MX2008006699A - Glucagon receptor antagonists, preparation and therapeutic uses - Google Patents

Abstract

The present invention discloses novel compounds of Formula (I), or pharmaceutically acceptable salts thereof, which have glucagon receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of using them to treat diabetic and other glucagon related metabolic disorders, and the like.

Description

GLUCAGON RECEPTOR ANTAGONISTS, PREPARATION AND THERAPEUTIC USES This patent application claims the benefit of US Provisional Patent Application No. 60 / 739,692 filed on November 23, 2005. This invention relates to compounds that are antagonists or inverse agonists of the glucagon receptor, and to pharmaceutical compositions thereof. , and the uses of these compounds and compositions in the treatment of the human or animal body. The present compounds show high affinity and selective binding to the glucagon receptor, and as such, are employed in the treatment of disorders responsive to the modulation of glucagon receptors, such as diabetic and other metabolic disorders related to glucagon, and the like. Glucagon is a key hormonal agent that, in cooperation with insulin, mediates the homeostatic regulation of the amount of glucose in the blood. Glucagon acts mainly by stimulating certain cells (important among these are liver cells), to release glucose when blood glucose levels drop. The action of glucagon is contrary to insulin agьella, which stimulates cells to take and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones. Glucagon is produced in the alpha islet cells of the pancreas and insulin is produced in beta islet cells. Glucagon exerts its action by binding and activating its receptor, which is a member of the Glucagon-Secretin branch of the transmembrane-7 G protein-coupled receptor family. The receptor works by activating the second adenylyl cyclase messenger system that results in an increase in cAMP levels. The glucagon receptor, or variants that originate naturally from the receptor, may possess intrinsic constitutive activity, in vitro, as well as in vivo (ie, activity in the absence of an agonist). Compounds that act as inverse agonists can inhibit this activity. Diabetes mellitus is a common disorder of glucose metabolism. The disease is characterized by hyperglycemia and can be classified as type 1 diabetes, the insulin-dependent form, or type 2 diabetes, which is non-insulin-dependent in character. Subjects with type 1 diabetes are hyperglycemic and hypoinsulinemic, and conventional treatment for this form of the disease is to provide insulin. However, in some patients with type 1 or type 2 diabetes, high absolute or relative levels of glucagon have been shown to contribute to the hyperglycemic state. Both in healthy control animals as well as in animal models of type 1 and type 2 diabetes, the removal of the glucagon circulation with selective and specific antibodies has resulted in the reduction of glycemic levels. Mice with a homozygous deletion of the glucagon receptor exhibit increased glucose tolerance. Also, inhibition of glucagon receptor expression using antisense oligonucleotides, relieves diabetic syndrome in db / db mice. These studies suggest that the suppression of glucagon or an action that antagonizes glucagon should be a useful adjunct to the conventional treatment of hyperglycemia in diabetic patients. The action of glucagon can be suppressed by providing an inverse agonist or antagonist, i.e. substances that inhibit or prevent glucagon receptor mediated responses, induced by glucagon, or constitutive. Several publications describe peptides that are declared to act as glucagon antagonists. Peptide antagonists of peptide hormones are often potent; however, they are generally known to not be orally available due to degradation by physiological enzymes and poor in vivo distribution. Therefore, orally available nonpeptide antagonists of peptide hormones are generally preferred. A number of publications have appeared in recent years that report non-peptidic agents that act on the glucagon receptor. For example, WO 03/048109, WO 2004/002480, and Kurukulasuriya et al., "Biaryl amide glucagon receptor antagonists" Bioorganic & amp;; Medicinal Chemistry Letters, vol. 14, no. 9, pages 2047-2050, 2004, each of which describes non-peptide compounds that allegedly have glucagon receptor antagonist activity. Due to the number of treatments for diseases involving glucagon, current therapies suffer from one or more defects, including poor or incomplete efficacy, unacceptable side effects and contraindications for certain patient populations. Thus, there is a need for improved treatment using improved or alternative pharmaceutical agents that modulate glucagon receptor activity and treat the disease that could benefit from modulation of the glucagon receptor. The present invention provides such a contribution to the technique based on the finding that a new class of compounds has a high affinity, potent and selective inhibitory activity at the glucagon receptor. The present invention is different in the particular structures and their activities.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound structurally represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are independently -H- or halogen; R3 is -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens), -cycloalkyl (C3-C7), -alkyl (C? -C6) -cycloalkyl (C3-C), or -cycloalkyl (C3-C7) ) -alkyl (C? -6) (optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen, -hydroxy, hydroxymethyl, -CN, (C1-C7) alkoxy, (C2-C7) alkenyl, or -alkyl (Ci-Cß), (optionally substituted with 1 to 3 halogens) ); R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are independently -H, -halogen, -alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens), -alkoxy (C? -C6), cycloalkyl (C3-C7), -C (O) R10 , -COOR10, -OC (O) R10, -OS (O) 2R10, -SR10, -S (O) Rl0, -S (O) 2R10, or -O-alkenyl (C2-C); R9 is independently -H, -halogen, -CN, -cycloalkyl (C3-C7), -C (O) R10, -COOR10, -OC (O) R10, -OS (O) 2R10, -SR10, -S (O) R10, -S (O) 2R10, or -O (C2-C7) alkenyl, -alkoxy (C? ~ C3) ) (optionally substituted with 1 to 3 halogens, or -alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens), and RIO is independently in each case -hydrogen or alkyl (Ci-Cß) (optionally substituted with 1 to Halogens) The present invention provides compounds that are used as antagonists of the glucagon receptor or inverse agonists The present invention further provides compounds that are selective antagonists or inverse agonists of the glucagon receptor on the GLP-1 receptor. provides a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient The present invention further provides methods for using these compounds and compositions in the treatment of disorders sensitive to modulation n of glucagon receptors, such as diabetic metabolic disorders and others related to glucagon.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention provides compounds of Formula I as described in detail herein. While all of the compounds of the present invention are useful, certain of the compounds are particularly interesting and are preferred. The following list sets forth several groups of preferred compounds. It will be understood that each of the list can be combined with other listings to create additional groups of preferred modalities as indicated in this document. In another embodiment, the invention provides a compound of formula I, wherein R 1 and R 2 are H; R3 is -alkyl (C? -C_) (optionally substituted with 1 to 3 halogens), -cycloalkyl (C3-Cg), -alkyl (Ci-Cß) -cycloalkyl (C3-C7-), or -cycloalkyl (C3-) C6) -alkyl (C? ~ 6) (optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen, or -alkyl (Ci-Ce), (optionally substituted with 1 to 3 halogens); R6 is wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are independently -H, -halogen, -alkyl (C1-C3) (optionally substituted with 1 to 3 halogens), -alkoxy (C? -C3), and R9 is independently -H, halogen, or -alkyl ( Ci-Cß) (optionally substituted with 1 to 3 halogens). In another embodiment, the invention provides a compound of Formula I, wherein R 1 and R 2 are -H; R3 is -alkyl (C? -C8) (optionally substituted with 1 to 3 halogens), -cycloalkyl (C3-C6), -alkyl (C? -C6) -cycloalkyl (C3-C6), or cycloalkyl (C3-C6) ) -alkyl (C? ~ 6) (optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen or -CH3 (optionally substituted with 1 to 3 halogens); R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are independently -H, or -halogen; and R9 is independently -alkyl (C? -C6) (optionally substituted with 1 to 3 halogens). In another embodiment, the invention provides a compound of formula I wherein R1 and R2 are -H; R3 is alkyl (C? -C8) (optionally substituted with 1 to 3 halogens), cycloalkyl (C3-C6), -alkyl (C? -C6) -cycloalkyl (C3-C6), or cycloalkyl (C3-Cd) - alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens); R4 and R5 are -CH3 (optionally substituted with 1 to 3 halogens) and each occupies a position adjacent to R6 in the phenyl ring in which R6 is attached; R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are -H; and R9 is independently -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens). In another embodiment, the invention provides a compound of formula I wherein R 1 and R 2 are independently hydrogen or halogen; R3 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, 3, 3-dimethylbutyl, 2-methylpropyl, 3-methyl-butyl, tertbutyl, 4-methylpentyl, 2,2-dimethylpropyl, 3, 3,3-trifluoropropyl, 4, 4, 4-trifluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R4 and R5 are independently hydrogen, methyl, ethyl, tertbutyl, cyclohexyl, pentyl, isopropoxy, chloro, fluoro, bromo, hydroxy, trifluoromethyl, -CN, methoxy, hydroxymethyl, 4-methylpentyloxy, or pentyloxy; R7 and R8 are independently hydrogen, fluoro, chloro, methyl, ethyl, pentyl, isopropyl, tertbutyl, trifluoromethyl, acetyl, 2-methylpropyl, methoxy, cyclohexyl, or trifluoromethoxy; R9 is hydrogen, bromine, fluoro, methyl, tertbutyl, trifluoromethyl, or isopropyl. Other embodiments of the invention are provided, wherein each of the embodiments described herein are further adjusted as described in the following preferences. Specifically, each of the references below is independently combined with each of the above modalities, and the particular combination provides another modality in which, the variable indicated in the preference is adjusted in accordance with the preference. Preferably Rl is -H. Preferably R1 is fluorine. Preferably R1 is chloro. Preferably R2 is -H. Preferably R2 is fluorine. Preferably R2 is chloro. Preferably R1 and R2 are -H. Preferably R1 is fluorine and R2 is fluorine. Preferably R3 is -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens). Preferably, R3 is ethyl, propyl, isopropyl, butyl, tertbutyl, 3-methyl-butyl, pentyl, hexyl, heptyl, octyl, 3, 3-dimethylbutyl, 2-methylpropyl, 4-methylpentyl, 2,2-dimethylpropyl, 3, 3,3-trifluoropropyl, or 4, 4, 4-trifluorobutyl. Preferably R3 is isopropyl, butyl, tertbutyl, 3-methyl-butyl, pentyl, 3, 3-dimethylbutyl, 2-methylpropyl, 4-methylpentyl, 2,2-dimethylpropyl, 3-trifluoropropyl, or 4, 4, -trifluorobutyl. Preferably R3 is isopropyl, 3-methyl-butyl, trifluoropropyl, or 4,4,4-trifluorobutyl. Preferably R3 is -cycloalkyl (C3-C7). Preferably R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Preferably R3 is cyclopropyl. Preferably R3 is cyclobutyl. Preferably R3 is cyclopentyl. Preferably R3 is cyclohexyl. Preferably R3 is -alkyl (C? -C6) -cycloalkyl (C3-C7). Preferably R3 is -alkyl (C? -C3) -cycloalkyl (C3-C6) • Preferably R3 is -alkyl (C? -C3) -cyclopropyl. Preferably R3 is -alkyl (C? -C3) -cyclobutyl. Preferably R3 is -alkyl (C? -C3) -cyclopentyl. Preferably R3 is-(C1-C3) alkyl-cyclohexyl. Preferably R3 is-(C3-C7) cycloalkyl-alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens). Preferably R3 is -cyclopropyl-alkyl (C? -C6) (optionally substituted with 1 to 3 halogens).

