-nitrobenzoyl chloride or 4-nitrobenzoyl bromide 4c, in an inert solvent such as methylene chloride , in the presence of an amine base such as 4-dimethylaminopyridine, at a temperature of 20 ° C to 50 ° C for 10-30 h, preferably at room temperature for 20 h, produces the corresponding benzamide 4d. Under the acylation reaction conditions, the thiophenol derivative 4d (D = S) is cyclized spontaneously in the benzothiazole derivative 4e (D = S). The phenol derivative 4d (D = O) can be cyclized into the benzoxazole derivative 4e (D = O) by treatment with diethylazodicarboxylate (DEAD) and triphenylphosphine (PhsP), in a solvent such as tetrahydrofuran, dimethylformamide, methylene chloride or dioxane , preferably tetrahydrofuran at 15 ° C to 35 ° C for 10-30 h, preferably at room temperature overnight. The nitro group of 4e can be reduced to form the aniline 1e4 by procedures familiar to those skilled in the art. For example, heating the nitro compound 4e with iron powder and calcium chloride in aqueous alcohol such as ethanol of about 60 ° C to 100 ° C for 4 to 10 h, preferably at reflux temperature for 5 h produces the aniline 1e4. Other reducing reagents such as iron and acetic acid, zinc and aqueous hydrochloric acid and catalytic hydrogenation are exemplified in Richard Larock, Comprehensive Organic Transformations. VCH Publishers. New York, 1989412. Scheme 5 Compounds of Formula 1e5 desired where R2 is hydrogen, B is a bond, Ar2 is an oxadiazole ring and J is as described above, can be prepared by Scheme 5 or by similar synthetic routes familiar to those skilled in the art. Acylation of 5- (4-nitrophenyl) -1H-tetrazole 5a commercially available with an acyl chloride 5b in pyridine at room temperature, followed by heating at 60 ° C for 1 h and at 100 ° C for 2 h, produces the 2- (4-nitrophenyl) -1,3,4-oxadiazole 5c. Reduction of the nitro group to the amine by procedures known to those skilled in the art produces aniline 1e5. For example, the reduction can be performed, as previously shown in Scheme 4b, with iron powder and calcium chloride in aqueous ethanol. Scheme 6 The desired compounds of Formula 1e6 wherein R2 is hydrogen, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is -L-CH2- or -CH2-L-, Ar2 is phenyl and J and q are as described above, can be prepared by the synthesis depicted in 6a, 6b and 6c of Scheme 6 or by similar synthetic routes familiar to those skilled in the art. The benzyloxynitrobenzene or benzylsulfanylnitrobenzene derivatives (6c) can be prepared by the Mitsunobu reaction, for example, by the reaction of 4-nitrophenol or 4-nitrothiophenol 6b with an appropriate benzyl alcohol 6a, in the presence of diethylazodicarboxylate (DEAD) and triphenylphosphine ( Pfi3P), in a solvent such as tetrahydrofuran, dimethylformamide, methylene chloride or dioxane, at between about 15 ° C and 35 ° C for about 10 to 30 h, preferably in tetrahydrofuran at room temperature overnight (Scheme 6a). The reaction conditions, solvents, temperature and reaction time for the Mitsunobu reaction are analyzed in Organic Reactions. Vol 42, 1992, 335, John Wiley, 2002. The reduction of the nitro group of 6c by methods known to those skilled in the art, including those illustrated in Scheme 4b, produces the corresponding aniline 1e6.

For example, in Scheme 6b, benzylsulfanyllanine 1e6-1 can be synthesized by treating 4-aminothiophenol 6d with an appropriately substituted benzyl chloride 6e in the presence of a base such as sodium hydride, cesium carbonate or sodium ferc-butoxide, in a solvent such as tetrahydrofuran, dimethylformamide or dimethoxyethane, preferably tetrahydrofuran, at a temperature of about 20 ° C to 70 ° C for about 8 to 30 h, preferably at room temperature overnight. The 4-benzyloxyaniline 1e6-2 can be prepared by the Mitsupobu reaction (Scheme 6c), where the reaction of 4-aminophenol 6f with an appropriate benzyl alcohol 6a, in a solvent such as tetrahydrofuran, is mediated by diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph3P), at room temperature overnight as exemplified for 6c. Scheme 7 2a 2c 1e7 The compounds of Formula 1e where R2 is hydrogen, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is a bond, Ar2 is phenyl and J and q are as described above, can be prepared by synthesis represented in Scheme 7 or by similar synthetic routes familiar to those skilled in the art. The biphenylamine derivatives 1e7 can be synthesized by a Suzuki coupling of 4-haloaniline 2a where halo is bromo or iodo and an appropriately substituted benzeneboronic acid derivative 2c, using methods known to those skilled in the art that have been exemplified in Scheme 2c . The benzeneboronic acid derivatives 2c are commercially available or can be easily prepared by literature procedures known to those skilled in the art as illustrated in Scheme 2c. For example, the reaction of 4-bromoaniline with an arylboronic acid 2c in the presence of a catalytic amount of dichloro [1,1'- £) / s (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct and 1,1'- £) / s (d-phenylphosphino) ferrocene, with potassium carbonate as the base and aqueous dioxane as solvent, at reflux temperature overnight produces the biphenylamine derivative 1e7. Scheme 8 Compounds of Formula 1e where R2 is hydrogen, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is L, Ar2 is phenyl and J and q are as described above, can be prepared by the synthesis depicted in Scheme 8 or by similar synthetic routes familiar to those skilled in the art. The phenoxyaniline and phenylsulfanylaniline derivatives 1e8 (Scheme 8) can be prepared by reaction of 4-halonitrobenzene 8b, where halo is chloro, bromo or iodo, with an appropriate phenol or thiophenol 8a in the presence of a base such as sodium hydride, fer-t-butoxide sodium or cesium carbonate in an inert solvent such as dimethylformamide, tetrahydrofuran or dimethoxyethane, at between about 60 ° C and 90 ° C for about 10 to 30 h, preferably at 80 ° C overnight, to yield the nitro derivative 8c . The aniline 1e8 can be produced by reducing the nitro derivative 8c, using methods known to those skilled in the art, such as those previously exemplified in Scheme 4b. Scheme 9 Compounds of Formula I wherein x is thiazolidinedione-5-yl-G-, G is (CH 2) S, s is 0, R is H, R (optionally present) is halo, alkyl, alkoxy or alkylthio and R 1, B, Ar2, J, p and q are as described above, can be prepared by the synthetic sequence indicated in Scheme 9, as shown by J. Med. Chem., 29, 773 (1986) and Chem. Pharm. Bull., 30, 3601 (1982). An appropriately substituted benzaldehyde 9a is treated with trimethylsilyl cyanide and a catalytic amount of zinc iodide in anhydrous methylene chloride or chloroform at about 20 ° C to 30 ° C for about 15 to 30 h, preferably at methylene chloride at room temperature overnight environment to produce cyanohydrin 9b (Z = OH).

Cyanohydrin 9b (Z = OH) is converted to chlorocyanide 9b (Z = Cl) with thionyl chloride in chloroform or methylene chloride at about 30 ° C to 65 ° C. for about 30 to 60 min, preferably in chloroform at reflux temperature for 45 min. The reaction of chlorocyanide 9b (Z = Cl) with thiourea in an alcoholic solvent such as ethanol of about 60 ° C to 80 ° C for about 4 to 10 h, preferably in ethanol at reflux temperature for 5 h followed by hydrolysis of the intermediate iminothiazolidinone with aqueous acid of about 95 ° C to 120 ° C for about 4 to 10 h, preferably 6 N aqueous hydrochloric acid at reflux temperature for 5 h leads to the thiazolidinedione 9c. Alternatively, the appropriate benzaldehyde 9a is treated with sodium cyanide in a mixture of water, acetic acid and ethylene glycol monomethyl ether at room temperature for 1.5 h followed by the addition of thiourea and concentrated hydrochloric acid and heating to approximately 100 °. C during 18 h to produce the thiazolidinedione 9c (Chem. Pharm. Bull., 45, 1984 (1997).

Heating the thiazolidinedione 9c in pure chlorosulfonic acid from about 90 ° C to 110 ° C for about 15 to 30 min, preferably at 100 ° C for 15 min produces the sulfonyl chloride 9d. Reaction of the sulfonyl chloride 9d with appropriately substituted anilines 1e using procedures known to those skilled in the art, such as the reaction described in Scheme 1, leads to the desired thiazolidinedione derivatives 9e. Scheme 10 The compounds of Formula I wherein x is thiazolidinedione-5-yl-G-, G r > is methylidine or (CH2) sys is 1, R is H, R (optionally present) is halo, alkyl, alkoxy or alkylthio and R1, B, Ar2, J, p and q are as described above, can be synthesized by the sequence of reaction indicated in Scheme 10, as shown by Chem. Pharm. Bull., 45, 1984 (1997). The condensation of an appropriately substituted benzaldehyde 9a and thiazolidinedione mediated by piperidine in acetic acid or ethanol or ammonium acetate in acetic acid from about 110 ° C to 120 ° C for about 8 to 30 h, preferably piperidine in refluxing acetic acid for about 20 h or by piperidine and benzoic acid in toluene at reflux for about 3 to 10 h leads to the benzylidene-thiazolidinedione 10b. Heating the thiazolidinedione 10b in pure chlorosulfonic acid at about 90 ° C to 110 ° C for about 15 to 25 min, preferably at about 100 ° C for 15 min produces the sulfonyl chloride 10c.

Reaction of the sulfonyl chloride 10c with appropriately substituted anilines 1e using procedures known to those skilled in the art, such as the procedure described in Scheme 1, leads to the benzylidene thiazolidinedione 10d derivatives. The reduction of olefinic bond of 10d using procedures familiar to those skilled in the art, such as lithium borohydride in pyridine / tetrahydrofuran from about 65 ° C to 90 ° C for about 2 to 6 hours or sodium borohydride / lithium chloride in pyridine / tetrahydrofuran of about 65 ° C to 90 ° C for about 3 to 6 h, or catalytic hydrogenation with 10% Pd-C in 1,4-dioxane or methanol of about 344.737 to 413.685 kPa (50 to 60 psi) during from about 36 to 60 h, preferably lithium borohydride in pyridine / tetrahydrofuran at reflux for 3 h, yields the desired thiazolidinedione derivative 10e. Scheme 11 11e 11f The compounds of Formula I, wherein x is -O- (CR32) -COOR4, R3 is CH3, R1 is alkyl, R2 is H, R (optionally present) is halo, alkyl, alkoxy or alkylthio and B, Ar2, J and q are as described above, can be prepared by the synthetic route indicated in Scheme 11 as shown by Monat. Chem. 99, 2048 (1968). The reaction of the substituted phenol 11a with lead tetraacetate in acetic acid from about 20 ° C to 30 ° C for about 3 to 6 h, preferably at room temperature for 3 h produces the quinol acetate 11b. After treatment with sodium sulfite in water of about 20 ° C to 30 ° C for about 3 to 6 h, preferably at room temperature for 3 h, the quinol acetate 11 b is converted to sulfonic acid 11c. The sulfonyl chloride 11d is prepared by heating the sulfonic acid 11c with phosphorus pentachloride from about 110 ° C to 130 ° C for about 25 to 55 min, preferably at about 120 ° C for about 30 min. Reaction of the sulfonyl chloride 11d with appropriately substituted anilines 1e using procedures known to those skilled in the art, such as the procedure described in Scheme 1, followed by alkaline hydrolysis of the acetate yields the sulfonamide 11e. Alkylation of sulfonamide 11e with ethyl 2-bromoisobutyrate and potassium carbonate in dimethylformamide or ethanol of about 80 ° C to 100 ° C for about 12 to 24 h, preferably dimethylformamide at about 95 ° C for about 18 h, followed by basic hydrolysis of the product, leads to the desired acid 11f. Scheme 12 12e The compounds of Formula I wherein X is -CH 2 (CR 5 w) -COOR 4 and R 5 is CH 3 CH 2, W is 1, R 2 is H, R (optionally present) is halo, alkyl, alkoxy or alkyothio and R 1, B, Ar 2 , J, p and q are as defined above, can be synthesized by the reaction sequence indicated in scheme 12. The reaction of an appropriately substituted benzaldehyde 9a with the carbanion formed from 2-phosphonobutyrate of tiethyl and potassium t-butoxide or Sodium hydroxide in tetrahydrofuran or dimethoxyethane at between about 20 ° C and 30 ° C for between about 2 and 5 hours, preferably at room temperature for 3 hours, yields the olefinic ester 12b. Ester 12b is converted to sulfonyl chloride 12c by heating in chlorosulfonic acid from about 55 ° C to 70 ° C for about 15-25 min, preferably at about 60 ° C for about 15 min. Reaction of the sulfonyl chloride 12c with appropriately substituted anilines 1e using procedures known to those skilled in the art, such as the procedure described in Scheme 1, produces the sulfonamide 12d. The reduction of the olefinic bond of 12c using procedures known to those skilled in the art, such as magnesium in methanol or ethanol of about 60 ° C to 85 ° C until the magnesium is consumed, 0 catalytic hydrogenation with 10% Pd-C in 1,4-dioxane or methanol of about 344,737 to 413,685 kPa (50 to 60 psi) for about 36 to 60 h, preferably magnesium in methanol at about 65 ° C, followed by alkaline hydrolysis of the product, produces the desired acid 12e. Scheme 13 HD13a? 13b «• 13c s (J?> 13d * Compounds of Formula 1 wherein Ar 1 is different from phenyl can be prepared by the reaction sequence indicated in the Scheme 1 replacing the aniline 1e by condensed anilines to a member selected from thiazolyl, furanyl, oxazolyl, pyridine, pyrimidine, phenyl or thienyl which are prepared from intermediates that are commercially available or are known in the literature by known methods for specialists in the technique. For example, Scheme 13 represents a process in which Ar 1 is benzooxazole or benzothiazole, B is a bond, Ar 2 is phenyl and J and q are as defined above. In the first step of Scheme 13, a 2-aminophenol or 2-aminothiophenol (where D is O or S) 13a is reacted with an appropriate benzoic acid in polyphosphoric acid at about 190 ° C for about 6 h as exemplified in Scheme 4a, producing benzoxazole or benzothiazole 13b. Nitration of 13b with concentrated nitric acid and sulfuric acid at about 75 ° C for about 30 min and at about 100 ° C for about 1 h leads to nitro derivative 13c, which is reduced to give the aminobenzoxazole or aminobenzothiazole 13d using the procedures shown in Scheme 4b. Scheme 14 The compounds in which Ar1 is quinolin, B is a bond, Ar2 is phenyl and J and q are as defined above can be prepared, for example, from chloroquinoline 14a, which is known in the literature [J. Amer. Chem. Soc, 60, 2104 (1938)], by reaction with an aryl- or alkyl-boronic acid using the procedures illustrated in Scheme 2.

Scheme 15 The compounds in which Ar 1 is quinazoline and B, Ar 2, J and q are as defined above can be prepared, for example, by the procedure described in Synlett, p. 1993 (1999). The reaction of an appropriate amidine 15b with the nitrobenzaldehyde 15a in acetonitrile in the presence of potassium carbonate and molecular sieves at reflux temperature for about 5 to 10 h produces the nitroquinazoline 15c. The reduction of 15c in the desired amine 15d can be accomplished by the procedures described in Scheme 4b. Scheme 16 The compounds in which Ar1 is benzothiophene, B is -L-CH2-, L is O or S, and Ar2, J and q are as defined above can be prepared, for example, from the hydroxymethylbenzothiophene 16a, which is known in the art. the bibliography (J. Heterocycl, Chem., 20, 129 (1983)). The reaction of 16a with methanesulfonyl chloride and pyridine in methylene chloride, as shown by J. Med. Chem., 35, 457 (1992), at room temperature overnight leads to chloromethylbenzothiophene 16b. The treatment of 16b with an appropriate alcohol or mercaptan in the presence of a base such as sodium hydride or sodium ferc-butoxide in an inert solvent such as tetrahydrofuran, dimethoxyethane or dimethylformamide at about 20 ° C to 60 ° C for about 6 to 30 h, preferably at room temperature overnight, produces the nitro derivative 16c. The reduction of 16c in the desired amine 16d can be carried out by the procedures described in Scheme 4b. Scheme 17 The compounds in which Ar1 is benzofuran, B is CH2 and Ar2, J and q are as defined above can be prepared as shown by J. Med. Chem., 39, 3897 (1996), for example, by the reaction of 5-nitrosalicylaldehyde 17a with an appropriate bromomethylaryl ketone and a base such as diisopropylethylamine, potassium fluoride or potassium carbonate in a solvent such as dimethylformamide, ethanol or acetone, at a temperature of about 75 to 95 ° C, for about 3 to 24 h, preferably diisopropylethylamine in dimethylformamide at 92 ° C for 4 h. The ketone 17c is reduced in the corresponding alcohol with sodium borohydride in methanol, which is converted to the nitro compound 17d with triethylsilane in trifluoroacetic acid. The reduction of 17d in the desired amine can be carried out by the procedures described in Scheme 4b. The compounds of this invention may also be used in conjunction with other pharmaceutical agents (e.g., agents that lower the level of LDL cholesterol, agents that lower the level of triglycerides) for the treatment of the diseases / conditions described herein. For example, they can be used together with an HMG-CoA reductase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor, a CETP inhibitor, an MTP / Apo B secretion inhibitor, another cholesterol modulator, PPAR and other cholesterol lowering agents such as a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor and a bile acid sequestrant. Other pharmaceutical agents would also include the following: a bile acid reuptake inhibitor, an ileus bile acid transporter inhibitor, an ACC inhibitor, an amphihypertensive agent (such as NORVASC®), a selective estrogen receptor modulator, a modulator selective of the androgen receptor, an antibiotic, an antidiabetic (such as metformin, a PPAR activator, a sulphonylurea, insulin, an aldose reductase inhibitor (ARI) and a sorbitol dehydrogenase inhibitor (SDI)), and aspirin (acid) acetylsalicylic). A slow-release form of niacin is available and is known as Niaspan. Niacin can also be combined with other therapeutic agents such as statins, namely, lovastatin, which is an inhibitor of HMG-CoA reductase and is described in detail below. This combination therapy is known as ADVICOR® (Kos Pharmaceuticals Inc.). In treatment with combination therapy, the compounds of this invention and other drug therapies are administered to mammals (e.g., humans, men or women) by conventional methods. The term "HMG-CoA reductase inhibitor" refers to compounds that inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art in accordance with conventional tests (eg, Meth. Enzymol, 1981).; 71: 455-509 and references cited in that document). Various of these compounds are described and referenced below although other HMG-CoA reductase inhibitors will be known to those skilled in the art. Atorvastatin calcium (ie, atorvastatin hemicalcium), described in U.S. Patent No. 5,273,995, which is incorporated herein by reference, is currently marketed as Lipitor® and has the formula Atorvastatin calcium is a selective and competitive inhibitor of HMGCoA. As such, atorvastatin calcium is a potent lipid lowering compound. The free carboxylic acid form of atorvastatin may exist predominantly as the lactone of formula and is described in U.S. Patent No. 4,681,893, which is incorporated herein by reference. Statins also include compounds such as rosuvastatin described in U.S. RE37,314 E, pitivastatin disclosed in EP 304063 B1 and US 5,011,930, simvastatin, described in U.S. 4,444,784, which is incorporated herein by reference; pravastatin, described in U.S. 4,346,227 which is incorporated herein by reference; cerivastatin, described in U.S. 5,502,199, which is incorporated herein by reference; Mevastatin, described in U.S. 3,983,140, which is incorporated herein by reference; velostatin, described in U.S. 4,448,784 and U.S. 4,450,171, both incorporated herein by reference; fluvastatin, described in U.S. 4,739,073, which is incorporated herein by reference; compactin, described in U.S. 4,804,770, which is incorporated herein by reference; lovastatin, described in U.S. 4,231,938, which is incorporated herein by reference; Dalvastatin, described in European Patent Application Publication No. 738510 A2; fluindostatin, described in European Patent Application Publication No. 363934 A1; and dihydrocompactin, described in U.S. 4,450,171, which is incorporated herein by reference. Any compound that decreases gene expression of HMG-CoA reductase can be used in the combination aspect of the invention. These agents can be transcription inhibitors of HMG-CoA reductase that block DNA transcription or translation inhibitors that prevent or diminish the translation of mRNA encoding HMG-CoA reductase in proteins. Such compounds may directly affect transcription or translation or may be biotransformed into compounds having the above-mentioned activities by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite having the aforementioned activities. Such compounds can cause this effect by decreasing the levels of SREBP (sterol receptor binding protein) by inhibiting the activity of the protease "from site 1 (S1P) or by agonizing the oxogenic receptor or SCAP." Such regulation is easily determined by the specialists in the art according to conventional assays (Meth, Enzymol, 1985; 110: 9-19) Several compounds are described and referenced below, although other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. The technique U.S. Patent No. 5,041,432 (the disclosure of which is incorporated herein by reference) discloses certain 15-substituted lanosterol derivatives.Other oxygenated stellates that suppress the synthesis of HMG-CoA reductase are analyzed by El Mercer (Prog. Lip. Res. 1993; 32: 357-416).