Preferably R3 is -cyclobutyl-alkyl (C? -C6) (optionally substituted with 1 to 3 halogens). Preferably R3 is -cyclopentyl-alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens). Preferably R3 is -cyclohexyl-alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens). Preferably R 4 is -H, -halogen, -hydroxy, hydroxymethyl, or -alkyl (Ci-Cβ) (optionally substituted with 1 to 3 halogens). Preferably R 4 is -H, -halogen, or-(C 1 -C 3) alkyl (optionally substituted with 1 to 3 halogens). Preferably R4 is -H, -halogen, or -CH3. Preferably R4 is -H. Preferably R4 is fluorine, chlorine, 0 bromine Preferably R4 is -CH3. Preferably R5 is -H, -halogen, -hydroxy, hydroxymethyl, or -alkyl (C? -C6) (optionally substituted with 1 to 3 halogens). Preferably R 5 is -H, -halogen, or-(C 1 -C 3) alkyl (optionally substituted with 1 to 3 halogens). Preferably R5 is -H, -halogen, or -CH3. Preferably R5 is -H. Preferably R5 is fluorine, chlorine, or bromine. Preferably R5 is -CH3. Preferably R4 and R5 are -H. Preferably R4 is halogen and R5 is -H. Preferably R4 is -H and R5 is -CH3. Preferably R4 and R5 are -CH3. Preferably R4 and R5 are -CH3 and each occupies a position adjacent to R6 on the phenyl ring to which R6 is attached. Preferably R7 is -halogen, -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens), alkoxy ( C? -C6), -cycloalkyl (C3-C7), -C (O) R10, -COOR10, OC (O) R10, -OS (O) 2R10, -SR10, -S (O) R10, -S ( O) 2R10, or Oalkenyl (C2-C7). Preferably R7 is -halogen, alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens), or -alkoxy (Ci-Cd). Preferably R7 is -H or -halogen. Preferably R7 is -H. Preferably R8 is -halogen, -alkyl (C? ~ Ce) (optionally substituted with 1 to 3 halogens), -alkoxy (Ci-C6), -cycloalkyl (C3-C7), -C (O) R10, -COOR10, -OC (O) R 10, OS (O) 2 R 10, -SR 10, -S (O) R 10, -S (O) 2 R 10, or -O (C 2 -C 7) alkenyl. Preferably R8 is -halogen, -alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens), or -alkoxy (Ci-Cß). Preferably R8 is -H or -halogen. Preferably R8 is -H. Preferably R7 is -H and R8 is -H. Preferably R9 is -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens). Preferably R9 is methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, trifluoromethyl, 3-methyl-butyl, pentyl, hexyl, 3,3-dimethylbutyl, 2-methylpropyl, 4-methylpentyl, 2,2-dimethylpropyl, 3-trifluoropropyl. , or 4-trifluorobutyl. Preferably R9 is isopropyl, tertbutyl, or trifluoromethyl. Preferably R7 is -H, R8 is -H, and R9 is isopropyl, tertbutyl, or trifluoromethyl. Preferably RIO is independently in each case, -alkyl (Ci-Cd) (optionally substituted with 1 to 3 halogens). Additional embodiments of the invention include the compounds of formula XI to Xll. A further embodiment of the invention are any of the preparations of novel intermediates described herein, which are employed to prepare the glucagon receptor antagonists or the inverse agonists of formulas I, or XI to Xll.

Table 1 Due to the interaction with a glucagon receptor, the present compounds are employed in the treatment of a wide range of conditions and disorders in which an interaction with the glucagon receptor is beneficial. These disorders and conditions are defined herein as "diabetic metabolic disorders and others related to glucagon.". One of skill in the art is able to identify "diabetic and other metabolic disorders related to glucagon"; for the inclusion of glucagon receptor-mediated signaling either in the pathophysiology of the disorder or in the homeostatic response to the disorder. Thus, the compounds can find use for example, to prevent, treat or alleviate diseases or conditions or symptoms or associated sequelae, of the endocrine system, the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, and the gastrointestinal system, while reducing and / or eliminating one or more of the unwanted side effects associated with current treatments. "Diabetic and other glucagon-related metabolic disorders" include but are not limited to, diabetes, type 1 diabetes, type 2 diabetes, hyperglycemia, hyperinsulinemia, beta-cell arrest, improved beta-cell function by restoration of the first-phase response, prandial hyperglycemia, prevention of apoptosis, glucose impaired by fasting (IFG), metabolic syndrome, hypoglycemia, hyper- / hypocalcemia, normalizing glucagon levels, improved LDL / HDL ratio, reduction of snack intake, eating disorders, weight loss, syndrome polyguide ovary (PCOS), obesity as a consequence of diabetes, latent autoimmune diabetes in adults (LADA); insulitis, islet transplantation, pediatric diabetes, gestational diabetes, late diabetic complications, micro- / macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic foot ulcers, reduced intestinal mobility due to administration of glucagon, short bowel syndrome, increased gastric secretion , antidiarrheal, reduced blood flow, erectile dysfunction, glaucoma, post-surgical stress, isgemic heart damage, heart failure, congestive heart failure, stroke, myocardial infarction, arrhythmia, premature death, anti-apoptosis, wound healing, tolerance to impaired glucose (IGT), insulin resistance syndromes, syndrome X, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gast rointestinales, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc. In addition, the present invention provides a compound of Formula I, or a pharmaceutical salt thereof, or a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient; for use in the inhibition of the glucagon receptor; for use in the inhibition of a cellular response mediated by the glucagon receptor in a mammal; for use in reducing the glycemic level in a mammal; for use in the treatment of a disease that originates from excessive glucagon; for use in the treatment of diabetic and other metabolic disorders related to glucagon in a mammal; and for use in the treatment of diabetes, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy and wound healing.

Thus, the methods of this invention encompass prophylactic and therapeutic administration of a compound of formula I. The present invention further provides the use of a compound of Formula I, or a pharmaceutical salt thereof for the manufacture of a medicament for inhibiting the glucagon receptor; for the manufacture of a medicament for inhibiting a cellular response mediated by the glucagon receptor in a mammal; for the manufacture of a medicament for reducing the glycemic level in a mammal; for the manufacture of a medicament to treat a disease that originates from excessive glucagon; for the manufacture of a medicament for the treatment of diabetic and other metabolic disorders related to glucagon in a mammal; and for the manufacture of a drug to prevent or treat diabetes, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy and inappropriate wound healing. The present invention further provides a method for treating conditions that result from excessive glucagon in a mammal; a method for inhibiting the glucagon receptor in a mammal; a method for inhibiting a cellular response mediated by the glucagon receptor in a mammal; a method for reducing the glycemic level in a mammal; a method for treating diabetic and other metabolic disorders related to glucagon; a method to prevent or treat diabetes, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy, and inappropriate wound healing; said methods comprises administering to a mammal in need of such treatment, an amount which inhibits the glucagon receptor of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In addition, the present invention provides a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient: adapted for use in the inhibition of the glucagon receptor; adapted for use in the inhibition of cellular responses mediated by the glucagon receptor; adapted for use in reducing the glycemic level in a mammal; adapted for use in the treatment of diabetic and other metabolic disorders related to glucagon in a mammal; and adapted for use in the prevention or treatment of diabetes, obesity, hyperglycemia, atherosclerosis, ischemic heart disease, stroke, neuropathy and wound healing. The compound or salt of the present invention further provides a diagnostic agent for identifying patients who have a defect in the glucagon receptor, as a therapy for increasing gastric acid secretions and for reversing intestinal hypomobility due to the administration of glucagon . The invention also provides a method for the treatment of disorders or diseases, wherein an antagonistic action of glucagon is beneficial, the method comprising administering to a subject in need thereof, an effective amount of a compound according to the invention. In another embodiment of the invention, the present compounds are used for the preparation of a medicament for the treatment of any of the conditions and diseases mediated by glucagon. In another embodiment of the invention, the present compounds are used for the preparation of a medicament for the treatment of hyperglycemia. In yet another embodiment of the invention, the present compounds are used for the preparation of a medicament for reducing blood glucose in a mammal. The present compounds are effective in reducing blood glucose, both in the fasting and post-prandial state. Still in another embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT. In a further embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. Still in a further embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the delay or prevention of the progress of IGT to type 2 diabetes. Still in another embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delay or prevention of the progress of type 2 diabetes that does not require insulin to diabetes type 2 that requires insulin. In a further embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes. Such treatment is normally accompanied by insulin therapy. Still in a further embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of obesity. Still in a further embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment of disorders of lipid metabolism. In still another embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of a disorder that expends energy or regulates appetite. In a further embodiment of the invention, the treatment of a patient with the present compounds is combined with diet and / or exercise. In a further aspect of the invention, the present compounds are administered in combination with one or more of the active substances in any of the appropriate ratios. Such additional active substances may, for example, be selected from antidiabetics, anti-obesity agents, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity. The following list shows several groups of combinations. It will be understood that each of the appointed agents can be combined with other appointed agents to create additional combinations. Thus, in a further embodiment of the invention, the present compounds can be administered in combination with one or more antidiabetics. Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those described in EP 792 290 (Novo Nordisk A / S), for example human insulin NeB29-tetradecanoyl des (B30), EP 214 826 and EP 705 275 (Novo Nordisk A / S), for example, human insulin AspB28, US 5,504,188 (Eli Lilly), for example human insulin LysB28 ProB29, EP 368 187 (Aventis), for example Lantus®, which are all incorporated in this reference document, GLP-1 and GLP-1 derivatives such as those described in WO 98/08871 (Novo Nordisk A / S), which are incorporated herein by reference, as well as orally active hypoglycemic agents. Orally active hypoglycemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, insulin secretagogues such as glimepiride, α-glucosidase inhibitors, agents that act on the ATP-dependent potassium channel of the ß cells, for example, potassium channel openers such as those described in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, GLP-1 antagonists, inhibitors of DPP-IV (dipeptidyl peptidase-IV), inhibitors of PTPase (protein tyrosine phosphatase), inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose absorption, glucokinase (GK) activators , such as those described in WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478, WO 01/85706, WO 01/85707, and WO 02/08209 (Hoffman-La Roche) or those described in WO 03/00262, WO 03/00267 and WO 03/15774 (AstraZeneca), which are incorporated herein by reference, inhibitors of GSK-3 (glycogen synthase kinase-3), compounds which modify the lipid metabolism such as antilipidemic agents such as HMG CoA inhibitors (statins), compounds that reduce food absorption, PPAR (Peroxisome Proliferator Activated Receptor) ligands that include the PPAR-alpha, PPAR-gamma and PPAR-delta subtypes , and RXR agonists (receptor of tinoid X), such as ALRT-268, LG-1268 or LG-1069. In another embodiment, the present compounds are administered in combination with insulin or an insulin analog or derivative, such as human insulin N tetradecanoyl des (B30), human insulin AspB28, human insulin LysB28 ProB29, Lantus®, or a mixture preparation that it includes one or more of these. In a further embodiment of the invention, the present compounds are administered in combination with a sulfonylurea such as glibenclamide, glipizide, tolbmide, chloropamide, tolazamide, glimepride, glycazide and glyburide. In another embodiment of the invention, the present compounds are administered in combination with a biguanide, for example, metformin.