Any compound that has activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the present invention. The term "CETP inhibitor" refers to compounds that inhibit transport mediated by cholesteryl ester transfer protein (CETP) of various cholesteryl esters and triglycerides of HDL to LDL and VLDL. Such CETP inhibitory activity is readily determined by those skilled in the art in accordance with conventional assays (e.g., U.S. Patent No. 6,140,343). Those skilled in the art will be aware of various CETP inhibitors, for example, those described in the commonly assigned United States Patent No. 6,140,343 and the commonly assigned United States Patent No. 6,197,786. The CETP inhibitors described in these patents include compounds such as [2 4SJ-4 - [(3,5-α) / s-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl acid ethyl ester. -6-trifluoromethyl-3,4-dihydro-2A-quinolin-1-carboxylic acid, which is also known as torcetrapib. U.S. Patent No. 5,512,548 discloses certain polypeptide derivatives having activity as inhibitors of CETP, while certain rosenonolactone derivatives inhibitors of CETP and analogs containing cholesteryl ester phosphate are described in J. Antibiot, 49 ( 8): 815-816 (1996) and Bioorg. Med. Chem. Lett.; 6: 1951-1954 (1996), respectively. Any other PPAR modulator may be used in the combination aspect of this invention. In particular, the modulators of PPARβ and / or PPAR? they may be useful in conjunction with the compounds of the present invention. Any inhibitor of MTP / Apo B secretion (microsomal triglyceride and / or apolipoprotein B transfer protein) can be used in the combination aspect of this invention. The term "inhibitor of MTP / Apo B secretion" refers to compounds that inhibit the secretion of triglycerides, cholesteryl ester and phospholipids. Such inhibition is readily determined by those skilled in the art in accordance with conventional assays (eg, Wetterau, J.R. 1992; Science 258: 999). Various of these compounds are described and referenced below, although other inhibitors of MTP / Apo B secretion will be known to those skilled in the art, including imputapride (Bayer) and other compounds such as those described in WO 96/40640 and WO 98/23593, (two illustrative publications). For example, the following MTP / Apo B inhibitors are particularly useful: [2- (1 H- [1, 2,4] triazol-3-ylmethyl) -1, 2,3,4-tetrahydro-isoquinoline-6 il] -amide of 4'-trifluoromethyl-biphenyl-2-carboxylic acid; [2- (2-Acetylamino-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide of the acid 4, -trifluoromethyl-biphenyl-2-carboxylic acid; (2- {6 - [(4, -trifluoromethyl-biphenyl-2-carbonyl) -amino] -3,4-dihydro-1H-isoquinolin-2-yl} -ethyl} -carbamic acid methyl ester; [1- (1-f-imidazol-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide of 4-trifluoromethyl-biphenyl-2-carboxylic acid; [4-Trifluoromethyl-biphenyl-2-carboxylic acid [2- (2,2-diphenyl-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide; and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-ethoxy-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide.

(SJ-N ^ -fibenzymethyl aminoj ^ -oxo-l-phenylethyl-1-methyl-d-μ'- (trifluoromethyl) [1,1'-biphenyl] -2-carboxamido] -1H-indole-2-carboxam (S) -2 - [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid (S) -2- [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -indole (phenylcarbamoyl-phenyl-methyl) -amide; -2-carboxamide, 1-methyl-N - [(1 S) -2- [methyl (phenylmethyl) amino] -2-oxo-1-phenylethyl] -5 - [[[4- (trifluoromethyl)] [1, 1] '-biphenyl-2-yl] carbonyl] amino]; and N - [(1 S) -2- (benzylmethylamino) -2-oxo-1-phenylethi-1-methyl-5 - [[[4' - (trifluoromethyl)] ) biphenyl-2-yl] carbonyl] amino] -1H-indole-2-carboxamide Any inhibitor of cholesterol absorption can be used as an additive in the combination aspect of the present invention The term inhibitor of cholesterol absorption refers to the ability of a compound to prevent cholesterol contained in the lumen of the intestine from entering the intestinal cells and / or passing from within the intestinal cells to the lymphatic system and / or the bloodstream. The inhibitory activity of cholesterol absorption is readily determined by those skilled in the art according to conventional tests (eg, J. Lipid Res. (1993) 34: 377-395). Inhibitors of cholesterol absorption are known to those skilled in the art and are described, for example, in PCT WO 94/00480. An example of a cholesterol absorption inhibitor is ZETIA ™ (ezetimibe) (Schering-Plow / Merck). Diabetes can be treated by administering to a patient having diabetes (especially Type II), insulin resistance, impaired glucose tolerance, metabolic syndrome or the like, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy, or cataracts, a therapeutically effective amount of a compound of the present invention together with other agents (e.g., insulin) that can be used to treat diabetes. This includes the classes of anti-diabetic agents (and specific agents) described in this document. Any glycogen phosphorylase inhibitor can be used as the second agent together with the compound of the present invention. The term "glycogen phosphorylase inhibitor" refers to compounds that inhibit the bioconversion of glycogen into glucose-1-phosphate which is catalyzed by the enzyme glycogen phosphorylase. Such glycogen phosphorylase inhibitory activity is readily determined by those skilled in the art in accordance with conventional assays (eg, J. Med. Chem. 41 (1998) 2934-2938). Several of the glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96/39384 and WO 96/39385. Any aldose reductase inhibitor may be used in conjunction with a compound of the present invention. The term "aldose reductase inhibitor" refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase. The inhibition of aldose reductase is readily determined by those skilled in the art in accordance with conventional assays (eg, J. Malone, Diabetes, 29: 861-864 (1980). "Red Cell Sorbitol, an Indicator of Diabetic Control "). Various aldose reductase inhibitors are known to those skilled in the art, such as those described in U.S. Patent No. 6,579,879, which includes 6- (5-chloro-3-methyl-benzofuran-2-sulfonyl) -2H-pyridazin-3-one.

Any sorbitol dehydrogenase inhibitor can be used in conjunction with a compound of the present invention. The term "sorbitol dehydrogenase inhibitor" refers to compounds that inhibit the bioconversion of sorbitol to fructose that is catalyzed by the enzyme sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitory activity is readily determined by those skilled in the art in accordance with conventional assays (eg, Analyt, Biochem (2000) 280: 329-331). Several inhibitors of sorbitol dehydrogenase are known, for example, US Pat. Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. Any glucosidase inhibitor may be used in conjunction with a compound of the present invention. A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glucoside hydrolases, for example amylase or maltase, into simple bioavailable sugars, for example, glucose. The rapid metabolic action of the glucosidases, particularly after the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to an increased secretion of insulin, an increase in the synthesis of fats and reduction of fat degradation. After such hypergiukaemias, hypoglycemia frequently appears, due to the increase in the levels of insulin present. In addition, it is known that the remaining chyme in the stomach promotes the production of gastric juices, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, it is known that glucosidase inhibitors have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. In addition, the conversion of carbohydrates into fatty tissue lipids and the subsequent incorporation of dietary fats into fatty tissue deposits is therefore reduced or delayed, with the concomitant benefit of reducing or preventing harmful abnormalities resulting therefrom. Such glycoside inhibitory activity is readily determined by those skilled in the art in accordance with conventional assays (e.g., Biochemistry (1969) 8: 4214). A generally preferred glucosidase inhibitor includes an amylase inhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen in maltose. Such amylase inhibitory activity is readily determined by those skilled in the art in accordance with conventional assays (eg, Methods Enzymol. (1955) 1: 149). Inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant detrimental conditions resulting therefrom. Various glucosidase inhibitors are known to a person skilled in the art and examples are given below. Preferred glucosidase inhibitors are those inhibitors that are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimycin-Q and salbostatin. The glucosidase inhibitor, acarbose, and the various amino sugar derivatives related thereto are described in U.S. Patent Nos. 4,062,950 and 4,174,439, respectively. The glucosidase inhibitor, adiposine, is described in U.S. Patent No. 4,254,256. The glucosidase inhibitor, voglibose, 3,4-dideoxy-4 - [[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -2-C- (hydroxymethyl) -D-epi-isositol and the various pseudo- N-substituted amino sugars related thereto are described in U.S. Patent No. 4,701,559. The glucosidase inhibitor, miglitol, (2 /? 3 /? 4 /? 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3, 4,5-piperidinatriol and the various 3,4,5-trihydroxypiperidines related thereto, are described in U.S. Patent No. 4,639,436. The glucosidase inhibitor, emiglitato, p- [2 - [(2?, 3f?, 4 5S) -3,4,5-trihydroxy-2- (hydroxymethyl) piperidino] ethoxy] -ethylbenzoate, the various Related derivatives thereof and pharmaceutically acceptable acid addition salts thereof are described in U.S. Patent No. 5,192,772. The glucosidase inhibitor, MDL-25637, 2,6-dideoxy-7-O-β-D-glucopyran-syl-2,6-imino-glycero-1-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof are described in U.S. Patent No. 4,634,765. The glucosidase inhibitor, camiglibose, 6-deoxy-e- ^ .SJ ^ fJ.dSJ-S ^ .d-trihydroxy ^ -hydroxymethi piperidinoj-aD-glucopyranoside methyl sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the Various pharmaceutically acceptable salts thereof and synthetic procedures for their preparation are described in U.S. Patent Nos. 5,157,116 and 5,504,078. The glucosidase inhibitor, salbostatin and the various pseudosaccharides related thereto, are described in U.S. Patent No. 5,091,524. Various amylase inhibitors are known to one skilled in the art. The amylase inhibitor, tendamistat and the various cyclic peptides related thereto, are described in U.S. Patent No. 4,451,455. The amylase inhibitor AI-3688 and the various cyclic polypeptides related thereto are described in U.S. Patent No. 4,623,714. The amylase inhibitor, trestatin, which consists of a mixture of trestatin A, trestatin B and trestatin C and the various amino sugars containing trehalose related thereto are described in U.S. Patent No. 4,273,765. Other anti-diabetic compounds, which may be used as a second agent together with a compound of the present invention, include, for example, the following: biguanides (eg, metformin), insulin secretagogues (eg, sulfonylureas and glinides), glytazones , PPAR agonists? no glitazone, PPARβ agonists, DPP-IV inhibitors, PDE5 inhibitors, GSK-3 inhibitors, glucagon antagonists, f-1,6-BPase inhibitors (Metabasis / Sankyo), GLP-1 / analogues (AC 2993) , also known as exendin-4), insulin and insulin mimics (Meck natural products). Other examples would include inhibitors of PKC-β and AGE cleavage agents. The compounds of the present invention can be used in conjunction with other anti-obesity agents. Any anti-obesity agent can be used as a second agent in the combinations and examples provided herein. Such anti-obesity activity is easily determined by those skilled in the art according to conventional assays known in the art. Suitable anti-obesity agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, β3 adrenergic receptor agonists, inhibitors of apolipoprotein-B secretion protein / microsomal triglyceride transfer (apo-B / MTP), MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (eg, sibutramine), sympathomimetic agents, serotonergic agents, cannabinoid receptor-1 (CB-1) antagonists (eg, rimonabant (SR-141.716) A)), dopamine agonists (eg, bromocriptine), melanocyte-stimulating hormone receptor analogues, 5HT2c agonists, melanin concentration hormone antagonists, leptin (the OB protein), leptin analogs, beta-agonists, leptin receptor, galanin antagonists, lipase inhibitors (eg, tetrahydrolipstatin, ie, oriistat), bombesin agonists, anorectic agents (eg, an agonist) bombesin sta), neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones or analogs thereof, agonists or antagonists of the glucocorticoid receptor, orexin receptor antagonists, urocortin-binding protein antagonists, peptide-1 receptor agonists, glucagon type, ciliary neurotrophic factors (e.g., Axokine ™), human agouti-related proteins (AGRP), ghrelin receptor antagonists, antagonists or inverse histamine 3 receptor agonists, neuromedine U receptor agonists and the like. Rimonabant (SR141716A also known under the trade name Acomplia ™ is available from Sanofi-Synthelabo) can be prepared as described in U.S. Patent No. 5,624,941. Other suitable CB-1 antagonists include those described in U.S. Patent Nos. 5,747,524, 6,432,984 and 6,518,264.; U.S. Patent Publications No. US2004 / 0092520, US2004 / 0157839, US2004 / 0214855 and US2004 / 0214838; U.S. Patent Application Serial No. 10/971599 filed October 22, 2004; and PCT Patent Publication Nos. WO 02/076949, WO 03/075660, WO04 / 048317, WO04 / 013120 and WO 04/012671. Preferred inhibitors of the apolipoprotein-B secretion protein / microsomal triglyceride transfer (apo-B / MTP) for use as anti-obesity agents are selective intestine MTP inhibitors such as dirlotapide described in U.S. Pat. 6,720,351; 4. (4- (4- (4. ((2 - ((4-methyl-4H-1, 2,4-triazol-3-ylthio) methyl) -2- (4-chlorophenyl) -1, 3-dioxolan-4-yl) methoxy) phenyl) piperazin-1-yl) phenyl) -2-sec-butyl-2H-1,2,4-triazole-3 (4 7) -one (R103757) described in U.S. Patent Nos. 5,521,186 and 5,929,075; and implitapide (BAY 13-9952) described in U.S. Patent No. 6,265,431. As used herein, the term "gut selective" means that the MTP inhibitor has a high exposure to gastro-intestinal tissues versus systemic exposure. Any thyromimetic can be used as a second agent together with a compound of the present invention. Such thyromimetic activity is easily determined by those skilled in the art according to conventional tests (eg, Atherosclerosis (1996) 126: 53-63). Various thyromimetic agents are known to those skilled in the art, for example those described in U.S. Patent Nos. 4,766,121; 4,826,876; 4,910,305; 5,061,798; 5,284,971; 5,401,772; 5,654,468; and 5,569,674. Other anti-obesity agents include sibutramine which can be prepared as described in U.S. Patent No. 4,929,629, and bromocriptine which can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888.