In still another embodiment of the invention, the present compounds are administered in combination with a meglitinide, for example, repaglinide or nateglinide. In still another embodiment of the invention, the present compounds are administered in combination with a thiazolidinedione insulin sensitizer, for example, troglitazone, ciglitazone, piolitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 / CI-1037 or T 174 or the documents described in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference. In still another embodiment of the invention, the present compounds can be administered in combination with an insulin sensitizer, for example, such as Gl 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds described in WO 99/19313, WO 00/50414, WO 00/63191, WO 00 / 63192, WO 00/63193 such as ragaglitazar (NN 622 or (-) DRF 2725) (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A / S), which are incorporated herein by reference. In a further embodiment of the invention, the present compounds are administered in combination with an α-glucosidase inhibitor, for example, voglibose, emiglitate, miglitol or acarbose. In another embodiment of the invention, the present compounds are administered in combination with an agent that acts on the ATP-dependent potassium channel of the β-cells, for example, tolbutamide, glibenclamide, glipizide, glycoside, BTS-67582 or repaglinide. In yet another embodiment of the invention, the present compounds can be administered in combination with nateglinide. In yet another embodiment of the invention, the present compounds are administered in combination with an antilipidemic agent or an antihyperlipidemic agent, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, pitavastatin, rosuvastatin, probucol, dextrothyroxine, fenofibrate or atorvastin In still another embodiment of the invention, the present compounds are administered in combination with compounds that reduce the absorption of food. In another embodiment of the invention, the present compounds are administered in combination with one or more of the aforementioned compounds for example, in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; repaglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulphonylurea; insulin and troglitazone; insulin and lovastatin; etc. In a further embodiment of the invention, the present compounds can be administered in combination with one or more anti-obesity agents or appetite regulating agents. Such agents may be selected from the group consisting of agonists CART (transcript regulated by cocaine amphetamine), NPY (neuropeptide Y) antagonists, MC4 agonists (melanocortin 4), MC3 agonists (melanocortin 3), orexin antagonists, TNF agonists ( tumor necrosis factor), CRF agonists (corticotropin releasing factor), CRF BP antagonists (corticotropin releasing factor binding protein), urocortin agonists, β3 adrenergic agonists such as CL-316243, AJ-9677, GW- 0604, LY362884, LY377267 or agonists AZ-40140 MSH (melanocyte stimulation hormone), MCH antagonists (melanocyte concentration hormone), CCK agonists (cholecystokinin), serotonin reuptake inhibitors such as fluoxetine, seroxat or citalopram, inhibitors of re-uptake of serotonin and noradrenaline, mixed noradrenergic and serotonin compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin and placental lactogen, growth hormone releasing compounds, HRT agonists release of tiretropine), modulators UCP 2 or 3 (protein without coupling 2 or 3), leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators (peroxisome proliferator-activated receptor), modulators RXR (retinoid X receptor), TRβ agonists, AGRP inhibitors (Agouti-related protein), histamine H3 antagonists), opioid antagonists (such as natrexone), exendin-4, GLP-1 and ciliary neurotrophic factor (such as abaxin) , cannabinoid receptor antagonist for example, CB-1 (such as rimonobant). In another embodiment, the anti-obesity agent is dexamfetamine, or amphetamine. In another embodiment, the anti-obesity agent is leptin. In another embodiment, the anti-obesity agent is fenfluramine or exfenfluramine. In yet another embodiment, the anti-obesity agent is sibutramine. In a further embodiment, the anti-obesity agent is orlistat. In another embodiment, the anti-obesity agent is mazindol or phentermine. In yet another embodiment, the antiobesity agent is phendimetrazine, diethylpropione, fluoxetine, bupropion, topiramate or ecopipam. In addition, the present compounds can be administered in combination with one or more antihypertensive agents. Examples of anti-hypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, inhibitors SCE (enzyme that converts angiotensin) such as benazepril, captopril, enalapril, fosinopril, lisinopril, guinapril and ramipril, blockers of the calcium channel such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. Additional reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co. , Easton, PA, 1995. The compounds of the present invention can be administered in combination with FAS inhibitors. The compounds of the present invention can also be administered in combination with non-chemical couplers, hormone-sensitive lipase inhibitor, imidazolines, 11-β-hydroxysteroid dehydrogenase inhibitors, lipoprotein lipase activator, AMPK activators, immunosuppressive drugs, nicotinamide, ASIS, anti-androgens or carboxypeptidase inhibitors. It should be understood that any suitable combination of the compounds according to the invention with diet and / or exercise, one or more of the aforementioned compounds is considered to be within the scope of the present invention. The general terms used in the description of the compounds, compositions and methods described in this document carry their usual meanings. Through the present application, the following terms have the indicated meanings: "GLP-1" means peptide 1 similar to glucagon. The term "glucagon receptor" means one or more receptors that interact specifically with glucagon to result in a biological signal. The term "GLP-1 receptor" means one or more receptors that specifically interact with peptide 1 to simulate glucagon to result in a biological signal. The term "glucagon receptor antagonist" means a compound of the present invention with the ability to block the production of cAMP in the glucagon response. The term "inverse glucagon receptor agonist" means a compound of the present invention with the ability to inhibit the constitutive activity of the glucagon receptor. The term "selective" antagonist or inverse agonist means a compound that has a higher affinity for the glucagon receptor compared to the affinity for the GLP-1 receptor. In the general formulas of this document, the general chemical terms have their usual meanings. For example: "Halogen" or "halo" means fluoro, chloro, bromo and iodo. The term "alkyl", unless otherwise indicated, refers to those alkyl groups of a designated number of carbon atoms of either a straight or branched saturated configuration. As used herein, "(C 1 -C 3) alkyl", are one to three carbons, such as methyl, ethyl, propyl, n-propyl, isopropyl and the like and the isomeric or branched forms thereof, and optionally to be substituted with one to three halogens or a designated number of substituents as set forth in the embodiments mentioned herein. "Alkyl (Ci-Cß)", are one to six carbon atoms such as methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, pentyl, isopentyl, hexyl and the like, and isomeric or branched forms thereof, and optionally may be substituted with one to three halogens or a designated number of substituents as set forth in the embodiments mentioned herein. "Alkyl (Cl-Cß)" are one to eight carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and the like, and branched or isomeric forms thereof, and may optionally be substituted with one to three halogens as stated in the modalities mentioned in this document. The term "(C3-C7) cycloalkyl" refers to a saturated or partially saturated carbocycle containing one or more rings of 3 to 7 carbon atoms. Examples of (C3-C7) cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "(C3-C6) cycloalkyl" refers to a saturated carbocycle ring of 3 to 6 carbon atoms. Examples of (C3-C6) cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "(C1-C3) alkoxy", represents an alkyl group of one to three carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy and the like. The term "(C? -C6) alkoxy" represents an alkyl group of one to six carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy and Similar. The term "(C? -C) alkoxy" represents an alkyl group of one to seven carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy and the like , and can be optionally substituted with three halogens as set out in the modalities mentioned in this document. The term "(C2-C7) alkenyl" means a hydrocarbon chain of two to seven carbon atoms of either a branched or straight configuration having at least one carbon-carbon double bond which can occur at any point at chain length, such as ethenyl, propenyl, butenyl, pentenyl, vinyl, alkyl, 2-butenyl and the like, and may be optionally substituted with one to three halogens as set forth in the embodiments mentioned herein. The term "optionally substituted" or "optional substituents" as used herein, means that the groups in question are either substituted or unsubstituted with one or more of the specified substituents. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. In addition, when the terms "independently," independently are ", and" independently selected from ", it means that the groups in question may be the same or different, Certain of the terms defined in this document may occur more than once in the structural formulas, and after such incidence, each term must be defined independently of the other.

The term "patient" includes human and non-human animals, such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals created for food production. Ruminants or animals of "regurgitation" such as cows, bulls, steers, oxen, sheep, buffaloes, bison, goats and antelopes, are examples of cattle. Other examples of livestock include pigs and poultry (poultry), such as chickens, ducks, turkeys and geese. Still other examples of cattle include fish, shellfish and crustaceans originating in aquaculture. Also included are exotic animals used in food production such as crocodiles, carabaos, and running birds (eg, emu, ñandú, or ostriches). The patient to be treated is preferably a mammal, in particular a human being. The term "a glucagon receptor-mediated cellular response" includes several responses by mammalian cells for glucagon stimulation or glucagon receptor activity. For example, "cellular responses mediated by the glucagon receptor" include, but are not limited to, glucose release from the liver or other cells, in response to glucagon stimulation or glucagon receptor activity. One of ordinary skill in the art can readily identify other cellular responses mediated by glucagon receptor activity, for example, by observing a change in the sensitive cell endpoint after contacting the cell with an effective dose of glucagon. The terms "treatment", "treating" and "treating", as used herein, include their meanings generally accepted, ie, the management and care of a patient for the purpose of preventing, prohibiting, restricting, alleviating, lessen, reduce, stop, delay, or reverse the progress or severity of a disease, disorder or pathological condition described herein, which includes the relief or assistance of symptoms or complications, or the cure or elimination of the disease, disorder or condition . "Composition" means a pharmaceutical composition and is intended to encompass a pharmaceutical product comprising the active ingredients that include compounds of Formula I, the inert ingredients that make the carrier. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier. The term "suitable solvent" refers to any solvent, or mixture of solvents, inert or the reaction in progress, which sufficiently solubilizes the reactants to provide a medium within which to effect the desired reaction.