The compounds of the present invention may also be used in conjunction with other antihypertensive agents. Any antihypertensive agent can be used as a second agent in the combinations and examples provided herein. Such antihypertensive activity is easily determined by those skilled in the art in accordance with conventional tests (e.g., blood pressure measurements). Amlodipine and related dihydropyridine compounds are described in U.S. Patent No. 4,572,909. which is incorporated herein by reference, as potent anti-ischemic and antihypertensive agents. U.S. Patent No. 4,879,303, which is incorporated herein by reference, discloses the benzenesulfonate salt of amlodipine (also called amlodipine besylate). Amlodipine and amlodipine besylate are potent and long-lasting calcium channel blockers. As such, amlodipine, amlodipine besylate, amlodipine maleate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and anti-ischemic agents. Amlodipine besilate is currently marketed as Norvasc®. Amlodipine has the formula The starting materials and reagents for the compounds described above of the present invention and the combination agents are also readily available or can easily be synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used in this document relate to, or are derived from, compounds in which there is great scientific interest and commercial need, and therefore many of those compounds are commercially available or are indicated in the literature. or are readily prepared from other commonly available substances by methods indicated in the literature. Some of the compounds of the present invention or intermediates in their synthesis have asymmetric carbon atoms and are therefore enantiomers or diastereomers. The diastereomeric mixtures can be separated into their individual diastereomers according to their physical and chemical differences by known methods, for example by chromatography and / or fractional crystallization. The enantiomers can be separated, for example, by chiral HPLC methods or by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, alcohol), separating the diastereomers and converting (eg, hydrolyzing) the diastereomers. individual in the corresponding pure enantiomers. In addition, an enantiomeric mixture of the compounds or an intermediate in their synthesis containing an acid or basic moiety can be separated into their corresponding pure enantiomers by forming a diastereomeric salt with an optically pure base or chiral acid (e.g., 1-phenylethylamine or tartaric acid) and separating the diastereomers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers. All such isomers, including the diastereomers, enantiomers and mixtures thereof are considered part of the present invention. In addition, some of the compounds of the present invention are atropisomers (e.g., substituted biaryls) and are considered part of the present invention. More specifically, the compounds of the present invention can be obtained by fractional crystallization of the basic intermediate with an optically pure chiral acid to form a diastereomeric salt. Neutralization techniques are used to remove the salt and provide the enantiomerically pure compounds. Alternatively, the compounds of the present invention may be obtained in enantiomerically enriched form by resolving the racemate of the final compound or an intermediate in its synthesis (preferably the final compound) using chromatography (preferably high performance liquid chromatography [HPLC]) or an asymmetric resin (preferably Chiralcel ™ AD or OD (obtained from Chiral Technologies, Exton, Pa.)) With a mobile phase consisting of a hydrocarbon (preferably heptane or hexane) containing isopropanol between 0 and 50% (preferably between 2 and 20%) and between 0 and 5% of an alkylamine (preferably 0.1% diethylamine). The concentration of the fractions containing the product produces the desired materials. Some of the compounds of the present invention are acidic and form a salt with a pharmaceutically acceptable cation. Some of the compounds of the present invention are basic and form a salt with a pharmaceutically acceptable anion. All these salts are within the scope of the present invention and can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in aqueous, non-aqueous or partially aqueous media, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by [i] phylation, as appropriate. The compounds can be obtained in crystalline form by dissolution in appropriate solvent (s) such as ethanol, hexanes or water / ethanol mixtures. The compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs are adapted for therapeutic use as agents that activate the activity of the peroxisome proliferator activating receptor (PPAR) in mammals, particularly humans. In this way, it is believed that the compounds of the present invention, activating the PPAR receptor, stimulate the transcription of key genes involved in the oxidation of fatty acids and also those involved in the binding of high density lipoproteins (HDL) ( for example, transcription of the apolipoprotein Al gene), thereby reducing all body fat and increasing the level of HDL cholesterol. By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and their associated components in mammals, particularly humans, as well as increase HDL cholesterol and apolipoprotein Al. Therefore, these compounds They are useful for the treatment and correction of various dyslipidemias that are observed to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia. The present compounds are also useful for the modulation of lipids or lipoproteins in plasma and / or serum or tissue, such as the HDL subtypes (eg, they increase, including pre-beta HDL, HDL particles 1, 2 and 3). which are measured by precipitation or by apo-protein content, size, density, NMR profile, FPLC, charge and number of particles and their constituents; and the LDL subtypes (including LDL subtypes, for example, lowering LDL of low density, oxidized LDL, VLDL, apo (a) and Lp (a)) that is measured by precipitation, or by, the apo-protein content, size, density, NMR profile, FPLC, load; IDL and remains (decreases); phospholipids (for example, increases HDL phospholipids); apo-lipoproteins (increases A-1, A-1, A-IV, decreases the total level and of LDL and B-100, decreases B-48, modulates C-11, C-III, E, J); paraoxonase (increases, anti-oxidant effects, anti-inflammatory effects); decreases post-prandial (hyper) lipemia; decreases triglycerides, decreases non-HDL; it elevates HDL levels in subjects with low HDL and optimizes and increases the relationships between HDL and LDL (for example, more than 0.25). Given the positive correlation between triglycerides, LDL cholesterol and its associated apolipoproteins in the blood with the development of cardiovascular, vascular cerebral and peripheral vascular diseases, the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of its pharmacological action, are useful for the prevention, interruption and / or regression of atherosclerosis and its associated disease states. These include cardiovascular disorders (e.g., cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, vascular hemostatic disease, cardiac ischemia and myocardial infarction), complications due to cardiovascular disease and cognitive dysfunction (including, but not limitation, dementia secondary to atherosclerosis, transient cerebral ischemic attacks, neurodegeneration, neuronal deficiency and delayed onset or progression of Alzheimer's disease). In this way, given the ability of the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs to reduce the level of plasma triglycerides and the total plasma cholesterol level, and increase the level of HDL cholesterol in plasma, these are of use in the treatment of diabetes, including impaired glucose tolerance, diabetic complications, insulin resistance and metabolic syndrome, as described above. In addition, the compounds are useful for the treatment of polycystic ovarian syndrome. In addition, the compounds are useful for the treatment of obesity given the ability of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs to increase the oxidation of hepatic fatty acids. The utility of the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above diseases / conditions in mammals (e.g., humans, men and women) is demonstrated by the activity of the compounds of the present invention in one or more of the conventional assays and in vivo assays described below. In vivo assays (with appropriate modifications within the practice of the art) can be used to determine the activity of other lipid or triglyceride control agents as well as the compounds of the present invention. In this way, the protocols described below can also be used to demonstrate the utility of the combinations of the agents (ie, the compounds of the present invention) described herein. In addition, such assays provide a means by which the activities of the compounds of the present invention, their prodrugs and the salts of said compounds and prodrugs (or the other agents described herein) can be compared with each other and with the activities of others. known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases. The following protocols, of course, can be varied by those skilled in the art. PPAR FRET Assay The measurement of coactivator recruitment by a nuclear-ligand receptor association is a procedure to evaluate the ability of a ligand to produce a functional response through a nuclear receptor. The PPAR FRET (Fluorescence Resonance Energy Transfer) assay measures the ligand-dependent interaction between the nuclear receptor and the coactivator. The GST / ligand binding domain (LBD) complex of PPAR (a, β and β) is labeled with an anti-GST antibody labeled with europium, while a synthetic peptide SRC-1 (Coactivator-1 of the Sterol Receptor) containing a long-chain biotin molecule at the amino terminus is labeled with streptavidin-binding allophycocyanin (APC). Ligand binding to the LBD of PPAR produces a conformational change that allows it to bind to SRC-1. After binding to SRC-1, the donor molecule FRET (europium) is very close to the acceptor molecule (APC), resulting in a transfer of fluorescence energy between the donor (excitation at 337 nm and emission at 620 nm) and the acceptor (excitation at 620 nm and emission at 665 nm). The increases in the ratio between the emission at 665 nm and the emission at 620 nm is a measure of the ability of the PPAR-LBD to recruit the synthetic peptide SRC-1 and, therefore, a measure of the capacity of a ligand to produce a functional response through the PPAR receptor. [1] GST / LBD expression of PPAR. The LBD of human PPARa (amino acids 235-507) is condensed to the carboxyl terminus of glutathione S-transferase (GST) in pGEX-6P-1 (Pfizer, Inc.). The GST / LBD fusion protein of PPARa is expressed in BL21 [DE3] pLysS cells using induction with 50 μM IPTG at room temperature for 16 hours (cells induced at an A6oo of ~ 0.6). The fusion protein is purified on beads of glutathione sepharose 4B, eluted in reduced glutathione 10 mM and dialyzed against 1 x PBS at 4 ° C. The fusion protein is quantified by the Bradford assay (MM Bradford, Analst. Biochem. 72: 248-254, 1976), and stored at -20 ° C in 1 x PBS containing 40% glycerol and 5 mM dithiothreitol. . [2] FRET assay. The FRET assay reaction mixture consists of 1 x FRET buffer (50 mM Tris-IC pH 8.0, 50 mM KCl, 0.1 mg / ml BSA, 1 mM EDTA and 2 mM dithiothreitol) containing GST / LBD from PPARa 20 nM, a 40 nM concentration of SRC-1 peptide (amino acids 676-700, 5-long-chain biotin-CPSSHSSLTERHKILHRLLQEGSPS-NH2, purchased from American Peptide Co., Sunnyvale, CA), a 2 nM concentration of anti-HIV antibody. GST conjugated with europium (Wallac, Gaithersburg, MD), a 40 nM concentration of APC conjugated with streptavidin (Wallac), and control and test compound. The final volume is brought to 100 μl with water and transferred to a 96-well black plate (Microfuor B, Dynex (Chantilly, VA)). The reaction mixtures are incubated for 1 hour at 4 ° C and the fluorescence is read on a Victor 2 plate reader (Wallac). The data is presented as a relation between the emission at 665 nm and the emission at 615 nm. Evaluation of lipid modulating activity in mice [1] Triglyceride reduction. The activity of hypolipidemic treatment of the compounds of the present invention can be demonstrated by methods based on conventional procedures. For example, the in vivo activity of these compounds to reduce plasma triglyceride levels can be determined in hybrid B6CBAF1 / J mice. Male B6CVAF1 / J mice (8-11 weeks old) are obtained from The Jackson Laboratory and enclosed 4-5 / cage and maintained in a cycle of 12 hours of light / 12 hours of darkness. Animals are allowed access ad /// ?. to rodent feed Purina and water. The animals are administered daily (9 AM) by means of an oral vehicle probe (water or 0.5% methylcellulose, 0.05% Tween 80) or vehicle containing test compound at the desired concentration. Plasma triglyceride levels are determined 24 hours after the administration of the last dose (day 3) from blood collected from the retroorbital sinus with heparinized hematocrit tubes. Triglyceride determinations are performed using a Triglyceride E kit available commercially in Wako (Osaka, Japan). [2] Elevation of HDL cholesterol. The activity of the compounds of the present invention for raising the plasma level of high density lipoproteins (HDL) in a mammal can be demonstrated in transgenic mice expressing the human apoAl and CETP transgenes (HuAICETPTg). Transgenic mice for use in this study have been previously described in Walsh et al., J. Lipid Res 1993, 34: 617-623, Agellon et al., J. Biol. Chem. 1991, 266: 10796-10801. Mice expressing human apoAl and CETP transgenes are obtained by pairing transgenic mice expressing the human apoAl transgene (HuAITg) with CETP mice (HuCETPTg). Male HuAICETPTg mice (aged 8-11 weeks) are grouped according to their human apoAl levels and are allowed free access to Purine rodent feed and water. The animals are administered daily by means of oral vehicle probe (water or 0.5% methylcellulose, 0.05% Tween 80) or vehicle containing test compound at the desired dose for 5 days. HDL-cholesterol and human apoAl are determined initially (day 0) and 90 minutes after dosing (day 5) using procedures based on conventional procedures. Mouse HDL is separated from lipoproteins containing apoB by precipitation with dextran sulfate as described elsewhere in this document (Francone et al., J. Lipid. Res. 1996, 37: 1268-1277). Cholesterol is measured enzymatically using a cholesterol / HP Reagent kit available on the market (Boehringer MannHeim, Indianapolis, IND) and quantified spectrophotometrically in a microplate reader. Human apoAl is measured by an enzyme-linked immunosorbent assay of the sandwich type as previously described (Francone et al., J. Lipid, Res. 1996, 37: 1268-1277). Measurement of glucose reduction in the ob / ob mouse The hypoglycemic activity of the compounds of the present invention can be determined by the amount of test compound that reduces glucose levels relative to a vehicle without test compound in ob / mice ob male The assay also allows the determination of an approximate minimum effective dose (MED) value for the in vivo reduction of the plasma glucose concentration in such mice for such test compounds. Male C57BU6J-ob / ob mice are enclosed from five to eight weeks of age (obtained at Jackson Laboratory, Bar Harbor, ME), five per cage, according to conventional practices for the care of animals. After a one-week acclimatization period, the animals are weighed and 25 μl of blood from the retro-orbital sinus is collected before any treatment. The blood sample is immediately diluted 1: 5 with saline containing 0.025% sodium heparin, and kept on ice for analysis of metabolites. The animals are assigned to treatment groups so that each group has a similar average for the plasma glucose concentration. After allocation of the groups, the animals are administered orally each day, for four days, the vehicle consisting of: (1) 0.25% methyl cellulose w / v in water without adjusting the pH; or (2) Pluronic® P105 Block Copolymer Surfactant (BASF Corporation, Parsippany, NJ) 0.1% in 0.1% saline without pH adjustment. On day 5, the animals are weighed again and then orally receive a test compound or vehicle alone. All compounds are administered in vehicle consisting of: (1) methyl cellulose at 0.25% w / v in water; (2) 10% DMSO / 0.1% Pluronic® in 0.1% saline without pH adjustment; or (3) pure PEG 400 without pH adjustment. Blood is then drawn from the animals through the retro-orbital sinus three hours later to determine the levels of metabolites in the blood. The freshly collected samples are centrifuged for 2 minutes at 10,000 x g at room temperature. The supernatant is analyzed for glucose content, for example, by Abbott VP ™ (Abbott Laboratories, Diagnostics Division, Irving, TX) and VP Super System® Autoanalyzer (Abbott Laboratories, Irving, TX) or by Abbott Spectrum CCX ™ (Abbott Laboratories, Irving, TX) using the A-Gent ™ Glucose-UV asreagent system (Abbott Laboratories, Irving, TX) (a modification of the procedure by Richterich and Dauwaider, Schweiz? Rische Medizinische Wochenschriñ, 101: 860 (1971)) (hexokinase procedure) using a 100 mg / dl standard. Then the plasma glucose is calculated by the equation: Plasma glucose (mg / dl) = Sample value x 8.14 where 8.14 is the dilution factor, adjusted for the plasma hematocrit (assuming that the hematocrit is 44 %). The animals administered vehicle maintain substantially unchanged hyperglycemic glucose levels (eg, greater than or equal to 250 mg / dl), and animals treated with compounds having hypoglycemic activity at adequate doses have reduced glucose levels significantly. The hypoglycemic activity of the test compounds is determined by means of a statistical analysis (t-test without pairs) of the mean plasma glucose concentration between the groupr with test compound and the group treated with vehicle on day 5. The previous test performed with a series of doses of a test compound allows the determination of an approximate minimum effective dose (MED) value for the in vivo reduction of the plasma glucose concentration.

Measurement of insulin, triglyceride and cholesterol levels in the ob / ob mouse The compounds of the present invention readily adapt to clinical use as reversal agents of hyperinsulinemia, triglyceride reducing agents and hypocholesterolemic agents. Such activity can be determined by the amount of test compound that reduces the levels of insulin, triglycerides or cholesterol with respect to a control vehicle without test compound in male ob / ob mice. Since the concentration of cholesterol in blood is closely related to the development of cardiovascular, cerebrovascular or peripheral vascular system disorders, the compounds of the present invention, thanks to their hypocholesterolemic action, prevent, arrest and / or revert atherosclerosis. As the concentration of insulin in blood is related to the promotion of vascular cell growth and the increase in renal sodium retention (in addition to other actions, for example, the promotion of glucose utilization) and these functions are known causes of hypertension, the compounds of the present invention, thanks to their hypoinsulinemic action, prevent, stop and / or revert hypertension. As the concentration of triguecerides in blood contributes to the overall levels of blood lipids, the compounds of the present invention, thanks to their triglyceride reducing activity and / or reducing free fatty acids, prevent, stop and / or revert hyperlipidemia. Free fatty acids contribute to the total level of blood lipids and independently have been negatively correlated with insulin sensitivity in a variety of physiological and pathological states.

C57BL / 6J-ob / ob male mice are enclosed for five to eight weeks (obtained in Jackson Laboratory, Bar Harbor, ME) five per cage, according to conventional practices for the care of animals and fed with a conventional diet of rodents ad libitum After a one-week acclimation period, the animals are weighed and 25 microliters of blood from the retro-orbital sinus is collected before any treatment. The blood sample is immediately diluted 1: 5 with saline containing 0.025% sodium heparin and kept on ice for the analysis of plasma glucose. The animals are assigned to treatment groups so that each group has a similar average for plasma glucose concentration. The compound to be tested is administered by oral gavage as a solution of about 0.02% to 2.0% (w / v) in (1) 10% DMSO / Pluronic® P105 Block Copolymer Surfactant (BASF Corporation, Parsippany, NJ) 0.1% in 0.1% saline without pH adjustment or (2) 0.25% w / v methylcellulose in water without pH adjustment. Alternatively, the compound to be tested can be administered by means of an oral probe dissolved or suspended in pure PEG 400. Only one dose per day (s.i.d.) or two doses per day (b.i.d.) is maintained during 1a, for example, 15 days. Control mice receive 10% DMSO / 0.1% Pluronic® P105 in 0.1% saline without pH adjustment or 0.25% methylcellulose w / v in water without pH adjustment, or pure PEG 400 without pH adjustment. Three hours after the last dose is administered, the animals are sacrificed and blood is collected in 0.5 ml serum separator tubes containing 3.6 mg of a 1: 1 weight / weight mixture of sodium fluoride: potassium oxalate. The freshly collected samples are centrifuged for 2 minutes at 10,000 xg at room temperature and the serum supernatant is transferred and diluted 1: 1 volume / volume with a solution of aprotinin 1 TiU / ml in 0.1% saline without adjusting the pH. The diluted serum samples are then stored at -80 ° C until analysis. The thawed diluted serum samples are analyzed with respect to the levels of insulin, triglycerides, free fatty acids and cholesterol. The concentration of insulin in serum is determined using the Equate® RIA INSULIN kit (double antibody procedure); as specified by the manufacturer) available at Binax, South Portland, ME. The coefficient of variation between tests is < 10% Serum triglycerides are determined using the Abbott VP ™ and VP Super System® Autoanalyzer equipment (Abbott Laboratories, Irving, TX) or the Abbott Spectrum CCX ™ (Abbott Laboratories, Irving TX) using the A-Gent ™ reagent assay system. Triglycerides (Abbott Laboratories, Diagnostics Division, Irving, TX) (enzymatic procedure coupled to lipase, a modification of the procedure of Sampson, et al., Clinical Chemistry 21: 1983 (1975)). Total serum cholesterol levels are determined using the Abbott VP ™ and VP Super System® Autoanalyzer equipment (Abbot Laboratories, Irving, TX) and the A-Gent ™ Cholesterol assay reagent system (enzymatic procedure coupled to cholesterol esterase; modification of the procedure of Allain et al., Clinical Chemistry 20: 470 (1974)) using 100 and 300 mg / dl standards. The concentration of free fatty acids in serum is determined using a WAKO kit (Osaka, Japan) adapted for use with the Abbott VP ™ autoanalyzer and VP Super System® (Abbott Laboratories, Irving, TX) or the Abbott Spectrum CCX ™ (Abbott Laboratories, Irving, TX). Then the levels of insulin, triglycerides, free fatty acids and total cholesterol in serum are calculated by the equations: serum insulin (μU / ml) = Sample value x 2; serum triglycerides (mg / dl) = sample value x 2; Total serum cholesterol (mg / dl) = Sample value x 2; serum free fatty acid (μEq / l) = Sample value x 2; where 2 is the dilution factor. Animals receiving vehicle maintain substantially unchanged and elevated serum levels of insulin (eg 275 μU / ml), triglycerides (eg 235 mg / dl), free fatty acids (1500 mEq / ml) and cholesterol total (for example, 190 mg / dl). The reducing activity of the serum levels of insulin, triglycerides, free fatty acids and total cholesterol of the test compounds is determined by statistical analysis (t-test without partners) of the average serum concentration of insulin, triglycerides or total cholesterol between the group of Test compound and control group treated with vehicle. Measurement of energy expenditure in rats As can be appreciated by those skilled in the relevant art, during an increase in energy expenditure, animals generally consume more oxygen. In addition, metabolic fuels such as, for example, glucose and fatty acids are oxidized to CO2 and H2O with associated heat release, commonly referred to in the thermogenesis art. In this way, the measurement of oxygen consumption in animals, including humans and companion animals, is an indirect measure of thermogenesis. Indirect calorimetry is commonly used in animals, for example, humans, by those skilled in the relevant art to measure such energy expenditure.

Those skilled in the art understand that the increase in energy expenditure and the associated combustion of metabolic fuels resulting in the production of heat can be effective with respect to the treatment of, for example, obesity. The ability of the compounds of the present invention to generate a thermogenic response can be demonstrated according to the following protocol: this in vivo research is designed to evaluate the efficacy of compounds that are PPAR agonists, using as an efficacy endpoint the measurement of the whole body's oxygen consumption. The protocol involves: (a) administering a dosage to obese Zucker rats for approximately 6 days, and (b) measuring oxygen consumption. Male obese Zucker rats having a range of body weights of about 400 g to about 500 g are enclosed for a period of about 3 to about 7 days in individual cages under conventional laboratory conditions before the start of the study. A compound of the present invention and a vehicle are administered by oral gavage as a single daily dose administered between about 3 p.m. and about 6 p.m for about 6 days. A compound of the present invention is dissolved in vehicle containing approximately 0.25% methylcellulose. The dosage volume is about 1 ml. Approximately one day after the last dose of the compound is administered, the oxygen consumption is measured using an open-circuit indirect calorimeter (Oxymax, Columbus Instruments, Columbus, OH 43204). The Oxymax gas detectors are calibrated with N2 gas and a gas mixture (approximately 0.5% CO2, approximately 20.5% O2 and approximately 79% N2) before each experiment. The rats are removed from their cages and their body weights are recorded. The rats are placed in hermetically sealed chambers (43 x 43 x 10 cm) of the Oxymax, the chambers are placed in the activity controllers and then the air flow through the chambers is set at a speed of approximately 1.6 l / min at approximately 1.7 l / min. The Oxymax software then calculates the oxygen consumption (ml / kg / h) for the rats based on the air flow through the chambers and the difference in oxygen content in the inlet and outlet holes. The activity controllers have 15 infrared beams separated approximately one inch (2.54 cm) on each axis, and ambulatory activity is recorded when two consecutive beams are broken, and the results are recorded as counts. Oxygen consumption and ambulatory activity are measured approximately every 10 minutes for a period of approximately 5 hours to approximately 6.5 hours. Resting oxygen consumption is calculated in individual rats by calculating the mean of the values excluding the first five values and the values obtained during periods of time in which the ambulatory activity exceeds approximately 100 accounts. Atherosclerosis Test In vivo The anti-atherosclerotic effects of the compounds of the present invention can be determined by the amount of compound required to reduce the deposition of lipids in rabbit aorta. New Zealand White male rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (fed once a day). Blood is drawn from the rabbits through the marginal vein of the ear and the total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar SD mean for the total plasma cholesterol concentration, the HDL cholesterol concentration and the triglyceride concentration. After the allocation of the groups, the rabbits are daily administered the compound as a mixture in the diet or as a small piece of gelatin-based confection. Control rabbits receive only the dosing vehicle, in the feed or in the manufacture of gelatine. The cholesterol / coconut oil diet is continued along with the administration of the compound throughout the study. Plasma cholesterol, HDL cholesterol, LDL cholesterol and triglyceride values can be determined at any time during the study by obtaining blood from the marginal vein of the ear. After 3-5 months, the rabbits are sacrificed and the aortas are removed from the thoracic arch to the branch of the iliac arteries. The aortas are cleared of adventitia, open longitudinally and then stained with Sudan IV as described by Holman et al. (Lab. Invest. 1958, 7, 42-47). The percentage of stained surface area is quantified by densitometry using an Optima Image analysis system (Image Processing Solutions; North Reading MA). The reduction of lipid deposition is indicated by a reduction in the percentage of surface area stained in the compound receiving group compared to the control rabbits. The utility of the compounds of formula I useful in the present invention, their prodrugs and the salts of such compounds and prodrugs as agents in the treatment of the diseases / conditions described above in ruminants is further demonstrated by the activity of the compounds of the present invention. invention in the assays described below. Negative energy balance To determine the negative energy balance, serum concentrations of NEFA or ketone bodies, or triglyceride levels in liver tissue, are measured. Levels of NEFA and / or triglycerides and / or ketone bodies greater than "normal" are indicators of a negative energy balance. The levels considered "higher than normal" or "excessive" are: NEFA > 800 μmol / l in serum. Triglycerides > 10% w / w in liver tissue. Ketone bodies > 1.2 μmol / l in serum. Determination of changes in blood levels of non-esterified fatty acids (NEFA) and hepatic triglyceride levels: Compounds are administered once or several times during the transition period to dosage levels that are predicted to be effective by comparison of affinity assay results of in vitro receptors in laboratory species and by pharmacokinetic evaluations in cattle. NEFA levels are determined by conventional laboratory procedures, for example, using the commercial WAKO NEFA kit (Wako Chemical Co., United States, Dallas, TX, 994-75409), and the content of hepatic triglycerides is determined using the procedure described in the literature (JK Drackley, JJ Veenhuizen, MJ Richard and JM Young, J Dairy Sci, 1991, 74, 4254)).

All animals can be obtained from a commercial dairy farm approximately 30 days before the anticipated date of delivery. Cows are placed in separate constructions, approximately 10-14 days before their expected dates of calving, and are switched to the TMR-Close-Up dry diet. The inclusion of the animals in the study begins approximately 7 days before their expected dates of delivery. The animals can be moved to the "test" rack, weighed and each AM enclosed in feeding props. At that time, the appropriate doses are administered and the appropriate blood samples are obtained (see the table below with respect to the sample data for the PPAR alpha agonist, compound Z, 2-methyl-5- (4 '- trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid (EXAMPLE 193) The animals included in T01 were treated with vehicle control every other day (eod) starting on estimated day - 7 before delivery, and again at delivery The animals included in T02 were treated with compound Z, 2-methyl-5- (4'-trifluoromethoxy-b-phenyl-4-ylsulfamoyl) -benzoic acid (EXAMPLE 193) every other day not starting on the estimated day -7 before delivery, and again in labor.

As soon as possible after delivery (~ 30 minutes), the cow is transferred to the free stall barn for the next scheduled milk withdrawal (6:00 am and 7:00 pm). Treatments in animals after delivery are given every other day not until day 8. NEFA samples before and after parturition are analyzed using the WAKO NEFA-C test kit (No. 994-75409). Liver biopsies are performed after delivery in all cows on days 5, 10 and 14 after delivery. The tissues are transported on ice and stored frozen at -70 ° F (-21 ° C). At the conclusion of the study, samples are analyzed for hepatic triglyceride levels using the procedure described by Drackiey, J.K. et al., (1991, J Dairy Sci (74): 4254-4264). All animals treated with the test article (T02) showed significantly lower serum NEFA levels (p <0.10) compared to controls on days 1-8, with the exceptions of T02 on day 5 (p. = 0.17). All treatment regimens significantly reduced hepatic triglyceride levels compared to placebo at all time points measured (days 5, 10 and 14 after delivery). Ketone bodies The levels of ketone bodies in serum can be measured by conventional procedures well known to those skilled in the art, for example, using the kits available on the market for this purpose, including the Sigma BHBA kit of order number 310-A. . Milk content: The machines to test the protein, fat or lactose content of the milk are available on the market (MilkoScanTM50, MilkoScanTM4000, MilkoScanTM FT6000 available from Foss Group). The machines for testing the content of somatic cells are also available on the market (Fossomatic TM FC, Fossomatic TM Minor available from Foss Group). The compounds used in this invention can be administered alone or together with one or more other compounds of the invention or together with one or more other drugs (or in the form of any combination thereof). For example, the compounds of this invention can also be mixed with one or more biologically active compounds or agents selected from sedatives, analgesics, anti-inflammatories, analeptics, antibacterials, antidiarrheals, anti-endotoxin, antifungals, respiratory stimulants, corticosteroids, diuretics, parasiticides, preparations of electrolytes and nutritional supplements, growth promoters, hormones and treatments of metabolic diseases, giving an even wider spectrum of veterinary or agricultural utility. Examples of suitable compounds or active agents are listed below: Amylase inhibitors: Acarbose; Glucosidase Inhibitors: Acarbose; Sedatives: ilazine; Analgesics and anti-inflammatories: Lignocaine, Procaine, flunyxine, oxytetracycline, ketoprofen, meloxícam and carprofen; Analeptics: Etamifilína, Doxapram, Diprenorfina, Hioscina, Ketoprofeno, Meloxicam, Petidina, Xilazina and Butorfanol; Antibacterials: Chlortetracycline, Tilosin, Amoxicillin, Ampicillin, Aproamícina, cefquinome, Cephalexin, Clavulanic acid, Florfenicol, Danofloxacin, Enrofloxacin, Marbofloxacin, Framycetin, Procaine penicillin, procaine benzylpenicillin, Benzathine penicillin, sulfadoxlna, Trimethoprim, sulphadimidine, baquiloprim, streptomycin, dihydrostreptomycin, sulfamethoxypyridazine, sulfametoxipuridazina, oxitetracicllna, flunixin, tilmicosin, cloxacillin, erythromycin, neomycin, nafcillin, aureomycin, lineomycin, cefoperazone, cephalonium, oxytetracycline, formosulfathiazole, sulfadiazine and zinc; Antidiarrheals: Hyoscine, Dipyron, carbon, attapulgite, kaolin, isphaghula shell; Anti-endotoxins: Flunixin, ketoprofen; Antifungals: Enilconazole, Natamycin; Respiratory stimulants: florfenicol; Corticosteroids: dexamethasone, betamethasone; Diuretics: frusemide; Parasiticides - amitraz, deltamethrin, moxidectin, doramectin, alpha-cypermethrin, fenvalerate, eprinomectin, permethrin, ivermectin, abamectin, ricobendazole, levamisole, febantel, triclabendazole, fenbendazole, albendazole, netobimin, oxfenazole, oxyclozanide, nitroxinil, morantel; Electrolyte preparations and nutritional supplements: dextrose, lactose, propylene glycol, serum, glucose, glycine, calcium, cobalt, copper, iodine, iron, magnesium, manganese, phosphorus, selenium, zinc, biotin, vitamin B12, vitamin E and other vitamins; Growth promoters: monensin, flavophospholipol, bambermicin, salinomycin, tylosin; Hormones: chorionic gonadotropin, serum gonadotropin, atropine, melatonin, oxytocin, dinoprost, cloprostenol, etiproston, luprostiol, buserelin, estradiol, progesterone and bovine somatotropin; and Metabolic Disease Treatments: calcium gluconate, calcium borogluconate, propylene glycol, magnesium sulfate. The compounds of this invention can also be mixed with one or more biologically active compounds or agents selected from antiprotozoa such as imidocarb, swelling remedies such as dimethicone and poloxalene, and probiotics such as Lactobacilli and streptococci. The administration of the compounds of the present invention can be carried out by any method that releases a compound of this invention systemically and / or locally. These procedures include oral routes, parenteral routes, intraodal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) can be used, for example, when oral administration is inappropriate or when the patient is unable to ingest the medication. drug. In general, an amount of a compound of the present invention is used which is sufficient to achieve the desired therapeutic effect (e.g., lipid depletion).

In general, an effective dose for the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs is in the range of about 0.001 to about 100 mg / kg / day, preferably from about 0.005 to about 5 mg / kg /day. A dose of the combination pharmaceutical agents is used to be used in conjunction with the PPAR agonists which is effective for the indication being treated. Such doses may be determined by conventional tests such as those indicated and provided hereinbefore. The combination agents can be administered simultaneously or sequentially in any order. For example, typically, an effective dose for inhibitors of HMGCoA reductase is in the range of about 0.01 to about 100 mg / kg / day. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a carrier, pharmaceutically acceptable diluent or excipient. In this manner, the compounds of the present invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used together with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc are usually very useful for forming tablets. Solid compositions of similar type are also used as fillers in hard and soft gelatin capsules; Preferred materials in this regard also include lactose or milk sugar as well as high molecular weight polyethylene glycols. A preferred formulation is a solution or suspension in an oil, for example, olive oil, Miglyol ™ or Capmul ™, in a soft gelatin capsule. Antioxidants may be added to prevent long-term degradation as appropriate. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of the present invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as with diluents such as water, ethanol , propylene glycol, glycerin and various similar combinations thereof. For parenteral administration purposes, solutions in sesame oil or arachis oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts may be employed. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, the sterile aqueous medium employed can be readily obtained by conventional techniques well known to those skilled in the art.

For purposes of transdermal (e.g., topical) administration, dilute, aqueous or partially aqueous solutions (usually in a concentration of about 0.1% to 5%) or solutions similar to the above parenteral solutions are prepared. Processes for preparing various pharmaceutical compositions with a certain amount of active ingredient are known or will be obvious in view of this description for those skilled in the art. As examples of methods of preparing pharmaceutical compositions, see Reminqton's Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 19th edition (1995). The pharmaceutical compositions according to the present invention may contain 0.1% -95% of the compounds of the present invention, preferably 1% -70%. In any case, the composition or formulation that is administered will contain an amount of compound (s) according to the present invention in an amount effective to treat the disease / condition of the subject being treated, for example, atherosclerosis. As the present invention has an aspect that relates to the treatment of the diseases / conditions described herein with a combination of active ingredients, which can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. . The kit comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of such a compound or such prodrugs and a second compound as described above. The kit, for example, comprises means for containing the separate compositions such as a container, a divided bottle or a divided laminated container. Typically, the kit comprises guidelines for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), are administered at different dosage intervals, or when the individual components of the combination are desired to be titrated. the doctor who prescribed. An example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules and the like). The blister packs generally consist of a sheet of relatively rigid material covered with a sheet of a preferably transparent plastic material. During the packaging process, cells are formed in the plastic sheet. The alveoli have the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the alveoli and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet opposite the direction in which the alveoli were formed. As a result, the tablets or capsules are hermetically sealed in the alveoli between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister by manually applying pressure on the cells, whereby an opening is formed in the sheet at the site of the socket. Then, the tablet or capsule can be withdrawn through said opening.

It may be desired to provide a reminder in the kit, for example, in the form of numbers close to the tablets or capsules, so that the numbers correspond to the days of the regimen in which the tablets or capsules are to be ingested. Another example of such a reminder is a calendar printed on the card, for example, as indicated below "First Week, Monday, Tuesday, ... etc ... Second Week, Monday, Tuesday, ..." etc. Other variations of reminders will be obvious. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. further, a daily dose of a compound of the present invention can consist of a tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The reminder should reflect this. In another specific embodiment of the invention, a dispenser is provided for dosing the daily doses one at a time in the desired order of use. Preferably, the dispenser has a reminder, to facilitate compliance with the regime. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been dosed. Another example of such a reminder is a battery-powered micro-chip memory coupled with a liquid crystal reader, or an audible reminder signal, for example, that reads aloud the date on which the last daily dose was taken and / or remember when the next dose should be taken. The compounds of the present invention, alone or in combination with each other, or other compounds, will generally be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention. In the formulations shown below, "active ingredient" means a compound of the present invention. Formulation 1: Gelatin capsules Hard gelatine capsules are prepared using the following: Ingredient Amount (mg / capsule) Active Ingredient 0.25-100 Starch, NF 0-650 Fluid starch powder 0-50 silicone fluid 350 centistokes (3.5 cm2 / s) 0-15 A tablet formulation is prepared using the following ingredients: Formulation 2: Tablets t5 Ingredient Quantity (mg / tablet) Active Ingredient 0.25-100 Cellulose, microcrystalline 200-650 Silicon dioxide, pyrolysis 10-650 Stearic acid 5-15 20 The components are mixed and compressed to form tablets. Alternatively, tablets are prepared each containing 0.25-100 mg of active ingredients as follows: Formulation 3: Tablets Ingredient Quantity (mg / tablet) Active Ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (in the form of a 10% solution 4 in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch and cellulose are They pass through a US No. 45 mesh screen and mix thoroughly. The polyvinylpyrrolidone solution is mixed with the resultant powders which are then passed through a US No. 14 mesh screen. The granules produced in this manner are dried at 50 ° -60 ° C and passed through a No. 18 mesh US sieve. Sodium carboxymethyl cellulose, magnesium stearate and talc, previously passed through a US No. 60 mesh screen, are then added to the granules which, after mixing , they are compressed into a tablet machine to produce tablets. Suspensions are prepared each containing 0.25-100 mg of active ingredient per 5 ml dose as follows: Formulation 4: Suspensions Ingredient Quantity (mg / 5 ml) Active Ingredient 0.25-100 mg Sodium carboxymethylcellulose 50 mg Syrup 1, 25 mg Benzoic acid solution 0.10 ml Aromatizante q.v. Coloring q.v. Purified water up to 5 ml The active ingredient is passed through a US sieve of No. 45 mesh and mixed with the sodium carboxymethylcellulose and the syrup to form a uniform paste. The benzoic acid solution, the flavor and the dye are diluted with a little water and added with stirring. Then enough water is added to produce the required volume. An aerosol solution is prepared containing the following ingredients: Formulation 5: Spray Ingredient Quantity (% by weight) Active Ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the mixture it is added to a portion of the propellant 22, cooled to 30 ° C and transferred to a refilling device. Then, the required quantity is fed to a stainless steel vessel and diluted with the remaining propellant. Then, valve units are fitted to the vessel. Suppositories are prepared as follows: Formulation 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 5 Saturated fatty acid glycerides 2,000 The active ingredient is passed through a US No. 60 mesh sieve and suspended in the saturated fatty acid glycerides. previously using the minimum necessary heat. Afterwards, the mixture is. Pour into a suppository mold with a nominal capacity of 2 g and allow to cool. An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution Ingredient _ Amount Active ingredient dissolved in 1% ethanol 20 mg Intralipid ™ emulsion 1,000 ml The solution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per minute. Hard gelatine capsules are prepared using the following: Formulation 8: Hard gelatin capsule with oil formulation Ingredient Quantity (mg / capsule) 20 Active Ingredient 10-500 Olive oil or Miglyol ™ 500-1000 Oil The active ingredient above also It can be a combination of therapeutic agents.

GENERAL EXPERIMENTAL PROCEDURES The following examples are set forth to provide those skilled in the art with a description of how the compounds, compositions and methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of the invention. what the inventors consider their invention. Unless otherwise indicated, the percentage is percentage by weight given the component and the total weight of the composition, the temperature is in ° C or is the ambient temperature and the pressure is or is close to atmospheric. The commercial reagents were used without further purification. Ambient temperature refers to 20-25 ° C. All non-aqueous reactions were performed under a nitrogen atmosphere for convenience and to maximize yields. Concentration under vacuum means that a rotary evaporator was used. The names of the compounds of the invention were created by the batch version of PC Autonom 2.0 of Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4). "DMSO" means dimethyl sulfoxide. The NMR spectrum was recorded on a Varian Unity 400 NMR spectrometer (Varian Co., Palo Alto, CA) at room temperature. Chemical shifts are expressed in parts per million (d) relative to an external standard (tetramethylsilane). The shapes of the peaks are indicated by the following: s, singlet; d, doublet, t, triplet, c, quadruplet, m, multiplet, indicating the prefix to a widened signal. The coupling constant data (J) given have a maximum error of +0.41 Hz due to the digitization of the spectrum that is acquired. The mass spectra were obtained by (1) chemical ionization at atmospheric pressure (APCI) in alternating positive and negative ion mode using a Fisons Platform II Spectrometer or a Micromass MZD Spectrometer (Micromass, Manchester, UK) or (2) ionization by electrospray in alternating positive and negative ion mode using a Micromass MZD Spectrometer (Micromass, Manchester, UK) with a Gilson LC-MS interface (Gilson Instruments, Middleton, Wl) or (3) a QP-8000 mass spectrometer (Shimadzu Corporation, Kyoto, Japan) that operates in the control mode of individual positive or negative ions, using ionization by electronebulization or chemical ionization at atmospheric pressure. When the intensity of the ions containing chlorine or bromine is described, the expected intensity ratio (approximately 3: 1 for ions containing 35CI / 37CI and 1: 1 for ions containing 79Br / 81Br) was observed and only the position of the ion of the smaller mass. Column chromatography was performed with Baker Silica Gel silica gel (40 μm) (J.T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (40-63μm) (EM Sciences, Gibbstown, N.J.). Flash chromatography was performed using a Flash 12 or Flash 40 column (Biotage, Dyar Corp., Charlottesville, VA). Purification by preparative HPLC was performed on a Shimadzu 10A preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) using a SIL-10A automatic sampling device model and HPLC pump model 8A. Preparative HPLC-MS was performed on an identical system, modified with a QP-8000 mass spectrometer operating in the control mode of individual positive or negative ions, using ionization by electrospray or chemical ionization at atmospheric pressure. Elution was performed using water / acetonitrile gradients containing 0.1% formic acid or ammonium hydroxide as modifier. In acid mode, typical columns used include Waters Symmetry C8, 5 μm, 19 x 50 mm or 30 x 50 mm, WatersXTerra C18, 5 μm, 50 x 50 (Waters Corp, Milford, MA) or Phenomenex Synergi Max-RP 4 μm, 50 x 50 mm (Phenomenex Inc., Torrance, CA). In the basic mode, columns were used Phenomenex Synergi Max-RP of 4 μm, 21.2 x 50 mm or 30 x 50 mm (Phenomenex Inc., Torrance, CA). Optical rotations were determined using a Jasco P-1020 Polarimeter (Jasco Inc., Easton, MD). ._ Dimethylformamide, tetrahydrofuran, toluene and dichloromethane were of anhydrous quality supplied by Aldrich Chemical Company (Milwaukee, Wl).

Unless otherwise specified, the reagents were used in the manner that were obtained from commercial sources. The terms "concentrated" and "Evaporated" refers to the removal of the solvent at 1-200 mm (0.13-26.66 kPa) of mercury pressure in a rotary evaporator with a bath temperature of less than 45 ° C. The abbreviation "min" refers to "minutes" and "h" refers to "hours". The abbreviation "g" refers to grams. The abbreviation "μl" refers to microliters. EXAMPLE 1: 5- (4-Benzyloxy-phenylsulfamoyl) -2-methyl-benzoic acid A solution of sodium bicarbonate was added to a solution of 5-chlorosulfonyl-2-methylbenzoic acid (200 mg, 0.85 mmol) and p-benzyloxyaniline (187 mg, 0.94 mmoi) in 6 acetone and 3 ml dimethylformamide. (215 mg, 0.56 mmol) in 2 ml of water. The resulting mixture was stirred overnight at room temperature. Then, the acetone was removed under reduced pressure and the residual mixture was partitioned between 25 ml of a 1 N aqueous hydrochloric acid solution and 25 ml of ethyl acetate. The aqueous phase was separated and extracted with 2 x 25 ml of ethyl acetate. The combined ethyl acetate extracts were dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 15 g) eluting with 9: 1 chloroform / methanol to yield a white solid (154 mg). The solid was triturated with dichloromethane to yield the title compound (93 mg, 28% yield) as a white solid. MS: 395.6 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.57 (s, 3 H), 4.96 (s, 2 H), 6.81 (m, 2 H), 6.93 (m, 2 H), 7.30 ( m, 6H), 7.60 (m, 1 H), 8.20 (m, 1 H). The title compounds of EXAMPLES 2-26 were prepared using procedures analogous to those of EXAMPLE 1 from the appropriate starting materials. EXAMPLE 2: 2-Methyl-5-r4- (6-methyl-benzothiazol-2-yl) -phenylsulfamoip-benzoic acid 8% yield. MS: 439.4 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d, 44 (s, 3 H), 2.53 (s, 3 H), 7.23 (m, 2 H), 7.29 (m, 1 H), 7.34 (m , 1H), 7.72 (m, 1H), 7.75 (m, 1H), 7.80 (m, 1H), 7.88 (m, 2H), 8.19 (m, 1H).

EXAMPLE 3: 2-Methyl-5-r4- (5-methyl-benzooxazol-2-yl) -phenylsulfamam-benzoic acid 4% yield. MS: 423.4 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.42 (s, 3 H), 2.51 (s, 3 H), 7.17 (m, 1 H), 7.26 (m, 2 H), 7.35 ( m, 1H), 7.44 (m, 2H), 7.56 (m, 1H), 8.0 (m, 2H), 8.15 (m, 1H). EXAMPLE 4: 5- (4-Benzooxazol-2-yl-phenylsulfamoyl) -2-methyl-benzoic acid % yield. MS: 407.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.48 (s, 3 H), 7.38 (m, 3 H), 7.65 (m, 1 H), 7.7 (m, 1 H), 7.92 ( m, 3H), 8.22 (m, 1 H). EXAMPLE 5: 2-Methyl-5-f4- (5-phenyl-benzooxazol-2-yl) -phenylsulfamoin-benzoic acid 7% yield. MS: 483.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.48 (s, 3 H), 7.35 (m, 2 H), 7.44 (m, 2 H), 7.64 (m, 3 H), 7.71 ( d, 1H), 7.82 (m, % yield. MS: 44.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.47 (s, 3H), 7.37 (m, 2H). 7.63 (d, 1H), 7.7 (a, 1 H), 7.81 (m, 1H), 7.92 (m, 3H), 8.21 (m, 2H). EXAMPLE 7: 5- (4-Be? Zothiazol-2-yl-phenylsulfamoyl) -2-methyl-benzoic acid 7% yield; MS: 425.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.46 (s, 3 H), 7.26 (m, 3 H), 7.37 (t, 1 H), 7.47 (t, 1 H), 7.62 (d, 1H), 7.91 (m, 4H), 7.98 (a, 1H). EXAMPLE 8: 2-Methyl-5-r4- (4-trifluoromethyl-benzylsulfan-p-phenylsulfamoip-benzoic acid Performance of 33%. MS: 480.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.49 (s, 3 H), 4.04 (s, 2 H). 6.96 (d, 2H), 7.1 (d, 2H), 7.23 (d, 1 H), 7.29 (m, 2H), 7.47 (m, 3H), 7.94 ( a, 1 H). EXAMPLE 9: 2-Methyl-5-r4- (4-trifluoromethyl-benzyloxy) -phenylsulfamam-benzoic acid 28% yield. MS: 464.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.56 (s, 3 H), 5.07 (s, 2 H), 6.83 (m, 2 H), 6.95 (m, 2 H), 7.30 ( d, 1H), 7.57 (m, 3H), 7.63 (d, 2H), 8.13 (s, 1H).