The term "unit dosage form" means physically discrete units suitable as unitary dosages for human subjects and other non-human animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier . The compounds of the present invention may be chiral, and it is intended that any of the enantiomers, whether pure, partially purified, or racemic mixtures, are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of an asymmetry or a link with restricted rotation capacity, is present in the diastereomers of the molecule, they can be formed. It is intended that any of the diastereomers, such as separate, pure or partially purified diastereomers or mixtures thereof, are included within the scope of the invention. In addition, some of the compounds of the present invention can exist in different tautomeric forms and it is intended that any of the tautomeric forms, in which the compounds are capable of being formed, are included within the scope of the present invention. The invention also includes tautomers, enantiomers and other stereoisomers of the compounds of Formula I. Such variations are contemplated to be within the scope of the invention. Compounds of Formula I, when they exist as a diastereomeric mixture, can be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional means, for example, by the use of an optically active acid as a resolving agent. Alternatively, any enantiomer of a compound of Formula I can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration or through enantioselective synthesis. The term "enantiomeric enrichment", as used herein, refers to the increase in the amount of the enantiomer compared to the other. A conventional method to express the enantiomeric enrichment achieved, is the concept of enantiomeric excess, or "ee"; which is found using the following equation: ee = E1 - E2 X 100 E1 + E2 where E1 is the quantity of the first enantiomer and E2 is the quantity of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and sufficient enantiomeric enrichment is achieved to produce a final ratio of 70:30, the ee with respect to the first enantiomer It is 40%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee greater than 90% is preferred, an ee greater than 95% is more preferred and an ee greater than 99% is more especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as high-performance liquid chromatography or gas with a chiral column. The choice of the appropriate chiral column, levigant and conditions necessary to effect the separation of the enantiomeric pair, is also within the knowledge of one of ordinary skill in the art. In addition, the specific stereoisomers and enantiomers of compounds of Formula I can be prepared by one of ordinary skill in the art using well-known techniques and processes such as those described by J. Jacques, et al. , "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds," (Wiley-Interscience 1994), and European Patent Application No. EP-A-838448, published April 29, 1998). Examples of resolutions include recrystallization techniques or chiral chromatography. Unless indicated otherwise, a compound indicated to be "isomer 1" will be the first isomer levigated from the chiral separation column and "isomer 2" will be the second. In general, the term "pharmaceutical" when used as an adjective means substantially non-toxic to living organisms. For example, the term "pharmaceutical salt", as used herein, refers to salts of the compounds of Formula I, which are substantially non-toxic to living organisms. The present invention also encompasses pharmaceutically acceptable salts of the present compounds. The pharmaceutically acceptable salts and the common methodology for preparing them are well known in the art. See, for example, P. Stahl, et al. , "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," (VCHA / Wiley-VCH, 2002); Berge, S.M., Bighley, L.D., and Monkhouse, D.C., "Pharmaceutical Salts," J. Pharm. Sci. , 66: 1, 1977. The invention also encompasses prodrugs of the present compounds, which upon administration are subjected to chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of present compounds, which are readily convertible in vivo to a compound of the present invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The compounds of Formula I can be prepared by one of ordinary skill in the art after a variety of procedures, some of which are illustrated in the procedures and schemes set forth below. The particular order of steps required to produce the compounds of Formula I is dependent on the particular compound to be synthesized, the starting compound, and the relative sensitivity of the substituted portions. Reagents or starting materials are readily available to one of skill in the art, and to the extent not commercially available, they are readily synthesized by one of ordinary skill in the art following the standard procedures commonly employed in the art, along with those of the art. Various procedures and schemes outlined below. The following Reaction Schemes, Preparations, Examples and Procedures are provided to better elucidate the practice of the present invention and should not be construed in any way to limit the scope thereof. Those skilled in the art will recognize that various modifications may be made as long as they do not depart from the spirit and scope of the invention. All publications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. The optimal time to carry out the reactions of the Reaction Schemes, Preparations, Examples and Procedures, can be determined by monitoring the progress of the reaction via conventional chromatographic techniques. In addition, it is preferred to conduct the reactions of the invention under an inert atmosphere, such as for example, argon, or particularly nitrogen. The choice of the solvent in general is not critical as soon as the solvent employed is inert to the reaction in progress and sufficiently solubilizes the reactants to effect the desired reaction. The compounds are preferably isolated and purified prior to their use in subsequent reactions. Some compounds can crystallize from the reaction solution during their formation and then be collected by filtration, or the reaction solvent can be removed by extraction, evaporation or decantation. The intermediates and final products of Formula I can also be purified if desired, by common techniques such as recrystallization or chromatography on solid supports such as silica gel or alumina. The person skilled in the art will appreciate that not all substituents are compatible with all reaction conditions. These compounds can be protected or modified at a convenient point in the synthesis by methods well known in the art. The terms and abbreviations used in the present Reaction Schemes, Preparations, Examples and Procedures have their normal meanings unless otherwise designated. For example, as used herein, the following terms have the indicated meanings: "psi" refers to pounds per square foot; "min" refers to minutes ";" h "or" hr "refers to hours;" CCD "refers to thin layer chromatography;" HPLC "refers to high performance liquid chromatography;" Rf "refers to retention factor, "Rt" refers to retention time, "d" refers to parts per million of low field of tetramethylsilane, "EM" refers to mass spectrometry, "EM (ER)" refers to spectrometry of Electron dew masses, "UV" refers to ultraviolet spectrometry;, 1H NMR "refers to nuclear magnetic resonance spectrometry of the proton. Further; "TA" refers to room temperature; "DEAD" refers to diethylazodicarboxylate; "PPh3" refers to triphenylphosphine; "ADDP" refers to 1,1 '- (azodicarbonyl) dipiperidine; "PBu3" refers to tributylphosphine; "OTF" refers to triflate; "LAH" refers to lithium aluminum hydride; "DIBAL-H" refers to diisobutylammonium hydride; "KOtBu", refers to potassium t-butoxide; "THF" refers to tetrahydrofuran; "TBP" refers to tributylphosphine; "EDCI" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiamide hydrochloride; "DMAP" refers to dimethylaminopyridine; "HNMe (OMe)" refers to N, N-dimethylhydroxyamine; "CDMT" refers to 2-crloro-4,6-dimethoxy- [1, 3, 5] triazine; "NMM" refers to N-methyl morpholine; "DCM" refers to dichloromethane; "DMSO" refers to dimethylsulfoxide; "ET3N" refers to triethylamine; "DMF" refers to dimethylformamide; "PBR3" refers to phosphorus tribromide; "Et" in a formula, refers to ethyl, for example, Et20 refers to diethyl ether, and EtOAc refers to ethylacetate; "PyBOP" refers to bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; "Me" refers to methyl as in MeOH which is methanol; "Pd / C" refers to palladium on 10% carbon. Unless otherwise indicated, isomer 1 refers to the first isomer to be levigated in a chiral separation and isomer 2 refers to the second isomer to be levigated in a chiral separation.

GENERAL REACTION SCHEMES All the compounds of the present invention can be chemically prepared for example, following the synthetic routes set forth in the Reaction Schemes and / or the following Preparations and Examples. However, the following discussion is not intended to be limiting to the scope of the present invention in any way. For example, the specific synthetic steps for each of the described routes can be combined in different ways, or in conjunction with the steps from different reaction schemes, to prepare additional compounds of Formula I.