EXAMPLE 10: 2-Methyl-5- (4-styryl-phenylsulfamoyl) -benzoic acid Performance of 33%. MS: 392.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.54 (s, 3 H), 7.05 (m, 4 H), 7.18 (t, 1 H), 7.26-7.4 (m, 5 H), 7.46 (m, 2H), 7.67 (m, 1H), 8.18 (s, 1H). EXAMPLE 11: 2-Methyl-5-r4- (3-trifluoromethyl-benzylsulfanyl) -phenylsulfamoip-benzoic acid 21% yield. MS: 480.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.59 (s, 3 H), 4.06 (s, 2 H), 6.98 (m, 2 H), 7.13 (m, 2 H), 7.34 ( m, 3H), 7.44 (m, 2H), 7.68 (m, 2H), 8.26 (d, 1 H). EXAMPLE 12: 5-r4- (4-Fer-butyl-benzylsulfanyl) -phenylsulfamoyl-2-methyl-benzoic acid Performance of 31%. MS: 468.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1, 24 (s, 9 H), 2.57 (s, 3 H), 3.95 (s, 2 H), 6.95 (m, 2 H), 7.05 ( d, 1H), 7.11 (m, 1H), 7.21 (d, 1H), 7.34 (d, 1H), 7.66 (m, 1H), 8.22 (d, 1H). EXAMPLE 13: 5- (4-Benzothiazol-2-yl-phenylsulfamoyl) -2-ethyl-benzoic acid 6% yield. MS: 439.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.18 (t, 3 H), 2.96 (c, 2 H), 7.27 (d, 2 H), 7.39 (t, 2 H), 7.49 ( t, 1H), 7.79 (d, 1H), 7.94 (m, 4H), 8.15 (d, 1H). EXAMPLE 14: 2-Ethyl-5-f4- (5-methy1-benzooxazol-2-yl-phenylsulfamoip-benzoic acid) 9% yield. MS: 437.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.18 (t, 3 H), 2.45 (s, 3 H), 2.95 (c, 2 H), 7.19 (m, 1 H), 7.29 ( m, 2H), 7.38 (d, 1H), 7.47 (d, 2H), 7.78 (m, 1 H), 8.04 (d, 2H), 8.2 (d, 1 H) ). EXAMPLE 15: 2-Ethyl-5-4- (4-trifluoromethyl-benzylsulfanip-phenylsulfamoip-benzoic acid) Performance of 32%. MS: 495.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1.17 (t, 3 H), 2.93 (c, 2 H), 4.04 (s, 2 H), 6.97 (m, 2 H), 7.11 ( m, 2H), 7.3 (m, 3H), 7.46 (d, 2H), 7.59 (m, 1H), 8.0 (d, 1H). EXAMPLE 16: 5-f4- (4-isopropyl-benzylsulfanyl) -enylsulfamoip-2-methyl-benzoic acid Yield: 10% MS: 454.2 (M-1); 1 H NMR (400 MHz, CD3OD): d 1.17 ( d, 6H), 2.8 (m, 1H), 3.94 (s, 2H), 6.95 (d, 2H), 7.04 (s, 4H), 7.1 (m, 2H), 7.31 (d, 1H), 7.61 (d, 1H), 8.16 (s, 1H) EXAMPLE 17: 2-Methyl-5-r4- (4-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoin- acid benzoic Performance of 29%. MS: 496.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.59 (s, 3 H), 4.01 (s, 2 H), 6.98 (m, 2 H), 7.06 (d, 2 H), 7.14 ( m, 2H), 7.20 (d, 2H), 7.36 (d, 1H), 7.67 (d, 1H), 8.22 (s, 1H). EXAMPLE 18: 5-r4- (4-Chloro-benzylsulfanyl) -phenylsulfamo-p-2-methyl-benzoic acid 7% yield. MS: 448.1 (M + 1); ? NMR (400 MHz, CD3OD): d 2.53 (s, 3H), 3.95 (s, 2H), 6.95 (d, 2H), 7.09 (t, 4H), 7.14 (d , 2H), 7.28 (d, 1H), 7.55 (m, 1H), 8.07 (d, 1H). EXAMPLE 19: 2-Methyl-5-r4- (3-phenoxy-benzylsulfanyl) -phenylsulfamoyl-T-benzoic acid % yield. MS: 504.2 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.54 (s, 3 H), 3.94 (s, 2 H), 6.77 (m, 4 H), 6.89 (d, 1 H), 6.95 ( d, 2H), 7.09 (m, 4H), 7.28 (m, 3H), 7.63 (m, 1H), 8.24 (d, 1H). EXAMPLE 20: 2-Methyl-5- (4- (2-r2- (4-trifluoromethyl-phenyl) -thiazole-4-in-ethoxy> -phenylsulphamoyl-benzoic acid Yield of 72%. MS: 563.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.54 (s, 3 H), 3.22 (t, 2 H), 4.27 (t, 2 H), 6.77 (m, 2 H), 6.93 ( m.2H), 7.29 (d, 1H), 7.34 (s, 1H), 7.55 (m, 1H), 7.74 (d, 2H), 8.09 (d, 3H). EXAMPLE 21: 2-Methyl-5- (4- (2-r2- (4-trifluoromethoxy-phenin-thiazole-4-yl-ethoxy) -phenylsulfamoiD-benzoic acid Yield: 31% MS: 579.1 (M +1); 1 H NMR (400 MHz, CD3OD): d 2.48 (s, 3H), 3.20 (t, 2H), 4.25 (t, 2H), 6.75 (d, 2H), 6.94 (d, 2H), 7.22 (m, 1 H), 7.29 (s, 1H), 7.35 (m, 2H), 7.44 (m, 1H), 7.89 ( s, 1H), 8.00 (d, 2H) EXAMPLE 22: 2,3-Dimethyl-5-r4- (5-methy1-benzooxazol-2-yl) -phenylsulfamoin-benzoic acid 7% yield. MS: 437.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.38 (s, 3 H), 2.39 (s, 3 H), 2.48 (s, 3 H), 7.23 (d, 1 H), 7.53 (m , 2H), 7.74 (s, 2H), 7.94 (d, 2H), 8.21 (d, 2H). EXAMPLE 23: 2,6-D -methyl-3-r4- (6-methyl-benzothiazol-2-yl) -phenylsulfamoip-benzoic acid 16% yield. MS: 453.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.33 (s, 3 H), 2.46 (s, 3 H), 2.63 (s, 3 H), 7.2-7.3 (c, 3 H), 7.32 (d, 1H), 7.73 (s, 1H), 7.8 (d, 1H), 7.88 (m.2H), 8.0 (d, 1H).

EXAMPLE 24: 2,6-Dimethyl-3-4- (3-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoip-benzoic acid / 6% yield. MS: 510.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.34 (s, .3 H), 2.57 (s, 3 H), 4.02 (s, 2 H), 6.95 (m, 2 H), 7.07 (d, 1H), 7.12 (m, 4H), 7.22 (m, 2H), 7.85 (d, 1H). EXAMPLE 25: 2,6-Dimethyl-3-r4- (4-trifluoromethoxy-benzylsulfanyl) -phonyl-sulphamoin-benz acid < 3Ico Performance of 32%. MS: 510.3 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.35 (s, 3 H), 2.62 (s 3 H), 4.01 (s, 2 H), 6, § 7 (m, 2 H), 7.12 (m; 5H), 7.24 (d, 2H), 7.77 (, 1H). EXAMPLE 26: 2,6-Dimethyl-3- (4'-trifluoromethoxy-biphenyl-4-ylsulfamoin-benzoic acid yield 13% .1H NMR (400 MHz, CD3OD): d 2.33 (s, 3H), 2.62 (s, 3H), 7.17 (m, 2H), 7.22 (d, 1H), 7.28 (d, 2H), 7.47 (m, 2H), 7.60 (m, 2H) 7.93 (d, 1H) EXAMPLE 27: 5-r4- (4-Fer-butyl-phenoxy) -phenylsulfamoyl-2-methyl-benzoic acid A solution of 4- (4-tert-butyl-phenoxy) -phenylamine (0.1 g, 0.41 mmol), 5-chlorosulfonyl-2-methylbenzoic acid (0.097 g, 0.41 mmol) and plridine (0, 1 ml, 1.24 mmol) in 2 ml of anhydrous tetrahydrofuran was heated at 60 ° C for 2 h. The reaction mixture was cooled to room temperature and diluted with 30 ml of ethyl acetate. The ethyl acetate solution was washed sequentially with 25 ml of a 1 N aqueous solution of hydrochloric acid and 25 ml of brine, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel), eluting with 9: 1 chloroform / methanol to yield the title compound.

Performance of 82%. MS: 438.3 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1.30 (s, 9H), 2.58 (s, 3H), 6.82 (m, 4H), 7.02 (d, 2H). 7.36 (d, 3H), 7.63 (d, 1H), 8.1 (a, 1H). The title compounds of EXAMPLES 28-40 were prepared using procedures analogous to those of EXAMPLE 27 from the appropriate starting materials. EXAMPLE 28: 5-r4- (4-Ethyl-benzylsulfanyl) -phenylsulfamoin-2-methyl-benzoic acid Performance 78%. MS: 442.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.15 (t, 3 H), 2.54 (c, 2 H), 2.57 (s, 3 H), 3.94 (s, 2 H), 6.94 ( m, 3H), 7.01 (m, 3H), 7.10 (d, 2H). 7.33 (d, 1H), 7.64 (m, 1H), 8.20 (d, 1H). EXAMPLE 29: 2-Methyl-5-f3-metii-4 - ('4-trifluoromethyl-benzyloxy) -phenylsulfamoip-benzoic acid 6% yield. MS: 478.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d, 17 (s, 3 H), 2.60 (s, 3 H), 5.11 (s, 2 H), 6.80 (m, 2 H), 6.88 (s) , 1H), 7.36 (d, 1H), 7.63 (m, 5H), 8.20 (d, 1H).

EXAMPLE 30: 2-Methyl-5-r 2 -methyl-4- (4-trifluoromethyl-benzyloxy) -phenylsulfamoip-benzoic acid 65% yield. 1 H NMR (400 MHz, CD3OD): d 2.00 (s, 3H), 2.62 (s, 3H), 5.10 (s, 2H), 6.71 (m, 1H), 6.79 (d, 1), 6.87 (d, 1H), 7.36 (d, 1H) , 7.59 (m, 3H), 7.66 (d, 2H). EXAMPLE 31: 5- (4- (2-5 5 - (3,5-dimethyl-phenyl-1,31-oxadiazol-2-ylsulfanip-ethyl) -phenylsulfamoyl) -2-methyl-benzoic acid 49% yield. MS: 524.4 (M + 1); 1 H NMR (400 MHz, CDCl 3): d 2.36 (s, 3 H), 2.59 (s, 3 H), 3.03 (t, 2 H), 3.41 (t, 2 H), 7.05 ( d, 2H), 7.13 (d, 3H), 7.27, (a, 1H), 7.61 (s, 2H), 7.75 (a, 1H), 8.14 (a, 1H) . EXAMPLE 32: D- - ^ - rd-O.d-dichloro-phenyldi-S-Ioxadiazole ^ -ylsulfanyl-T-ethyl) -phenylsulfamoyl) -2-methyl-benzoic acid 90% yield. MS: 566.3 (M + 1); 1 H NMR (400 MHz, CDCl 3): d 2.55 (s, 3 H), 2.97 (t, 2 H), 3.38 (t, 2 H), 7.03 (m, 5 H), 7.18 ( d, 1H), 7.53 (d, 1H), 7.63 (m, 1H), 7.77 (m, 1H), 8.02 (d, 1H). EXAMPLE 33: 5-f4- (3-difluoromethoxy-benzylsulfanyl) -phenylsulfamoin-2-methyl-benzoic acid 40% yield. MS: 478.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.58 (s, 3 H), 4.01 (s, 2 H), 6.98 (c, 5 H), 7.14 (m, 2 H). 7.20 (t, 1H), 7.33 (d, 1H), 7.63 (m, 1H), 7.87 (s, 1H), 8.19 (d, 1H). EXAMPLE 34: 2-Methyl-5-f4- (2-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoip-benzoic acid Yield of 27%. MS: 498.3 (M + 1); 1 H NMR (400 MHz, CDCl 3): d 2.60 (s, 3 H), 3.98 (s, 2 H), 7.01 (d, 2 H), 7.10 (c, 5 H), 7.23 ( c, 2H), 7.68 (m, 1H), 8.41 (d.1H). EXAMPLE 35: 2-Methyl-5-r4- (4-trifluoromethyl-phenylsulfamoip-phenylsulfamoip-benzoic acid 6% yield. MS: 512.9 (M-1); 1 H NMR (400 MHz, CD3OD): d 2.55 (s, 3H), 7.20 (m, 3H), 7.30 (d, 1H), 7.48 (d, 2H), 7.66 (m, 3H), 7.90 (s) , 1 H), 8.20 (d.h.H). EXAMPLE 36: 5- (4-R5- (4-ethyl-phenyl) -f1, 3.41-oxadiazol-2-in-phenylsulfamoyl) -2-methyl-benzoic acid 34% yield. 1 H NMR (400 MHz, CD 3 OD): d 1.28 (t, 3 H), 2.60 (s, 3 H), 2.74 (c, 2 H), 7.34 (m, 2 H), 7.43 ( m, 3H), 7.87 (m, 2H), 8.03 (m, 3H), 8.38 (d, 1H). EXAMPLE 37: 5-r4- (5-tert-butyl-p.3.41-oxadiazol-2-in-phenylsulfamoip-2-methyl-benzoic acid 51% yield. MS: 416.7 (M + 1); 1H FlIN (400 MHz, CD3OD): d 1.46 (s, 9H), 2.60 (s 3 H), 7.30 (m, 2 H), 7.42 (d, 1 H), 7.84 ( m, 1H), 7.89 (m, 2H), 8.35 (d, 1H). EXAMPLE 38: 2-Methyl-5-f4-y5- (4-trifluoromethoxy-phenyl) -ri.3.47-oxadiazol-2-ip-phenylsulfamoyl) -benzoic acid 6% yield. MS: 518.0 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.47 (s, 3 H), 7.2-7.34 (m, 4 H), 7.50 (d, 1 H), 7.67 (m, 1 H), 7.92-8.04 (m, 4H), 8.22 (d, 1H). EXAMPLE 39: 2-Methyl-5-r4- (5-trifluoromethyl-pyridin-2-ylcarbamoy-phenylsulfamoip-benzoic acid methyl ester 60% yield. MS: 492.0 (M-1) EXAMPLE 40: 5-R4- (5-cyclohexyl-H, 3,41-oxadiazol-2-yl) -phenylsulfamoip-2-methyl-benzoic acid methyl ester Performance of 32%. MS: 454.1 (M-1) The title compounds of EXAMPLES 41-82 were prepared using procedures analogous to those of EXAMPLE 1 from the appropriate starting materials.