Reaction Scheme I In Reaction Scheme I, Step A, a 4-halophenol of formula (1), (X = I or Br), is coupled with a phenylboronic acid of formula (2), using a Suzuki reaction to provide a hydroxy biphenyl of formula (3). It will be recognized by one of skill in the art that such Suzuki couplings using aryl halides and phenylboronic acids can be effected using a wide variety of reaction conditions. Preferred conditions use oxidi-2, 1- (phenylene) bis (diphenylphosphine) in the presence of palladium acetate and potassium fluoride in an inert solvent, such as tetrahydrofuran. The reaction is heated to a temperature of 50 ° C at the reflux temperature of the solvent for about 4 to 48 hours under nitrogen. Alternatively, the Suzuki reaction can be effected using tetrakis (triphenylphosphine) palladium with potassium fluoride under nitrogen. The reaction proceeds in an inert solvent such as toluene or benzene and water at a temperature of 40 ° C at the reflux temperature of the reaction for about 4 to 48 hours. In Reaction Scheme I, Step B, a hydroxy biphenyl of formula (3) is coupled with dimethyldiocarbamoyl chloride, subjected to thermal rearrangement and subsequent solvolysis of the intermediate dimethyl thiocarbamic acid ester to provide a biphenylthiol of formula (4) . The coupling reaction to give the thiocarbamate is carried out in the presence of 4-dimethylaminopyridine with an organic amine such as triethylamine or diisopropylethylamine. The reaction is carried out in an inert solvent such as dioxane, tetrahydrofuran, benzene or toluene, with dioxane being preferred at a temperature of 65 ° C at the reflux temperature of the solvent. The resulting thiocarbamate is thermally rearranged in tetradecane at a temperature of 200 to 250 ° C with the preferred temperature being about 245 ° C to give an ester of dimethyl thiocarbamic acid. Solvolysis with sodium methoxide in methanol or sodium ethoxide in ethanol provides the biphenyl thiol of formula (4).

Reaction Scheme II Stage E In Reaction Escape II, Step A, an ethyl thiophene 2-carboxylate of formula (5), is alkylated with an aldehyde (R3CH0) to give a secondary alcohol of formula (6). An ethyl thiophene 2-carboxylate of formula (5) is treated with lithium diisopropylamide at a temperature of -80 to -70 ° C and then treated with an aldehyde in an inert solvent such as tetrahydrofuran. The reaction is allowed to warm to room temperature for about 12 to 24 hours, and the product is isolated using extractive techniques to give the secondary alcohol of formula (6). In Reaction Scheme II, Step B, a secondary alcohol of formula (6) is coupled with a 4-halo thiophenol (X = Br or I) of formula (7), to give a 4-halophenyl thioether of formula (8) ). The coupling is effected with a Lewis acid, such as zinc iodide (Znl2), in an inert solvent such as dichloromethane or dichloroethane at a temperature of 0 to 50 ° C, with dichloroethane at room temperature, the preferred conditions being. The product is isolated using common extractive techniques to give the 4-halophenyl thioether of formula (8). Alternatively, the coupling of the secondary alcohol and thiophenol can be effected using Mitsinobu conditions. The common reduction systems, known to those skilled in the art, such as diethyl azodicarboxylate (DEAD) / triphenylphosphine, N, N, N'N'-tetramethylazodicarboxamide (TMAD) / tributylphosphine or 1,1'- (azodicarbonyl) dipiperidine (ADDP) / tributylphosphine, they can be used to effect the transformation. In Reaction Scheme II, Step C, a 4-halophenyl thioether of formula (8), is coupled with a phenylboronic acid of formula (2) in a Suzuki reaction to provide the biphenyl thioether of formula (9), using conditions such as is described for Reaction Scheme I, Step A. Alternatively, in Reaction Scheme II, Step D, a biphenylthiol of formula (3), is coupled using Mitsinobu conditions described for Reaction Scheme II, Step B to give a biphenyl thioether of formula (9). In Reaction Scheme II, Step E, the ethyl ester of thiophene carboxylic acid of formula (9), is hydrozylated to a carboxylic acid of formula (10). The ester is hydrolyzed in a suitable water-soluble solvent such as ethanol, methanol, dioxane or tetrahydrofuran, with tetrahydrofuran being preferred. The ester is treated with an inorganic base such as sodium or potassium hydroxide, with sodium hydroxide being preferred, at room temperature at the reflux temperature of the solvent for 2 to 48 hours. The thiophenecarboxylic acid of formula (10) is isolated by neutralization with hydrochloric acid followed by common extractive techniques.

Reaction Scheme III In Reaction Scheme III, Step A, a thiophenecarboxylic acid of formula (11) is acylated to give an amide of formula (12). It will be recognized by one skilled in the art that there are numerous conditions for the formation of the amide bond between a carboxylic acid and an amine. Such methods can be found in the text of R.C. Larock in "Comprehensive Organic Transformations", VCH Publishers, 1989, p. 972-976. Preferred conditions use a catalytic amount of 4-dimethylaminopyridine (DMAP), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI) and an organic base, such as diisopropylethylamine or triethylamine in a inert solvent such as dichloromethane or tetrahydrofuran. The active ester is treated with aminoacetonitrile hydrochloride at 0 ° C at the reflux temperature of the solvent, but preferably at room temperature for about 4 to 48 hours. Alternatively, in Reaction Scheme III, Step A, another series of preferred conditions use 2-chloro-4,6-dimethoxy-1,3,5-triazine to form the active ester in the presence of an organic base, such as N-methyl morpholine in an inert solvent such as tetrahydrofuran. The active ester is treated with aminoacetonitrile hydrochloride at 0 ° C to 50 ° C for 4 to 48 hours to form the amide of formula (12). In Reaction Scheme III, Step B, an amide of formula (12) is cyclized to a tetrazole of formula (13). It will be recognized by the person skilled in the art that useful reagents for forming tetrazoles from nitriles include azidotrimethylsilane, azidotributyltin, and sodium azide. Preferred conditions use sodium azide in the presence of alkylamine hydrochloride such as triethylamine or diisopropylethylamine hydrochloride in an inert solvent such as toluene, benzene, dimethylformamide, tetrahydrofuran or dioxane. Preferred conditions use toluene at a temperature of 40 ° C at the reflux temperature of the solvent for a period of 4 to 48 hours. The product is isolated by acidification with aqueous hydrochloric acid and extraction in an appropriate organic solvent, such as ethyl acetate.

PREPARATIONS AND EXAMPLES The examples provided in this document are illustrative of the invention claimed herein and are not intended to limit the scope of the claimed invention in any way. The names of the preparations and examples are derived using ChemDraw. The 1 H NMR spectrum was recorded on a 400 MHz Varian spectrometer at room temperature. The data are reported as follows: chemical change in ppm from internal standard tetramethylsilane in (scale, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quint and m = multiplet ), integration, coupling constant (Hz) and assignment XH NMR indicates a satisfactory NMR spectrum that is obtained for the described compound The monoisotopic mass spectral data is obtained in an Agilent G1956B MSD quad quadrupole instrument using electro dew ionization (ESI OR ER) Analytical thin-layer chromatography is performed on EM-Reagent 0.25-mm silica gel 60-F plates, visualization is performed with UV light, all examples are racemic unless indicated otherwise mode.