EXAMPLE 83: 2-Methyl-5-r4- (4-trifluoromethyl-benzylsulfaniD-phenylsulfamoip-benzoic acid methyl ester A solution of sodium bicarbonate (667 mg, 7.94 mmol) in 4.5 mL of water was added to a solution of 4- (4-trifluoromethyl-benzylsulfanyl) -phenylamine (750 mg, 2.65 mmol) and methyl ether of 5-chlorosulfonyl-2-methyl-benzoic acid (855 mg, 3.44 mmol) in 14 ml of acetone and the resulting mixture was stirred at room temperature overnight. Then, the reaction mixture was diluted with 60 ml of chloroform and washed sequentially with a 1 N aqueous solution of hydrochloric acid (2 x 50 ml), water (50 ml) and brine (40 ml). The chloroform solution was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to a brownish oil (1.59 g). The crude product was purified by flash column chromatography (silica gel, 40 g), eluting with 8: 2 hexane / ethyl acetate to yield a yellowish oil (1.3 g). Trituration of the oil in 5 ml of a 98: 2 mixture of hexane / diethyl ether and filtration of the resulting solid afforded the title compound as a white solid (1.13 g, 86% yield). MS: 480.2 (M-1) The title compounds of EXAMPLES 84-153 were prepared using procedures analogous to those of EXAMPLE 83 from the appropriate starting materials and are shown in the table below. 98 Methyl ester of Rendimi acid 5- [4- (3,4- difluoro- 83%. benzylsulfanyl) - MS: phenylsulfamoyl] -2- 462.2 methyl-benzoic acid (M-1) 99 Rendimi Methyl 5- [4- (3,5-ento-J-s-trifluoromethyl-85% benzylsulfanyl) -MS: phenylsulfamoyl] -2- 562.2 methyl-benzoic acid (M-1) 100 Rendimi methyl ester 2-methyl-5- [4- (4-trifluoromethyl-74% benzylsulfanyl) -MS: phenylsulfamoyl] -494,2 benzoic acid (M-1) acid Rendimi 5-methyl ester [4- (3,4-dimetyl- 92% benzylsulfanyl) -MS: phenylsulfamoyl] -2-454,3-methyl-benzoic acid (M-1) 110 Rendimidate methyl ester 5- [4- (3,5 - of difluoro-benzyloxy) - 91%. phenylsuifamoyl] -2- MS: methyl benzoic 446.1 (M-1) 111 Rendimi methyl ester 5- [4 - '(3,4-ento difluoro-benzyloxy) -77% acid. phenylsulfamoyl] -2- EM: methylbenzoic acid 446.2 (M-1) 12 Rendimi methyl ester 5- [4- (5,7-fluoro-difluoro-59% benzothiazole-2-EM: ilmethylsulfanyl) - 521.0 phenylsulfamoyl] -2- (M + 1) methyl-benzoic acid 13 Rendimi methyl ester 2-isopropyl- ento acid 5- [4- (6-methyl-48%, benzothiazol-2-yl) - MS: . phenylsulfamoyl] - 481.1. benzoic (M + 1) 10 t5 0 121 Rendimi methyl ester 5- (4- (4- (4-butoxy-benzylsulfanyl) -amino acid: phenylsulfamoyl) -2,48.2 methyl-benzoic acid (M-1) 122 Rendimi methyl ester 5- [4- (2,3-fluoro- difluoro- 79% benzylsulfanyl) -MS: phenylsulfamoyl] -2- 463,8 methylbenzoic acid (M + 1) 123 Rendimi Methyl 5- [4- (difluoro- 81% benzylsulfanyl) - MS: phenylsulfamoyl] -2- 462.2 methylbenzoic acid (M-1) 24 Rendimi V Methyl ester --Oo - CcH, 'H > 1H CH, 2-methyl-5- [4- (4-98% trifluoromethylsulfan MS: il-benzylsulfanyl) -528.3-phenylsulfamoyl] - (M + 1) acid. benzoic twenty EXAMPLE 152: 2.3-Dimethyl-5-f4- (4-trifluoromethoxy-benzylsulfaniD-phenylsulfamoip-benzoic acid methyl ester) 41% yield. 1 H NMR (400 MHz, CD3CI): d 2.31 (s, 3 H), 2.48 (s, 3 H), 3.88 (s, 3 H), 4.01 (s, 2 H), 6.95 ( d, 2H), 7.08 (d, 2H), 7.16 (d, 2H), 7.21 (d, 2H), 7.61 (s, 1 H), 8.04 (s, 1 H) ). EXAMPLE 153: Methyl ester of 5-f4- (1 H-benzoimidazol-2-n-phenylsulfamoip-2-isopropyl-benzoic acid methyl ester) t5 41% yield. 1 H NMR (400 MHz, CD3CI): d 1.16 (d, 6H), 3.67 (m, 1H), 3.83 (s, 3H), 7.11 (d, 2H), 7.23 ( c, 2H), 7.42 (d, 1H), 7.61 (c, 2H), 7.85 (c, 3H). 8.23 (d, 1H). EXAMPLE 154: 5- (4'-Butyl-2-phenyl-4-ylsulfamoyl-2-methylbenzoic acid methyl ester A mixture of 4-butylbenzeneboronic acid (174 mg, 0.975 mmol), 5- (4-bromo-phenylsulfamoyl) -2-methyl-benzoic acid methyl ester (150 mg, 0.39 mmol), dichloro [1.1] b / s (diphenylphosphino) ferrocene] palladium (II) adduct of dichloromethane (16 mg, 0.019 mmol), l.l '-? / Siddiphenylphosphinojferrocene (11 mg, 0.019 mmol) and potassium carbonate (0.39 ml of an aqueous solution 2 M, 0.78 mmol) in 15 ml of 1,4-dioxane was heated to reflux in a nitrogen atmosphere for 20 h. The reaction mixture was cooled to room temperature, diluted with 80 ml of water and extracted with 2 x 70 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 60 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 15 g), eluting with 6: 1 hexane / ethyl acetate to yield the title compound as a white solid (109 mg, 64% yield) ). MS: 422.1 (M-1) The title compounds of EXAMPLES 155-173 were prepared t5 using procedures analogous to those of EXAMPLE 154 from the appropriate starting materials and the results are presented below. twenty EXAMPLE 174: 2-Methyl-5-r4- (4-trifluoromethyl-benzylsulfanyl) -phenylsulfamoip-benzoic acid A solution of 1.0 N acid sodium hydroxide (9.1 ml, 9.16 mmol) was added to a solution of 2-methyl-5- [4- (4-trifluoromethyl-benzylsulfanyl) -methyl ester - phenylsulfamoyl] -benzoic acid (1.13 g, 2.29 mmol). in 100 ml of methanol and the resulting solution was heated to reflux overnight under a nitrogen atmosphere. Then, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was stirred in a 1.0 N aqueous solution of hydrochloric acid (25 ml) and filtered to give the title compound as a white solid (1.03 g, 94% yield). MS: 480.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.49 (s, 3 H), 4.04 (s, 2 H), 6.96 (d, 2 H), 7.1 (d, 2 H), 7.29 ( m, 2H), 7.33 (d, 1H), 7.47 (m, 3H), 7.94 (a, 1H). The title compounds of EXAMPLES 175-258 were prepared using procedures analogous to those of EXAMPLE 174 from the appropriate starting materials. EXAMPLE 175: 5-r4- (biphenyl-4-ylmethylsulfanyl) -phenylsulfamoip-2-methyl-benzoic acid Yield of 30%. MS: 488.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.48 (s, 3 H), 4.15 (s, 2 H), 6.99 (d, 2 H), 7.22 (m, 2 H), 7.32 ( m, 3 H), 7.43 (m, 3 H), 7.52 (m 2 H), 7.61 (m, 2 H), 7.70 (m, 1 H), 8, 18 (d, 1 H) . EXAMPLE 176: 5- (4-r2- (4-Chloro-phenylHiazol-5-ylmethylsulfan-n-phenylsulfamoiD-2-methyl-benzoic acid Yield: 99%) MS: 529.0 (M-1); 400 MHz, CD3OD): d 2.60 (s, 3H), 4.15 (s, 2H), 6.99 (m, 2H), 7.19 (m, 2H), 7.3-7.5 (c, 5H), 7.87 (d, 2H), 8.27 (d, 1H) EXAMPLE 177: 2-Methyl-5-r4- (quinolin-2-ylmethylsulfanyl) -phenylsulfamoin-benzoic acid 56% yield. MS: 465.2 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.59 (s, 3 H), 4.29 (s, 2 H), 6.95 (d, 2 H), 7.18 (d, 2 H), 7.29 ( d, 1 H), 7.41 (d, 1 H), 7.56 (m, 1 H), 7.64 (d, 1 H), 7.73 (m, 1 H), 7.88 (c, 2 H) ), 8.19 (d, 1H), 8.26 (s, 1H). EXAMPLE 178: 2-Methyl-5-r4- (5-phenyl-n.2.41-oxadiazol-3-ylmethylsulfanin-phenylsulfamoyl-benzoic acid 85% yield: MS: 481.0 (M-1); 1 H NMR (400 MHz , DMSO-D6): d 2.51 (s, 3H), 4.28 (s, 2H), 7.02 (d, 2H), 7.31 (d, 2H), 7.43 (d, 1H ), 7.61 (m, 2H), 7.70 (m, 2H), 8.04 (m, 2H), 8.19 (s, 1 H) EXAMPLE 179: 5-r4- (4-) acid fluoro-benzylsulfanyl) -phenylsulfamoip-2-methyl-benzoic acid Yield of 85%. MS: 430.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.53 (s, 3 H), 4.08 (s, 2 H), 7.01 (m, 4 H), 7.17 (m, 2 H), 7, 23 (m, 2H), 7.46 (d, 1H), 7.71 (m, 1H), 8.17 (d, 1H). EXAMPLE 180: 2-Methyl-5-f4- (naphthalen-2-ylmethylsulfanip-phenylsulfamoip-benzoic acid) Performance of 82%. MS: 462.0 (M-1); 1 H NMR (40Q MHz, DMSO-D6): d 2.49 (s, 3H), 4.27 (s, 2H), 6.97 (d, 2H), 7.21 (m, 2H), 7, 39 (m, 2H), 7.46 (m, 2H), 7.68 (m, 1H), 7.72-7.87 (m, 4H), 8.18 (d, 1H). EXAMPLE 181: 2-Methyl-5-r4- (3-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoip-benzoic acid 74% yield. MS: 496.3 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.49 (s, 3 H), 4.15 (s, 2 H), 6.97 (m, 2 H), 7.19 (c, 5 H), 7, 33 (m, 1 H), 7.44 (d, 1H), 7.71 (m, 1H), 8.17 (d, 1H). EXAMPLE 182: 2-Methyl-5- (4-naphthalen-1-yl-phenylsulfamoin-benzoic acid) 69% yield. MS: 416.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.49 (s, 3 H), 7.22 (d, 2 H), 7.34 (m, 3 H), 7.48 (m, 4 H), 7, 67 (d, 1H), 7.91 (m, 3H), 8.23 (d, 1H). EXAMPLE 183: 5- (3'.5'-Ib / s-trifluoromethyl-biphenyl-4-ylsulfamoyl) -2-methyl-benzoic acid 81% yield. MS: 501, 9 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.59 (s, 3 H), 7.27 (m, 2 H), 7.40 (d, 1 H), 7.59 (m, 2 H), 7.80 ( d, 1H), 7.82 (d, 1H), 8.08 (s, 2H), 8.35 (d.1H). EXAMPLE 184: 2-Methyl-5- (4-naphthalen-2-yl-phenylsulfamoyl) -benzoic acid 65% yield. MS: 416.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.53 (s, 3 H), 7.21 (d, 2 H), 7.49 (m, 3 H), 7.70 (d, 2 H), 7, 75 (m, 1H), 7.81 (m, 1H), 7.92 (m, 2H), 8.11 (s, 1H), 8.24 (d, 1H). EXAMPLE 185: 2-Methyl-5- (4'-trifluoromethyl-biphenyl-4-ylsulfamo-p-benzoic acid) 81% yield. MS: 434.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.53 (s, 3 H), 7.20 (m, 2 H), 7.49 (d, 1 H), 7.63 (d, 2 H), 7, 72-7.84 (m, 5H), 8.24 (d, 1H). EXAMPLE 186: 5- (4'-Ethylsulfanyl-biphenyl-4-ylsulfamoyl) -2-methyl-benzoic acid 79% yield. MS: 426.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 1.22 (t, 3 H), 2.53 (s, 3 H), 2.98 (c, 2 H), 7.15 (d, 2 H), 7, 32 (d, 2H), 7.51 (m, 5H), 7.79 (m, 1H), 8.22 (d, 1H). EXAMPLE 187: 5-r4- (1H-benzoimidazol-2-yl) -phenylsulfamoin-2-methyl-benzoic acid 94% yield. MS: 408.2 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.60 (s, 3 H), 7.46 (m, 3 H), 7.59 (m, 2 H), 7.76 (m, 2 H), 7.92 ( m, 1H), 8.00 (m, 2H), 8.40 (d, 1H). EXAMPLE 188: 2-Methyl-5- (3'-trifluoromethyl-biphenyl-4-ylsulfamoiD-benzoic acid Performance of 43%. MS: 434.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.53 (s, 3 H), 7.19 (d, 2 H), 7.48 (d, 1 H), 7.64 (c, 4 H), 7, 81 (m.1H), 7.88 (c, 2H), 8.23 (d, 1H). EXAMPLE 189: 5- (4-Benzoyl-1-thiophen-2-yl-phenylsulfamoyl) -2-methyl-benzoic acid 80% yield. MS: 422.0 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.53 (s, 3 H), 7.18 (d, 2 H), 7.33 (m, 2 H), 7.49 (d, 1 H), 7.65 ( m, 2H), 7.73 (s. 1H), 7.80 (m, 2H), 7.92 (m, 1H), 8.23 (d, 1H). EXAMPLE 190: S - ^ '- Benzyloxy-biphenium-1-sulphamoyl-methyl-benzoic acid 74% yield. MS: 472.3 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.52 (s, 3 H), 5.11 (s, 2 H), 7.03 (m, 2 H), 7.12 (d, 2 H), 7, 28-7.52 (c, 10 H), 7.78 (m, 1H), 8.21 (d, 1H). EXAMPLE 191: 2-Methyl-5- (4'-propoxy-biphenyl-4-ylsulfamoyl) -benzoic acid Performance of 61%. 1 H NMR (400 MHz, DMSO-D 6): d 0.95 (t, 3 H), 1.7 (m, 2 H), 2.52 (s, 3 H), 3.91 (t, 2 H), 6, 93 (d, 2H), 7.11 (d, 2H), 7.47 (d, 5H), 7.77 (d, 1H), 8.31 (s, 1H). EXAMPLE 192: 2-Methyl-5- (2'-methylsulfanyl-biphenyl-4-ylsulfamoyl) -benzoic acid 87% yield. MS: 412.3 (M-1); 1 H NMR (400 MHz, DMSO-D6): d 2.48 (s, 3H), 2.54 (s, 3H), 7.06-7.17 (c, 4H), 7.17-7.34 (c, 4H), 7.49 (d, 1H), 7.81 (m, 1H), 8.22 (d.1H). EXAMPLE 193: 2-Methyl-5- (4'-trifluoromethoxy-biphenl-4-ylsulfamoyl) -benzoic acid 69% yield. MS: 450.2 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d 2.48 (s, 3 H), 7.17 (d, 2 H), 7.38 (d, 2 H), 7.48 (d, 1 H), 7, 56 (d, 2H), 7.68 (d, 2H), 7.80 (m, 1H), 8.22 (d, 1H). EXAMPLE 194: 2-Methyl-5- (2'-trifluoromethyl-biphenyl-4-ylsulfamoip-benzoic acid 64% yield. MS: 434.3 (M-1); 1 H NMR (400 MHz, DMSO-D 6): d (s, 3 H), 7.11 (d, 2 H), 7.17 (d, 2 H), 7.30 (d, 1 H), 7.48 (d , 1H), 7.55 (m, 1H), 7.65 (m, 1H), 7.78 (m, 2H), 8.20 (d, 1 H), 7.78 (d, 2H). EXAMPLE 195: 2-Ethyl-5- (4'-trifluoromethyl-2-phenyl-4-ylsulfamo-p-benzoic acid) 90% yield. MS: 448.3 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1.19 (t, 3 H), 3.01 (c, 2 H), 7.23 (d, 2 H), 7.43 (d, 1 H), 7.56 ( d, 2H), 7.68 (d, 2H), 7.73 (d, 2H), 7.82 (m, 1H), 8.28 (d, 1H). EXAMPLE 196: 2-Methyl-5- (2-phenyl-benzooxazol-6-ylsulfamoyl) -benzoic acid Yield of 85%. MS: 409.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.58 (s, 3 H), 7.07 (m, 1 H), 7.38 (d, 1 H), 7.5-7.6 (c, 5 H), 7.75 (m, 1H), 8.18 (m, 2H), 8.29 (d, 1H). EXAMPLE 197: 2-Methyl-5- (2-phenyl-benzothiazol-6-ylsulfamoyl) -benzoic acid - ' 93% yield. MS: 425.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.58 (s, 3 H), 7.23 (m, 1 H), 7.38 (d, 1 H), 7.51 (c, 3 H), 7.76 ( c, 2H), 7.85 (d, 1H), 8.04 (c, 2H), 8.30 (d, 1H). EXAMPLE 198: 5-r4- (5-Fer-butyl-benzooxazol-2-yl) -phephenylsulfameth-2-methyl-benzoic acid 62% yield. MS: 465.4 (M + 1); 1 H NMR (400 MHz. CD 3 OD): d 1.38 (s, 9 H), 2.59 (s, 3 H). 7.31 (m, 2H), 7.42 (d, 1H), 7.46 (d, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.69 ( d, 1 H), 7.85 (m, 1 H). EXAMPLE 199: 5-r4- (3,4-d.fluoro-benzylsulfanin-phenylsuiphenamn-2-methyl-benzoic acid yield 77% .MS: 448.2 (M-1); 1 H NMR (400 MHz, CD3OD) : d 2.61 (s, 3H), 3.98 (s, 2H), 6.89 (c, 1H), 6.97-7.12 (c, 3H), 7.18 (m, 2H) 7.38 (d, 1H), 7.69 (m, 1H), 8.27 (d, 1H) EXAMPLE 200: 5-f4- (3.5-)) / s-trifluoromethyl-benzylsulfanyl) -fen Lsulfamoin-2-methyl-benzoic 80% yield. MS: 548.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.61 (s, 3 H), 7.02 (m, 2 H), 7.16 (m, 2 H), 7.37 (d, 1 H), 7.71 ( m, 2H), 8.30 (d, 1H). EXAMPLE 201: 2-Methyl-5-r4- (2-trifluoromethyl-benzylsulfanyl) -phenylsulfamoip-benzoic acid 86% yield. MS: 480.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.62 (s, 3 H), 4.15 (s, 2 H), 7.02 (m, 2 H), 7.14-7.25 (c, 3 H), 7, 34-7.42 (c, 3H), 7.61 (m, 1H), 7.73 (m, 1 H), 8.29 (d, 1H). EXAMPLE 202: 5-Ib -? / 3,4-dimethyl-benzylsulfanyl) -phenylsulfamoifl-2-methyl-benzoic acid Yield of 85%. MS: 439.9 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.15 (s, 3 H), 2.19 (3, 3 H), 2.61 (s, 3 H), 3.94 (s, 2 H), 6.83 ( d, 1H), 6.95 (c, 2H), 6.98 (m, 2H). 7.14 (m, 2H), 7.38 (d, 1H), 7.70 (m, 1H), 8.28 (d, 1H). EXAMPLE 203: 5-r4- (2.4-6 / s-trifluoromethyl-benzylsulfanyl) -phenylsulfamoyl-2-methyl-benzoic acid 80% yield. MS: 548.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.61 (s, 3 H), 4.21 (s, 2 H), 7.04 (m, 2 H), 7.19 (m, 2 H), 7.39 ( m, 2H), 7.67 (d, 1H), 7.74 (m, 1H), 7.87 (s, 1H), 8.28 (d, 1H). EXAMPLE 204: 5-l4- (2-Chloro-4-fluoro-benzyl-sulfanyl) -phenylsulfamoyl-2-methyl-benzoic acid. 84% yield. MS: 464.0 (M-1) EXAMPLE 205: 5-r4- (5,6-Difluoro-benzothiazol-2-ylmethylsulfanyl) -phenylsulfamoin-2-methyl-benzoic acid 49% yield. MS: 507.0 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.58 (s, 3H). 4.46 (s, 2H), 7.01 (d, 2H), 7.29 (m, 3H), 7.70 (ni, 2H), 7.85 (m, 1H), 8.26 (d , 1 HOUR). EXAMPLE 206: 5-r4- (5-Fluoro-benzothiazol-2-ylmethylsulfanH) -phenylsulfamap-2-methyl-benzoic acid 80% yield. MS: 489.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d, 58 (s, 3H). 4.47 (s, 2H), 7.02 (m, 2H), 7.21 (m, 1H), 7.28 (c, 3H), 7.55 (m, 1H),, 65 (m, 1 H), 7.89 (m, 1 H), 8.27 (d, 1 H).