Preparation 1 2, 6-dimethyl-4 '- (trifluoromethyl) biphenyl-4-ol 4-Bromo-3,5-dimethylphenol (115.00 g, 571.96 mmol), 4- (trifluoromethyl) phenyl boronic acid (130.36 g, 686.35 mmol), (oxidi-2, 1-phenylene) bis (diphenylphosphine) (126.00 g, 233.96 mmol), potassium fluoride (99.69 g, 1.72 mmol), and Pd (OAc) 2 (25.68 g, 114.39 mmol), to tetrahydrofuran spread with nitrogen (3.0 1) and heated to reflux. The consumption of the starting material, 4-bromo-3,5-dimethylphenol, is monitored by GC. The reflux is maintained until the 4-bromo-3,5-dimethylphenol has been consumed and in general, it is completed after 18 hours. After the reaction is complete, the batch is cooled to approximately 25 ° C. The crude reaction mixture is absorbed on silica (~ 500 g) and levigated on silica (1.5 kg) with 10% ethyl acetate in heptane, to obtain the product as a solid (132.9 g, 87.3%). The product is crystallized from heptane (23 1 / kg) and isopropanol (0.4 1 / kg), to provide the title compound (119.5 g.; 78.5% yield), as a whitish solid. MS (RE): 265.21 [Ml]. "A NMR (400 MHz, CDC13): d 7.68 (d, 2 H), 7.26 (d, 2 H), 6.62 (s, 2 H), 4.73 (s, 1 H), 1.97 (s, 6 H).

Preparation 2 4'-tert-butyl-2,6-dimethylbiphenyl-4-ol The title compound was prepared essentially following the procedure as described in Preparation 1, using 4-tert-butylphenylboronic acid. A NMR ((400 MHz, CDC13): 67.43 (d, 2 H), 7.06 (d, 2 H), 6.61 (s, 2 H), 4.85 (s, 1 H), 2.02 (s, 6 H), 1.38 (s, 9 H).

Preparation 3 (R, S) -5- (l-Hydroxy-3-methyl-butyl) -thiophene-2-carboxylic acid ethyl ester A solution of diisopropylamine (8.55 ml, 60 mmol) in THF (350 ml) under N2 it was cooled to -78 ° C and treated with n-butyl lithium (2.5 M in hexanes, 24 ml). The mixture was then heated at 0 ° C for 10 min, cooled to -78 ° C, treated dropwise with a solution of thiophene-2-carboxylic acid ethyl ester (7.8 g, 50 mmol) in THF (150 ml). , and stirred 5 min. 3-Methyl-butyraldehyde (6.48 ml, 60 mmol) was then added, and the reaction was allowed to warm to room temperature, while stirring overnight. Aqueous buffer (pH = 7) is added, and the product is extracted into ethyl acetate (3x). The combined organic layers are dried, filtered and concentrated. The resulting residue is applied to silica gel and levigate using hexanes with a gradient of ethyl acetate from 0% to 60% to give the title compound (8.03 g). Preparations 4 to 9 are prepared in a substantially similar manner as described in Preparation 3.

Preparation 4 (R, S) -5- (1-Hydroxy-propyl) -thiophene-2-carboxylic acid ethyl ester Preparation 5 (R, S) -5- (1-Hydroxy-butyl) -thiophene-2-carboxylic acid ethyl ester Preparation 6 (R, S) -5- (1-Hydroxy-pentyl) -thiophene-2-carboxylic acid ethyl ester Preparation 7 (R, S) -5- (l-Hydroxy-2, 2-dimethyl-propyl) -thiophene-2-carboxylic acid ethyl ester Preparation 8 (R, S) -5- (l-Hydroxy-2-methyl-propyl) -thiophene-2-carboxylic acid ethyl ester Preparation 9 (R, S) -5- (l-Hydroxy-3, 3-dimethyl-butyl) -thiophene-2-carboxylic acid ethyl ester Preparation 10 4'-tert-butyl-2,6-dimethyl-biphenyl-4-thiol Step A. O- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-yl) ester of dimethyl- thiocarbamic acid To a solution of 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol (10 g, 37.3 mmol) in dioxane (157 mL) was added 4-dimethylaminopyridine (476 mg, 3.9 mmol), triethylamine (10 mL, 78.6 mmol), and dimethylthiocarbamoyl chloride (6.1 g, 49.1 mmol). The reaction mixture was heated to reflux overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer is extracted again with ethyl acetate, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and levigate using 20% ethyl acetate in hexanes to give O- (1-tert-butyl-2,6-dimethyl-biphenyl-4-yl) dimethyl thiocarbamic acid ester (12.2 g). Step B. S- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-yl) ester of dimethyl thiocarbamic acid A suspension of O- ('-tert-butyl-2,6-dimethyl- biphenyl-4-yl) dimethyl thiocarbamic acid ester (12.1 g, 35.4 mmol) in tetradecane (80 ml) was heated at 245 ° C for 16 h. After cooling to room temperature, a precipitated solid was filtered, washed with heptane and dried under vacuum at 40 ° C. The resulting residue is applied to silica gel and levigating using hexanes with a gradient of ethyl acetate from 0% to 60% to give S- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-yl) dimethylcarbamic acid ester (8.86 g). Step C. 4'-tert-Butyl-2,6-dimethyl-biphenyl-4-thiol To a solution of S- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-yl) acid ester dimethyl thiocarbamic acid (8.8 g, 25.8 mmol) in methanol (65 ml) was added sodium methoxide (1.39 g, 25.8 mmol). The reaction mixture was heated to reflux overnight. After cooling to room temperature, the reaction mixture was neutralized with 5N HCl, concentrated to 1/3 volume, treated with brine, and extracted into dichloromethane. The aqueous layer was extracted again with dichloromethanes, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and levigate using hexanes with a gradient of ethyl acetate from 0% to 50% to give the title compound (5.84 g).

Preparation 11 2, 6-Dimethyl-4 '-trifluoromethyl-biphenyl-4-thiol The title compound was prepared in a substantially similar manner as described in Preparation 10 using 2,6-dimethyl-4' - (trifluoromethyl) biphenyl -4-ol. MS (RE): 281.1 [M-H] -.

Example 1 (R, S) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2-methyl (2H-tetrazol-5-ylmethyl) -amide. - propyl] -thiophen-2-carboxylic acid Step A. (R, S) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulphanyl) -2-methyl-propyl] -thiophene-2-ethyl ester carboxylic A solution of (R, S) -5- (l-hydroxy-2-methyl-propyl) -thiophene-2-carboxylic acid ethyl ester (1.26 g, 5.52 mmol) and 4'-tert-butyl-2, 6-Dimethyl-biphenyl-4-thiol (1.64 g, 6.07 mmol) in 1,2-dichloroethane (22 ml) was treated with zinc iodide (1.76 g, 5.52 mmol) and stirred overnight at room temperature. The reaction mixture is then divided between water and dichloromethane. The aqueous layer was extracted again with dichloromethane, and the combined organic layers are dried, filtered and concentrated. The resulting residue is applied to silica gel and levigate using hexanes with a gradient of ethyl acetate from 0% to 40% to give (R, S) -5- [1- (4'-tert-butyl) ethyl ester -2,6-dimethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid (2.08 g). MS (RE): 481.1 [M + H] +.