EXAMPLE 207: 5-r4- (3,5-Dimethyl-benzyloxy) -phene-sulphamoyl-2-methyl-benzoic acid 87% yield. MS: 424.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.28 (s, 6 H), 2.60 (s, 3 H), 4.90 (s, 2 H), 6.83 (m, 2 H), 6.95 ( c, 5H), 7.35 (d, 1H), 7.62 (m, 1H). 8.22 (d, 1H). EXAMPLE 208: 5-r4- (4-Butoxy-benzyloxy) -phenylsulphamoxy-2-methyl-benzoic acid 88% yield. MS: 468.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 0.98 (s, 3 H), 1.50 (m, 2 H), 1.73 (m, 2 H), 2.60 (s, 3 H), 3.96 ( t, 2H), 4.90 (s, 2H), 6.83 (d, 2H), 6.88 (d, 2H), 6.95 (d, 2H), 7.28 (d, 2H), 7.35 (d, 1H), 7.62 (m, 1H), 8.21 (d, 1H). EXAMPLE 209: 5-f4- (2-Chloro-4-fluoro-benzyloxy) -phenylsulfamoip-2-methyl-benzoic acid 84% yield; MS: 448.0 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.60 (s, 3 H), 5.05 (s, 2 H), 6.86 (m, 2 H), 6.98 (m, 2 H), 7.08 ( m, 1H), 7.25 (m, 1H), 7.36 (d, 1H), 7.53 (m, 1H), 7.64 (m, 1H), 8.21 (d, 1H). EXAMPLE 210: 5-f4- (2,3-difluoro-benzyloxy) -phenylsulfamoip-2-methyl-benzoic acid Performance of 82%. MS: 432.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.60 (s, 3 H), 5.08 (s, 2 H), 6.87 (m, 2 H), 6.99 (m, 2 H), 7.17 ( c, 1 H), 7.24 (c, 2 H), 7.36 (d, 1 H), 7.64 (m, 1 H), 8.22 (d, 1 H). EXAMPLE 211: 5-r4- (3,5-D-Fluoro-benzyloxy) -phenylsulfamoip-2-methyl-benzoic acid 56% yield. MS: 432.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.60 (s, 3 H), 5.02 (s, 2 H), 6.86 (c, 3 H), 6.99 (c, 4 H), 7.36 ( d, 1H), 7.63 (m, 1H), 8.22 (d, 1H). EXAMPLE 212: 5-R4- (3,4-difluoro-benzyloxy) -Henylsulphamoxy-2-methyl-benzoic acid Yield: 66% MS: 432.2 (M-1); 1 H NMR (400 MHz, CD3OD): d 2, 60 (s, 3H), 4.97 (s, 2H), 6.85 (c, 2H), 6.97 (c, 2H), 7.17-7.38 (c, 4H), 7.63. (m, 1H), 8.21 (d, 1H) EXAMPLE 213: 5-r4- (5,7-difluoro-benzothiazol-2-ylmethylsulfanyl) -phenylsulfamoip-2-methyl-benzoic acid 19% yield. MS: 507.0 (M + 1); 1 H NMR (400 MHz, CD3OD): d 2.47 (s, 3H), 4.49 (s, 2H), 7.02 (m, 2H), 7.12 (m, 2H), 7.26 (m, 2H), 7.46 (c , 2H), 7.97 (d, 1H). EXAMPLE 214: 2-isopropyl-5-r4- (6-methyl-benzthiazol-2-yl) -phenylsulfamap-benzoic acid 84% yield. MS: 467.1 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1, 21 (d, 6 H), 2.47 (s, 3 H), 3.81 (m, 1 H), 7.28 (m, 2 H), 7.32 ( m, 1H), 7.60 (d, 1H), 7.75 (s, 1H), 7.82 (d, 1H), 7.92 (c, 3H), 8.20 (d, 1H). EXAMPLE 215: 2-Methyl-5-r4- (5-trifluoromethyl-benzothiazol-2-ylmethylsulfanyl) -phenylsulfamoip-benzoic acid Yield of 17%. MS: 539.0 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.55 (s, 3 H), 4.52 (s, 2 H), 7.01 (d, 2 H), 7.27 (c, 4 H), 7.64 ( m, 2H), 8.12 (d, 1H), 8.22 (a, 1.H). EXAMPLE 216: 2-Etii-5-r4- (6-methyl-benzothiazol-2-yl) -phenylsulfamoip-benzoic acid 83% yield. MS: 453.0 (M + 1); 1 H NMR (400 MHz, CD3OD): d 1.18 (t, 3H), 2.47 (s, 3H), 3.01 (c, 2H), 7.27 (m, 2H), 7.32 (m, 1H), 7.45 (d , 1H), 7.84 (m, 2H), 7.93 (m, 2H), 8.32 (d, 1 H). EXAMPLE 217: 2,3-Dimethyl-5-yl- (6-methyl-benzothiazol-2-yl) -phenylsulfamoin-benzoic acid 75% yield. MS: 453.0 (M + 1); 1 H NMR (400 MHz, DMSO-D 6): d 2.30 (s, 3 H), 2.38 (s, 3 H), 2.42 (s, 3 H), 7.26 (m, 2 H), 7, 31 (m, 1H), 7.76 (s, 1 HOUR). EXAMPLE 218: 2,3-Dimethyl-5-r4- (3-trifluoromethyl-benzylsulfanyl) -phenylsulfamoyl-benzoic acid 75% yield. MS: 494.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.32 (s, 3 H), 2.48 (s, 3 H), 4.07 (s, 2 H), 7.0 (m, 2 H), 7.14 ( d, 2H), 7.34 (c, 2H), 7.46 (c, 2H), 7.63 (s, 1H), 8.0 (s, 1H). EXAMPLE 219: 5-r4- (4-Ethyl-benzylsulfanyl) -phenylsulphamop-2,3-dimethyl-benzoic acid 80% yield. MS: 456.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.17 (t, 3 H), 2.33 (s, 3 H), 2.49 (s, 3 H), 2.57 (c, 2 H), 3.97 ( s, 2H), 6.96-7.06 (c, 6H), 7.13 (c, 1H), 7.63 (d, 1H), 8.00 (d, 1H). EXAMPLE 220: 2-Isopropyl-5- (4'-trifluoromethoxy-biphenyl-4-ylsulfamoip-benzoic acid) Yield of 37%. MS: 480.0 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.22 (d, 6 H), 3.81 (m, 1 H), 7.20 (m, 2 H), 7.29 (d, 2 H), 7.51 ( m, 2H), 7.58 (d, 1H), 7.63 (m, 2H), 7.84 (m, 1H), 8.14 (d, 1H). EXAMPLE 221: 5-r2- (4-Fe? C-butyl-phenyl) -benzooxazol-5-ylsulfamo-p-2-methyl-benzoic acid 90% yield. MS: 465.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.37 (s, 9 H), 2.58 (s, 3 H), 7.13 (m, 1 H), 7.37 (d, 1 H), 7.43 (d, 1H), 7.53 (d, 1H), 7.61 (m, 2H), 7.72 (m, 1 H), 8.11 (m, 2H), 8.27 (d, 1 H). EXAMPLE 222: 5-r4- (3,5-dimethyl-benzyl-sulfanyl) -phenylsulphamoyl-2-methyl-benzoic acid 74% yield. MS: 440.2 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.19 (s, 6 H), 2.56 (s, 3 H), 3.93 (s, 2 H), 6.78 (s, 2 H), 6.82 ( s, 1H), 6.98 (d, 2H), 7.12 (d, 2H), 7.30 (d, 1H), 7.58 (d, 1H), 8.08 (a, 1H). EXAMPLE 223: 5-R4- (4-Butoxy-benzylsulfanyl) -phenylsulfamoin-2-methyl-benzoic acid Performance of 82%. MS: 484.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 0.97 (t, 3 H), 1.49 (m, 2 H), 1.72 (m, 2 H), 2.61 (s, 3 H), 3.91 ( t, 2H), 3.95 (s, 2H), 6.72 (m, 2H), 6.97 (m, 2H), 7.03 (m, 2H), 7.13 (m, 2H), 7.38 (d, 1H), 7.68 (m, 1H), 8.28 (d, 1H). EXAMPLE 224: 5-R4- (2,3-difluoro-benzylsulfanyl) -phenylsulfamo-p-2-methyl-benzoic acid 81% yield. MS: 448.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.57 (s, 3 H), 4.03 (s, 2 H), 6.81 (c, 1 H), 6.92 (c, 1 H), 7.00 ( d, 2H), 7.07 (m, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.61 (d, 1H), 8.14 (a, 1H). EXAMPLE 225: 5-γ4- (3,5-difluoro-benzylsulfanyl) -phenylsulfamoin-2-methyl-benzoic acid 84% yield. MS: 448.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.60 (s, 3 H), 4.01 (s, 2 H), 6.74 (c, 3 H), 7.00 (c, 2 H), 7.17 ( c, 2H), 7.37, (d, 1H), 7.68 (m, 1H), 8.28 (d, 1H). EXAMPLE 226: 2-Methyl-5-r4- (4-trifluoromethylsulfanyl-benzylsulfanin-phenylsulfamoip-benzoic acid 84% yield. MS: 512.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d, 63 (s, 3 H), 4.78 (s, 2 H), 6.98 (m, 2 H), 7.13 (m, 2 H), 7.21 (d , 2H), 7.40 (d, 1H),, 47 (d, 2H), 7.72 (m, 1 H), 8.28 (d, 1 H).

EXAMPLE 227: 2,3-Dimethyl-5-r4- (3-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoip-benzoic acid 77% yield. MS: 510.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.32 (s, 3 H), 2.48 (s, 3 H), 4.04 (s, 2 H), 6.98 (d, 2 H), 7.08 ( c, 3H), 7.15 (d, 2H), 7.24 (t, 1H), 7.62 (s, 1H), 7.99 (s, 1H). EXAMPLE 228: 2,3-Dimethyl-5- (4'-trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid 77% yield. MS: 464.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.33 (s, 3 H), 2.47 (s, 3 H), 7.18 (d, 2 H), 7.29 (d, 2 H), 7.50 ( m, 2H), 7.62 (m, 2H), 7.68 (s, 1H), 8.03 (s, 1H). EXAMPLE 229: 5-r2- (4-tert-Butyl-phenyl) -benzooxazol-5-ylsulfamoip-2-ethyl-benzoic acid 84% yield. MS: 479.4 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.17 (t, 3 H), 1. 37 (s, 9 H), 3.00 (c, 2 H), 7.13 (m, 1 H), 7.42 ( m, 2H), 7.53 (d, 1H), 7.61 (m, 2H), 7.75 (m, 1H), 8.11 (m, 2H), 8.23 (d, 1H). EXAMPLE 230: 2-Ethyl-5-r4- (4-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoin-benzoic acid 67% yield. MS: 510.3 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1.20 (t, 3 H), 2.97 (c, 2 H), 4.03 (s, 2 H), 7.01 (m, 2 H), 7.09 ( d, 2H), 7.14 (m, 2H), 7.23 (m, 2H), 7.34 (d, 1H), 7.63 (m, 1H), 8.06 (d, 1H). EXAMPLE 231: 2,3-D-methyl-5-r4- (4-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoyl] -benzoic acid 49% yield. MS: 510.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d, 32 (s, 3 H), 2.48 (s, 3 H), 4.02 (s, 2 H), 6.99 (m, 2 H), 7.06 (d , 2H), 7.14 (m, 2H),, 21 (m, 2H), 7.62 (t, 1H), 7.96 (d, 1H).

EXAMPLE 232: 2-Ethyl-5-y2- (4-trifluoromethoxy-phenin-benzooxazol-5-ylsulfamoip-benzoic acid) 77% yield. MS: 507.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.17 (t, 3 H), 2.97 (c, 2 H), 7.16 (m, 1 H), 7.38 (d, 1 H), 7.48 ( m, 3H), 7.54 (d, 1H), 7.71 (m, 1H), 8.14 (d, 1H), 8.29 (ra, 2H). EXAMPLE 233: 2-Ethyl-5- (4'-trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid Performance of 82%. MS: 464.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1.19 (t 3 H), 3.0 (c, 2 H), 7.20 (m, 2 H), 7.29 (d, 2 H), 7.43 ( d, 1H), 7.50 (m, 2H), 7.62 (m, 2H), 7.81 (m, 1H), 8.27 (d, 1H). EXAMPLE 234: 2-isopropyl-5-r4- (4-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoip-benzoic acid Yield of 71%. MS: 524.2 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1, 23 (d, 6 H), 3.75 (m, 1 H), 7.02 (m, 2 H), 7.09 (d, 2 H), 7.15 ( m, 2H), 7.23 (m, 2H), 7.51 (d, 1H), 7.71 (m, 1H), 8.01 (d, 1H). EXAMPLE 235: 2-Methyl-5-r2- (4-trifluoromethoxy-phenyl) -benzooxazol-5-ylsulfamoip-benzoic acid Yield of 71%. MS: 493.2 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.56 (s, 3 H), 7.15 (m, 1 H), 7.35 (d, 1 H), 7.48 (c, 3 H), 7.54 ( c, 1H), 7.68 (m, 1H), 8.19 (d, 1H), 8.31 (d, 2H). EXAMPLE 236: 2-ethyl-5-r4- (quinolin-2-ylmethylsulfanyl) -phenylsulfamoip-benzoic acid 100% yield. MS: 479.4 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1, 20 (t, 3 H), 3.03 (c, 2 H), 4.5 (d, 2 H), 7.01 (m, 2 H), 7.20 ( m, 2H), 7.42 (d, 1H), 7.78 (c, 2H), 7.93 (m, 1H), 7.99 (d, 1H), 8.12 (m, 1H), 8.23 (d, tH), 8.26 (d, 1H), 8.94 (d, 1H). EXAMPLE 237: 2-Isopropyl-5-r4- (quinolin-2-ylmethylsulfanyl) -phenylsulfamoip-benzoic acid 96% yield. MS: 493.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1, 23 (d, 6 H), 3.82 (m, 1 H), 4.49 (s, 2 H), 7.02 (m, 2 H), 7.2 (m, 2H), 7.58 (d, 1H), 7.76 (d, 1H), 7.82 (m, 1H), 7.95 (m, 1H), 8.04 (m, 1H) , 8.11 (c, 2H), 8.25 (d, 1 H), 8.92 (d, 1 H). EXAMPLE 238: 2-Ethyl-5-r2- (4-trifluoromethyl-phenyl) -benzooxazole-5-isulfamoyl-benzoic acid 10 Yield of 85%. MS: 491.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d t 5. 1, 17 (t, 3H), 3.00 (c, 2H), 7.19 (m, 1H), 7.41 (d, 1H), 7.51 (d, 1H), 7.58 ( d, 1 H), 7.76 (m, 1 H), 7.87 (d, 2 H), 8.23 (d, 1 H), 8.37 (d, 2 H). EXAMPLE 239: 2-Methyl-5-r2- (4-frifluoromethyl-phenyl) -benzooxazol-5-ylsulfamoip-benzoic acid Yield of 92%. MS: 477.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 2.58 (s, 3 H), 7.18 (m, 1 H), 7.38 (d, 1 H), 7.50 (d, 1 H), 7.38 ( d, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.73 (m, 1H), 7.88 (d, 2H), 8.27 (d, 1H), 8.38 (d, 2H). EXAMPLE 240: 5- (4-Cyclohexylmethylsulfanyl-phenylsulfamoyl) -2-methylbenzoic acid 74% yield. MS: 418.0 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 0.95 (c, 2 H), 1.19 (c, 3 H), 1.40 (c, 1 H), 1.67 (c, 3 H), 1, 83 (c, 2H), 2.60 (s, 3H), 2.72 (d, 2H), 7.00 (m, 2H), 7.17 (m, 2H), 7.38 (d, 1H) 7.70 (m, 1H), 8.27 (d, 1H). EXAMPLE 241: 5- (4-Cyclobutylmethylsulfanyl-phenylsulfamoyl) -2-methyl-benzoic acid , 83% yield. MS: 390 (M-1); 1 H NMR (400 MHz, CDCl 3): d 1.70 (c, 2 H), 1.85 (c, 2 H), 2.06 (c, 2 H), 2.47 (m, 1 H), 2.68 ( s, 3H), 2.93 (d, 2H), 6.99 (m, 2), 7.20 (m, 2H), 7.34 (d, 1H), 7.75 (m, 1H), 8.47 (d, 1H). EXAMPLE 242: 2-Isopropyl-5-y4- (5-methyl-benzooxazol-2-yl) -phenylsulfamoin-benzoic acid 89% yield. MS: 451.3 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1, 21 (d, 6 H), 2.45 (s, 3 H), 3.81 (m, 1 H), 7.20 (d, 1 H), 7.32. (d, 2H), 7.48 (d, 2H), 7.61 (d, 1 H), 7.91 (m, 1H), 8.07 (d, 2H), 8.21 (d, 1H) ). EXAMPLE 243: 5-f4- (1H-benzoimidazol-2-yl) -phenylsulfamoin-2-isopropyl-benzoic acid 94% yield. MS: 436.3 (M + 1); 1 H NMR (400 MHz, CD3OD): d 1. 22 (d, 6H), 3.81 (m, 1H), 7.48 (m, 2H), 7.61 (c, 3H), 7.77 (c, 2H), 8.00 (c, 3H) ), 8. 23 (d, 1H). EXAMPLE 244: 2-Isopropyl-5-r4- (3-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoip-benzoic acid 91% yield. MS: 524.3 (M-1); H NMR (400 MHz, CD3OD): d 1.23 (d, 6H), 3.82 (m, 1H), 7.00 (m, 2H), 7.08 (c, 3H), 7.16 ( m, 2H), 7.25 (m, 1H), 7.55 (d, 1H), 7.76 (m, 1 H), 8.11 (d, 1H).

Yield of 72%. MS: 510.1 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 1.20 (t, 3 H), 3.03 (c, 2 H), 4.04 (s, 2 H), 6.99 (m 2 H), 7.08 ( c, 3H), 7.16 (m.2H), 7.25 (m, 1H), 7.40 (d, 1H), 7.73 (m, 1H), 8.24 (d, 1H). EXAMPLE 246: 2-Ethyl-5- (4'-propoxy-bifmil-4-ylsulfampyl) -h0n ^ n acid Yield of 92%. MS: 438.3 (1); 1 H NMR (400 MHz, CD 3 OD): d 1.04 (t, 3 H), 1.19 (t, 3 H), 1.79 (m, 2 H). 3.0? (c, 2H), 3.94 (t, 2H), 6.92 (m, 2H), 7.13 (m, 2H). 7.43 (c, 5H), 7.78 (m, 1H), 8.3 (d, 1H). EXAMPLE 247: 2-isopropyl-5 - (/ 4'-prorJ) xi-biphenyl-4-ylsulfamoyl) -benzoic acid 93% yield. MS: 452.3 (MJ); 1 H NMR (400 MHz. CD 3 OD): d, 04 (t 3 H). 1.22 (d.6H), 1.79 (m, 2H), 3.81 n, 1H), 3.94 (m, 2H), 6.93 (m, 2H). , 14 (m, 2H), 7.44 (c, 4H), 7.57 (d, 1H), 7.80m, 1H), 8.13 (d, 1H).

EXAMPLE 248: 5-r2- (4-Fer-butyl-phenyl) -benzooxazol-5-ylsulfamoyl-2-isopropyl-benzoic acid 93% yield. MS: 493.4 (M + 1); 1 H NMR (400 MHz, CD 3 OD): d 1.20 (d, 6 H), 1.37 (s, 9 H), 3.80 (c, 1 H), 7.13 (m, 1 H), 7.45 ( d, 1H), 7.54 (t, 2H), 7.62 (d, 2H), 7.78 (m, 1H), 8.11 (m, 3H). EXAMPLE 249: 2-Methyl-5-f4- (5-trifluoromethyl-pyridin-2-ylcarbamoyl) -phenylsulfamoip-benzoic acid Yield of 2% (material, lost). MS: 478.0 (M-1); 1 H NMR (400 MHz, CD 3 OD): d 2.49 (s, 3 H), 7.19 (d, 1 H), 7.28 (m, 4 H), 7.67 (m, 1 H), 7.85 ( m, 2H), 8.05 (m, 2H). EXAMPLE 250: 5-r4- (5-Cyclohexyl-1 1.3.4) oxadiazol-2-in-phenylsulfamoip-2-methyl-benzoic acid - 86% yield. MS: 442.0 (M + 1); 1 H NMR (400 MHz, CDCl 3): d 1.15-1.4 (c, 3 H), 1.49-1.7 (c, 3 H), 1.76 (c, 2 H), 2.02 (c , 2H), 2.53 (s, 3H), 2.86 (c, 1 H), 7.20 (m, 3H), 7.73 (m, 3H), 8.39 (d, 1 H) .

EXAMPLE 259: 2-Methyl-5 - [(4'-propoxy-biphenyl-4-yl) -propyl-sulfamoip-benzoic acid methyl ester A mixture of 5 - [(4'-hydroxy-biphenyl-4-yl) -propyl-sulfamoyl] -2-methyl-benzoic acid methyl ester (100 mg, 0.25 mmoi), 1-iodopropane (36.7) μl, 0.38 mmol) and potassium carbonate (52 mg, 38 mmol) in 5 ml of acetone was heated at 56 ° C under a nitrogen atmosphere overnight. Additional 1-iodopropane (35.7 μL, 0.38 mmol) was added and the mixture was heated to 56 ° C under a nitrogen atmosphere overnight. Then, the reaction mixture was cooled to room temperature and diluted with 40 ml of ethyl acetate. The ethyl acetate solution was washed sequentially with 30 ml of water and 30 ml of brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel), eluting with 3: 1 toluene / ethyl acetate to yield the title compound as an off-white solid (21 mg, yield 17%) together with S- '-hydroxy-bifeniM-i-propyl-sulfamoyl] -2-methyl-benzoic acid methyl ester (64 mg, 58% yield). MS: 482.2 (M + 1) 2-Methyl-5 - [(4'-propoxy-biphenyl-4-yl) -propyl-sulfamoyl] -benzoic acid methyl ester MS: 440.1 (M + 1) 5 - [(4'-Hydroxy-biphenyl-4-yl) -propyl-sulfamoyl] -2-methyl-benzoic acid methyl ester EXAMPLE 260: 2-isopropyl-5-rpropyl- (4'-trifluoromethoxyphenyl) methyl ester - biphenyl-4-ip-sulfamoip-benzoic acid The title compound was prepared using a procedure analogous to that of EXAMPLE 257 but using 2-isopropyl-5- (4'-trifluoromethoxy-biphenif-4-ylsulfamoyl) -benzoic acid methyl ester in place of the methyl ester of the acid - [(4'-Hydroxy-2-phenyl-4-yl) -propyl-sulfamoyl] -2-methyl-benzoic acid. Performance of . 80% MS: 564.2 (M + 1). EXAMPLE 261: 4- (5-Met.l-benzooxazol-2-yl) -henylamine • 'A mixture of 2-amino-p-cresol (1.5 g, 12 mmol), 4-aminobenzoic acid (1.67 g, 12 mmol) and 40 g of polyphosphoric acid was heated at 190 ° C under a nitrogen atmosphere for 6 h.The reaction mixture was cooled to room temperature and 300 ml of water was added to the viscous liquid. collected by filtration and dissolved in 200 ml of ethyl acetate.The ethyl acetate solution was washed sequentially with 100 ml of a saturated aqueous solution of sodium bicarbonate, 100 ml of water and 100 ml of brine, dried (sulfate anhydrous sodium) and concentrated under reduced pressure to yield the title compound as an off-white solid (2.43 g, 89% yield) MS: 225.0 (M + 1) The title compounds of EXAMPLES 262-268 were prepared using procedures analogous to those of EXAMPLE 261 from the appropriate starting materials.

J: - - r uoromet - en ox - en am na A solution of p-aminophenol (0.200 g, 1.83 mmol), 4-trifluoromethylbenzyl alcohol (025 ml, 1.83 mmol) and triphenylphosphine (0.529 g, 2.02 mmol) in 5 ml of anhydrous tetrahydrofuran was added diethylazodicarboxylate (0.318 ml, 2.02 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Then, it was diluted with 70 ml of ethyl acetate and the resulting solution was washed sequentially with 50 ml of a saturated aqueous sodium bicarbonate solution, 50 ml of water and 50 ml of brine, dried (anhydrous sodium sulfate) and concentrated at reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 8: 2 hexane / ethyl acetate to give the title compound as an off-white solid (0.272 g, 55% yield). ). MS: 284.1 (M + 1) The title compounds of EXAMPLES 270-276 were prepared using procedures analogous to those of EXAMPLE 269 from the appropriate starting materials.

Sodium hydride [0.153 g (50% in mineral oil), 3.2 mmol] was added to a solution of 4-aminothiophenol (0.20 g, 1.6 mmol) in 5 ml anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 15 min and then 4-trifluoromethylbenzyl chloride (0.236 ml, 1.6 mmol) was added. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Then, water (50 ml) was added and the resulting mixture was extracted with 2 x 50 ml of ethyl acetate. The combined ethyl acetate extracts were washed sequentially with 60 ml of a saturated aqueous sodium bicarbonate solution, 60 ml of water and 60 ml of brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 85:15 hexane / ethyl acetate to yield the title compound as an off-white solid (0.318 g, 70% yield). ). MS: 284.1 (M + 1) The title compounds of EXAMPLE 278-304 were prepared using procedures analogous to those of EXAMPLE 277 from the appropriate starting materials.

EXAMPLE 3054- (3,5-Dimethyl-benzylsulfanyl) -nitrobenzene To a solution of 4-nitrothiophenol (0.400 g, 2.57 mmol), 3,5-dimethylbenzyl alcohol (0.38 ml, 2.57 mmol) and triphenylphosphine ( 0.743 g, 2.84 mmoi) in 10 ml of anhydrous tetrahydrofuran was added diethylazodicarboxylate (0.446 ml, 2.84 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Afterwas diluted with 90 ml of ethyl acetate and the resulting solution was washed sequentially with 70 ml of a saturated aqueous sodium bicarbonate solution, 70 ml of water and 70 ml of brine, dried (anhydrous sodium sulfate) and concentrated to a reduced pressure. The solid residue was triturated with 95: 5 hexane / ethyl acetate (20 ml) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 15 g), eluting with 95: 5 hexane / ethyl acetate to yield the title compound as a yellow solid. , 35 g, 50% yield). 1 H NMR (400 MHz, CD3CI): d 2.30 (s, 6H), 4.18 (s, 2H), 6.92 (s.1H), 7.0 (s, 2H), 7.33 ( d, 2H), 8.10 (d, 2H). The title compounds of EXAMPLE 306-309 were prepared using procedures analogous to those of EXAMPLE 305 from the appropriate starting materials. EXAMPLE 306: 4- (4-Butoxy-benzylsulfanyl) -nitrobenzene Yield 26%. 1 H NMR (400 MHz, CD 3 Cl): d 0.97 (t, 3 H), 1.4-1.53 (c, 2 H), 1.7-1.8 (c, 2 H), 3.95 (m , 2H), 4.2 (s, 2H), 6.85 (d, 2H), 7.27 (d, 2H), 7.33 (d, 2H), 8.1 (d, 2H). EXAMPLE 307: 4- (2,3-Difluoro-benzylsulfanine-nitrobenzene 55% yield.) 1 H NMR (400 MHz, CD3CI): d 4.28 (s, 2H), 7.0-7, 16 (c, 3H), 7.37 (d, 2H), 8, 13 (d, 2H).

EXAMPLE 308: 4- (3,5-Difluoro-benzylsulfanyl) -nitrobenzene Yield 33%. 1 H NMR (400 MHz, CD 3 Cl): d 4.20 (s, 2 H), 6.73 (m, 2 H), 6.92 (m, 2 H), 7.32 (m, 2 H), 8.12 ( m, 2H). EXAMPLE 309: 4- (4-Trifluoromethylsulfanyl-benzylsulfanyl) -nitrobenzene 55% yield. MS: 344.1 (M-1). The title compounds of EXAMPLE 310-312 were prepared using procedures analogous to those of EXAMPLE 305 from the appropriate starting materials but using 4-nitrophenol or 3-nitrophenol in place of 4-nitrothiophenol. EXAMPLE 310: 4-22- (4-N -tro-phenoxy) -etin-2- (4-trifluoromethoxy-phenyl) -thiazole. Yield 78%. MS: 411.1 (M + 1) EXAMPLE 311: 4- [2- (4-Nitro-phenoxy) -etip-2- (4-trifluoromethyl-phenyl) -thiazole 70% yield. MS: 395.1 (M + 1) EXAMPLE 312: 3- (4-trifluoromethylbenzyloxy) -nitrobenzene Yield 22%. MS: 296.1 (M-1) EXAMPLE 313: 4- (4-tert-Butylphenoxy) nitrobenzene Sodium hydride [0.16 g (50% in mineral oil), 3.33 mmol] was added to a solution of 4-fer-butylphenol (0.5 g, 3.33 mmol) in 5 ml of dimethylformamide at room temperature. After 15 min, 1-chloro-4-nitrobenzene (0.262 g, 1.66 mmol) was added and the reaction mixture was heated at 80 ° C overnight. The reaction mixture was cooled to room temperature and diluted with 50 ml of ethyl acetate. The ethyl acetate solution was washed sequentially with 3 X 40 ml of water and 40 ml of brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude product (0.9 g) was purified by flash column chromatography (15 g of silica gel), eluting with 98: 2 hexane / ethyl acetate to yield the title compound as a yellowish solid (0.499). g, quantitative yield). 1 H NMR (400 MHz, CD3CI): d 1.35 (s, 9H), 7.0 (d, 2H), 7.43 (d, 2H), 8.19 (d, 2H). EXAMPLE 314: 4- (3,5-Dimethyl-benzylsulfanyl) -phenylamine A mixture of 4- (3,5-dimethyl-benzylsulfanyl) -nitrobenzene (0.35 g, 1.28 mmol), calcium chloride (0.071 g) , 0.64 mmol) and iron powder (-325 mesh) (0.573 g, 10.3 mmol) in 4 mL of water and 17 mL of ethanol was heated to reflux under a nitrogen atmosphere for 4.5 h. Then, the reaction mixture was cooled to room temperature, filtered through Celite and the filtrate was concentrated under reduced pressure. The residual oil was purified by column chromatography, eluting with 9: 1 hexane / ethyl acetate to yield the title compound as a yellowish oil (0.29 g, 91% yield). MS: 244.3 (M + 1) The title compounds of EXAMPLE 315-327 were prepared using procedures analogous to those of EXAMPLE 314 from the appropriate starting materials. EXAMPLE 315: 4- (4-Butoxy-benzylsulfanyl) -phenylamine 80% yield. 1 H NMR (400 MHz, CD3CI): d 0.96 (m, 3H), 1.4-1.52 (c, 2H), 1.7-1.8 (c, 2H), 3.85-3 , 96 (m, 4H), 6.57 (d, 2H), 6.77 (d, 2H), 7.07 (d, 2H), 7.13 (d, 2H). 106 EXAMPLE 328: 4'-Trifluoromethoxy-biphenyl-4-ylamine A mixture of 4-trifluoromethoxybenzeneboronic acid (300 mg, 1.45 mmol), p-bromoaniline (100 mg, 0.58 mmol), dichloro [1,1- bis (diphenylphosphino) ferrocene] palladium (II) adduct of dichloromethane (24 mg, 0.029 mmol), 1,1 '-? b / s (diphenylphosphino) ferrocene (16 mg, 0.029 mmol) and potassium carbonate (0.58 ml a 2 M aqueous solution, 1.16 mmol) in 5 ml of 1,4-dioxane was heated to reflux in a nitrogen atmosphere for 20 h. The reaction mixture was cooled to room temperature, diluted with 40 ml of water and extracted with 2 x 40 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 40 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 15 g), eluting with 10: 1 hexane / ethyl acetate to give the title compound as a tan solid (70 mg, 48% yield). ). MS: 254.1 (M + 1) EXAMPLE 329: 2-Cyclohexyl-5- (4-nitro-phenyl) -p .3.4-oxadiazole A mixture of 5- (4-nitro-phenyl) -1H-tetrazole (, 5 g, 2.62 mmol) and cyclohexanecarbonyl chloride (0.35 mL, 2.62 mmol) in 3 mL of anhydrous pyridine was stirred at room temperature under a nitrogen atmosphere for 20 min, then heated to 60 °. C for 1 h and finally it was heated at 100 ° C for 2 h. The reaction mixture was cooled to room temperature, then poured into ice (30 g) and the aqueous mixture was extracted with 30 ml of ethyl acetate. The ethyl acetate solution was sequentially washed with 30 ml water, 30 ml of a 1N aqueous solution of hydrochloric acid and 30 ml of brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 40 g), eluting with 4: 1 hexane / ethyl acetate to yield the title compound as a yellowish solid (0.5 g, 100%). MS: 274.2 (M + 1) EXAMPLE 330: 4-Nitro-4'-propoxybiphenyl To a solution of 4-hydroxy-4'-nitrobiphenyl in 5 ml of acetone were added potassium carbonate (240 mg, 1.74 g. mmol) and 1-iodopropane (0.17 ml, 1.74 mmol). The reaction mixture was heated to reflux for 24 h. Additional potassium carbonate (240 mg, 1.74 mmol) and 1-iodopropane (0.17 mL, 1.74 mmol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and diluted with 30 ml of ethyl acetate. The ethyl acetate solution was washed sequentially with 25 ml of water and 25 ml of brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel), eluting with 14: 1 hexane / ethyl acetate to yield the title compound (0.267 g, 89% yield) MS: 258.3 (M-1 ) EXAMPLE 331: 2- (4- erc-Butyl-phenyl) -5-nitro-benzooxazole-4-te / -c-butyl-N- (2-hydroxy-5-nitro-phenyl) -benzamide It was added in portions 4-dimethylaminopyridine (2.62 g, 21.4 mmol) with stirring to a solution of 4-tert-butylbenzoyl chloride (3.8 ml, 19.5 mmol) and 2-amino-4-nitrophenol (3.0 g, 19.5 mmol) in 60 ml of methylene chloride. The resulting solution was stirred overnight at room temperature. The reaction solution was diluted with 60 ml of methylene chloride and washed with 3 x 50 ml of water. The methylene chloride solution was separated, filtered to remove the precipitated solid, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure to yield the title compound as a brownish solid (5.01 g, 82% yield). 2- (4-Ferc-Butyl-phenyl) -5-nitro-benzooxazole Diethyl azodicarboxylate (0.275 ml, 1.75 mmol) was added dropwise with stirring to a solution of 4-tert-butyl-N- (2-hydroxyl) -5-n-phenyl) -benzamide (0.5 g, 1.59 mmol) and triphenylphosphine (0.458 g, 1.75 mmol) in 15 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and then diluted with 75 ml of ethyl acetate. The ethyl acetate solution was washed sequentially with 50 ml of water and 50 ml of brine, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (40 g of silica gel), eluting with 9: 1 hexane / ethyl acetate to yield a yellowish solid (0.305 g) which was further purified by column chromatography (15 g of silica gel), eluting with 95: 5 hexane / ethyl acetate, to give the title compound as a yellowish solid (0.125 g, 27% yield). MS: 297.3 (M + 1) The title compounds of EXAMPLE 332-333 were prepared using procedures analogous to those of EXAMPLE 331 from the appropriate starting materials. EXAMPLE 332: 2- (4-Trifluoromethoxy-phenyl) -5-nitro-benzooxazole 4-trifluoromethoxy-N- (2-hydroxy-5-nitro-phenyl) -benzamide Yield of 100% 2- (4-trifluoromethoxy-phenyl) -5-nitro-benzooxazole 66% yield. MS: 325.2 (M + 1) EXAMPLE 333: 2- (4-Trifluoromethoxy-phenyl) -5-nitro-benzooxazole 4-Trifluoromethyl-N- (2-hydroxy-5-n-phenyl) - Benzamide Yield 83% 2- (4-Trifluoromethyl-phenyl) -5-nitro-benzooxazole Yield 93%. MS: 309.3 (M + 1). EXAMPLE 334: 5-Chlorosulfonyl-2-methyl-benzoic acid A mixture of o-toluic acid (15 g, 0.11 mol) and chlorosulfonic acid (30 ml) was heated at 100 ° C under a nitrogen atmosphere for 2, 5 h. Then, the reaction mixture was poured onto ice (500 ml) and the resulting precipitate was filtered, yielding the title compound as an off-white solid (20 g, 78% yield). p.f. 151-155 ° C. The title compounds of EXAMPLE 335-337 were prepared using a procedure analogous to that of EXAMPLE 334 from the appropriate starting materials. EXAMPLE 335: 3-Chlorosulfonyl-2,6-dimethyl-benzoic acid 28% yield. 1H RM? (400 MHz, CD3OD) d 2.44 (s, 3H), 2.72 (s, 3H), 7.41 (d, 1H), 8.02 (d, 1H), EXAMPLE 336: 5-Chlorosulfonyl-2,3-dimethyl-benzoic acid Yield 77%. 1H RM? (400 MHz, CDCl 3) d 2.49 (s, 3H), 2.66 (s, 3H), 7.98 (s, 1H), 8.47 (s, 1H). EXAMPLE 337: 5-Chlorosulfonyl-2-ethyl-benzoic acid Yield 76%. MS: 247.0 (M-1). EXAMPLE 338: 5-Chlorosulfonyl-2-methyl-benzoic acid methyl ester Chlorosulfonic acid (106.2 ml) was carefully added over 1 min with stirring under a nitrogen atmosphere to 2-methyl-benzoic acid methyl ester (55, 9 ml, 0.4 mol). The reaction mixture was placed in an oil bath preheated at 100 ° C for 15 min and then poured onto ice (1000 ml). The resulting precipitate was filtered and dissolved in ethyl acetate (400 ml). The ethyl acetate solution was washed sequentially with 10 x 300 ml of saturated aqueous sodium bicarbonate, 300 ml of water and 300 ml of brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to yield the title compound in the form of a yellowish oil (37.3 g, 37% yield). 1 H NMR (400 MHz, CDCl 3) d 2.74 (s, 3 H), 3.96 (s, 3 H), 7.52 (d, 1 H), 8.04 (m, 1 H), 8.58 (d , 1 HOUR). The title compounds of EXAMPLE 339-343 were prepared using procedures analogous to those of EXAMPLE 338 from the appropriate starting materials. EXAMPLE 339: 5-Chlorosulfonyl-2-ethyl-benzoic acid methyl ester 42% yield. 1 H NMR (400 MHz, CDCl 3) d 1.29 (t, 3 H), 3.11 (c, 2 H), 3.96 (s, 3 H), 7.54 (d, 1 H), 8.06 (m , 1H), 8.53 (d, 1H). EXAMPLE 340: 5-Chlorosulfonyl-2-isopropyl-benzoic acid methyl ester 47% yield. 1 H NMR (400 MHz, CDCl 3) d 1,3 (d, 6 H), 3.87 (m, 1 H), 3.96 (s, 3 H), 7.67 (d, 1 H), 8.08 (m , 1H), 8.41 (d, 1H). EXAMPLE 341: 5-Chlorosulfonyl-2,3-dimethyl-benzoic acid methyl ester 41% yield. H NMR (400 MHz, CDCl 3) d 2.45 (s), 3H), 2.58 (s, 3H), 3.95 (s, 3H), 7.92 (d, 1 H), 8.31 (d, 1 H). EXAMPLE 342: 5-Chlorosulfonyl-2-ethoxy-benzoic acid ethyl ester 10% yield. 1 H NMR (400 MHz, CDCl 3) d 1.43 (t, 3 H), 1.52 (t, 3 H), 4.24 (c, 2 H), 4.40 (c, 2 H), 7.10 (d , 1H), 8.09 (m, 1H), 8.43 (d, 1H). EXAMPLE 343: 5-Chlorosulfonyl-2-methylsulfanyl-benzoic acid methyl ester 58% yield. 1 H NMR (400 MHz, CDCl 3) d 2.55 (s, 3 H), 3.98 (s, 3 H), 7.47 (d, 1 H), 8.05 (m, 1 H), 8.64 (d , 1 HOUR). Throughout this application, various publications have been referenced. The descriptions of these publications in their entirety are incorporated as a reference in this application for all purposes. It will be obvious to those skilled in the art that various modifications and variations may be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be obvious to those skilled in the art from consideration of the specification and practice of the invention described herein. It is understood that the specification and examples are considered as exemplary only, the true scope and spirit of the invention being indicated by the following claims.

Claims (10)

1. A compound wherein X is -COOR4; B is a bond, -L- (CY2) n- or - (CY2) n-L-, and L is O or S, and n is 0, 1 OR 2; Ar 1 is phenyl or phenol fused to a ring selected from the group consisting of: phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl.

2. A

3. A q is 1 or 2 and each J is independently halo, (C1-C3) alkyl optionally substituted with one to three halo, or (C1-C3) alkoxy optionally substituted with one to three halo.

4. A compound according to claim 3 wherein p is 1 and R4 is H or (C1-C3) alkyl.

5. A compound according to any of claims 1-4, wherein L is S, n is 1, and halo is fluoro.

6. A compound selected from the group consisting of: 2-Methyl-5- [4- (5-methyl-benzooxazol-2-yl) -phenylsulfamoyl] benzoic acid; 5- [4- (5-Chloro-benzooxazol-2-yl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2-Methyl-5- [4- (4-trifluoromethyl-benzylsulfanyl) -phenylsulphamoyl] -benzoic acid; 5- [4- (4-tert-Butyl-benzyl-sulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2-Ethyl-5- [4- (5-methyl-benzooxazol-2-yl) -phenylsuifamoyl] -benzoic acid; 5- [4- (4-Ethyl-benzylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 5- [4- (3,4-Difluoro-benzylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 5- [4- (3,4-Dimethyl-benzyl-sulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 5- [4- (5,7-difluoro-benzothiazol-2-ylmethylsulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2,3-Dimethyl-5- (4'-trifluoromethoxy-biphenyl-4-sulphamoyl) -benzoic acid; 2-Ethyl-5- [4- (4-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoyl] -benzoic acid; 2-Ethyl-5- (4, -trifluoromethoxy-biphenyl-4-ylsulfamoyl) -benzoic acid; 2-Isopropyl-5- [2- (4-trifluoromethoxy-phenyl) -benzooxazol-5-ylsulfamoyl] -benzoic acid; 2-Methyl-5- (4, -trifluoromethoxy-b-phenyl-4-ylsulfamoyl) -benzoic acid; 2-Methyl-5- (4, -trifluoromethoxy-bifepil-4-ylsulfamoyl) -benzoic acid; 2-Ethyl-5- [4- (6-methyl-benzothiazol-2-yl) -phenylsulphamoyl] -benzoic acid; 2-Methyl-5- (4'-trifluoromethyl-biphenyl) -4-ylsulfamoyl) -benzoic acid; 2-Isopropyl-5- [propyl- (4, -trifluoromethoxy-biphenyl-4-yl) -sulfamoyl] -benzoic acid; 2-Methyl-5 - [(4 I-propoxy-biphenyl-4-yl) -propyl-sulfamoyl] -benzoic acid; 2-Methyl-5- (4'-propoxy-biphenyl-4-ylsulfamoyl) -benzoic acid; 5- (4'-tert-Butyl-biphenyl-4-sulfosyl) -2-methyl-benzoic acid; 5- [4- (4-Chloro-benzyl-sulfanyl) -phenylsulfamoyl] -2-methyl-benzoic acid; 2-Methyl-5- [4- (3-trifluoromethoxy-benzylsulfanyl) -phenylsulfamoyl] -benzoic acid; 2-Methyl-5- [2- (4-trifluoromethyl-phenyl) -benzooxazol-5-ylsulfamoyl] -benzoic acid; 2-Methyl-5- [4- (5-phenyl-benzooxazol-2-yl) -phenylsulfamoyl] -benzoic acid; and 2-isopropyl-5- [4- (5-methyl-benzooxazol-2-yl) -phenylsulfamoyl] -benzoic acid; or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.

7. The use of a compound according to any of claims 1-6, or a pharmaceutically acceptable salt of said compound, to make a medicament useful for treating dyslipidemia, obesity, condition by overweight, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetes mellitus (Type 1 and / or Type 11), hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, thrombosis, peripheral vascular disease, cognitive dysfunction or insufficiency congestive heart

8. The use of a compound according to any of claims 1-6, or a pharmaceutically acceptable salt of said compound, to make a medicament useful for treating the negative energy balance.

9. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of any of claims 1-6, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or profárnriacb; a second compound, said second compound being a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a gene expression inhibitor of HMG-CoA reductase, an inhibitor of HMG-CoA synthase gene expression , an inhibitor of the secretion of MTP / Apo B, a CETP inhibitor, a bile acid absorption inhibitor, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, an inhibitor of squalene cyclase, a combined squalene epoxidase / squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor, a bile acid sequestrant, or a prodrug of said compound or a pharmaceutically acceptable salt of said prodrug compound; and a pharmaceutically acceptable carrier, vehicle or solvent.

10. The combination composition of claim g, wherein the second compound is rosuvastatin, rivastatin, pitavastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin or ethyl ester of acid [2 /? 4S] 4 - [( 3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.