Step B. (R, S) -5- [1- (4 • -tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid. mixture of (R, S) -5- [l- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulphane) -2-methyl-propyl] -thiophene-2-carboxylic acid ethyl ester (2.08 g, 4.33 mmol) in ethanol (43 ml) was added sodium hydroxide (5N aqueous, 4.33 ml) at room temperature, and stirred overnight. The reaction mixture was acidified by IN HCl (4.42 ml), extracted into ethyl acetate, dried and concentrated, then dried under vacuum to yield (R, S) -5- [1- (4'-ester) acid. butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid (1.82 g). MS (RE): 451.2 [MH]. "Step C. Cyanomethyl-amide of (R, S) -5- [1- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfane) -2-methyl-propyl] -thiophene-2-carboxylic acid To a mixture of (R, S) -5- [1- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) - 2-methyl-propyl] -thiophene-2-carboxylic acid (342 mg, 0.756 mmol) in DMF (7.6 ml) was added N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (290 mg, 1512 mmol), 1-hydroxybenzotriazole hydrate (123 mg, 0.907 mmol), and diisopropylethylamine (0.264 mL, 1512 mmol) at room temperature, and stirred 10 min. The mixture was then treated with aminoacetonitrile hydrochloride (84 mg, 0.907 mmol), and stirred overnight. The reaction mixture was treated with 0.1N HCl and extracted into ethyl acetate twice. The combined organic layers were washed with brine, dried and concentrated, and the resulting residue was applied to silica gel and levigate using hexanes with an ethyl acetate gradient from 0% to 70% to give acid cyanomethyl-amide (R , S) -5- [1- (4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid (289 mg). MS (RE): 491.1 [M + H] +. Step D. (R, S) -5- [1- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfane) -2- (2H-tetrazol-5-ylmethyl) -amide. methyl-propyl] -thio-en-2-carboxylic acid A solution of (R, S) -5- [1- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) cyanomethyl-amide) -2-methyl-propyl] -thiophene-2-carboxylic acid (195 mg, 0.397 mmol) in toluene (8 mL) was treated with triethylamine hydrochloride (275 mg, 2 mmol) and sodium azide (130 mg, 2 mmol) , then it was heated to reflux overnight (thermal conditions) or alternatively, it was placed in a CEM microwave reactor for 20 min. (300W, 180 ° C, cooling in N2) (microwave conditions). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate, the combined organic layers are dried and concentrated, and the resulting residue is poured onto Cié and leviga using water with a gradient of acetonitrile from 15% to 100% to give the title compound ( 91 mg). MS (RE): 534.2 [M + H] +. Examples 2 to 7 are prepared in a substantially similar manner using the thermal conditions as described in Example 1, Step D.

Example 2 (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -propyl] -thiophene- (2H-tetrazol-5-ylmethyl) -amide. 2- carboxylic MS (RE): 520.3 [M + H] +.

Example 3 (±) -5- [1- ('-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfañyl) -butyl] -thiophen-2 (2H-tetrazol-5-ylmethyl) -amide. - carboxylic MS (RE): 534.3 [M + H] Example 4 ((2) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl) (2H-tetrazol-5-ylmethyl) -amide). -4-ilsulfañil) -pentyl] -thiophen-2-carboxylic acid MS (RE): 548.3 [M + H] +.

Example 5 (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl acid (2H-tetrazol-5-ylmethyl) -amide. ] - thiophene-2-carboxylic acid MS (RE): 548.0 [M + H] +.

Example 6 ((±) -5- [1- (4 • -tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -3, 3- (2H-tetrazol-5-ylmethyl) -amide. dimethyl-butyl] thiophene-2-carboxylic acid MS (RE): 562.0 [M + H] +.

Example 7 (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2, 2-dimethyl (2H-tetrazol-5-ylmethyl) -amide. -propyl] thiophene-2-carboxylic acid MS (RE): 548.3 [M + H] +.

Examples 8 to 13 are prepared in a substantially similar manner using the microwave conditions as described in Example 1, Step D.

Example 8 (lH-tetrazol-5-ylmethyl) -amide (±) -5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophene-2-carboxylic acid MS (RE): 546.0 [M + H] +.

Example 9 (±) -5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenyl-4-ylsulfañyl) -2-methyl-propyl] - (lH-tetrazol-5-ylmethyl) -amide] - thiophene-2-carboxylic acid MS (RE): 545.8 [M + H] +.

Example 10 (±) -5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-4-ylsulphanyl) -2, 2-dimethylpropyl] - (lH-tetrazol-5-ylmethyl) -amide] -thiophen-2-carboxylic acid MS (RE): 560.0 [M + H] +.

Example 11 (±) -5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl] - (lH-tetrazol-5-ylmethyl) -amide] - thiophene-2-carboxylic acid MS (RE): 560.0 [M + H] +. Example 12 (1) -5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-4-ylsulfanyl) -3,3-dimethyl-benzyl (l) -tetrazol-5-ylmethyl) -amide. ] -thiophen-2-carboxylic acid MS (RE): 574.0 [M + H] +. Example 13 (±) -5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenyl-4-ylsulfanyl) -pentyl] - thiophen-2- (l) -tetrazol-5-ylmethyl) -amide. carboxylic MS (RE): 560.0 [M + H] +.

Example 14 5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] 2- (2H-tetrazol-5-ylmethyl) -amide] - thiophene-2-carboxylic acid (Isomer 1) Step A. 5- [1- (4'-Tert-Butyl-2,6-d-ethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophene-2-carboxylic acid cyanomethyl-amide ( Isomer 1) (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophen cyanomethyl-amide was prepared -2-carboxylic acid (500 mg) by chiral HPLC (column: Chiralpak AD 4.6 * 150 mm, levigant: 15/85 3A ethanol / heptane, with 12% dimethylethylamine, flow rate: 0.6 ml / min, UV absorbance wavelength: 300 nm) to provide cyanomethyl-amide of 5- [l- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophene-2-carboxylic acid (Isomer 1) (220 mg) . Step B. 5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2, 2-dimethyl-propyl] -2- (4H-tetrazol-5-ylmethyl) -amide] -thiophen-2-carboxylic acid (Isomer 1) A solution of 5- [1- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-1-cyanomethyl-amide. propyl] -thiophen-2-carboxylic acid (Isomer 1) (220 mg, 0.436 mmol) in toluene (8.7 ml) was treated with triethylamine hydrochloride (300 mg, 2.18 mmol) and sodium azide (142 mg, 2.18 mmol) , then heated to reflux overnight (thermal conditions) or alternatively, placed in a CEM microwave reactor for 20 min (300W, 180 ° C, N2 cooling) (microwave conditions). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate, and the combined organic layers are dried and concentrated to give the title compound (105 mg). MS (RE): 548.3 [M + H] +. Examples 15 to 17 are prepared in a substantially similar manner using the thermal conditions as described in Example 14, Step B.

Example 15 5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] 2- (2H-tetrazol-5-ylmethyl) -amide] - thiophen-2-carboxylic acid (Isomer 2) MS (RE): 548.3 [M + H] +.

Example 16 5- (1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -propyl] -thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl) -amide Isomer 1) Chiral MS (RE): 519. 8 [M + H] +.

Example 17 5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -propyl] -thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl) -amide ( Isomer 2) MS (RE): 520.3 [M + H] +.

Examples 18 to 29 are prepared in a substantially similar manner using the microwave conditions as described in Example 14, Step B.

Example 18 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophene-2-carboxylic acid (l-tetrazol-5-ylmethyl) -amide (Isomer 1) MS (RE): 546.0 [M + H] Example 19 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophen-2-carboxylic acid (l-tetrazol-5-ylmethyl) -amide (Isomer 2) MS (RE): 546.0 [M + H] +.

Example 5- (1- (2- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2- (lH-tetrazol-5-ylmethyl) -amide carboxylic (Isomer 1) MS (RE): 546.0 [M + H] +.

Example 21 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide. (Isomer 2) MS (RE): 546.0 [M + H] +.

Example 22 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophene-2-lhu-tetrazol-5-ylmethyl-amide -carboxylic (Isomer 1) MS (ER): 559 8 [M + H] \ Example 23 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophene-2-lhu-tetrazol-5-ylmethyl-amide -carboxylic (Isomer 2) MS (RE): 559.8 [M + H] +.

Example 24 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl] -thiophene-2- (lH-tetrazol-5-ylmethyl) -amide. carboxylic (Isomer 1) MS (RE): 560.0 [M + H] +.

Example 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl] -thiophene-2- (lH-tetrazol-5-ylmethyl) -amide. carboxylic (Isomer 2) MS (RE): 560.0 [M + H] +.

Example 26 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -3,3-dimethyl-butyl] -thiophen-2-acid (lH-tetrazol-5-ylmethyl) -amide. -carboxylic (Isomer 1) MS (RE): 573.8 [M + H] +.

Example 27: 5- [1- (2,6-Dimethyl-4 'tri-loromethyl-biphenyl-4-ylsulfanyl) -3,3-dimethyl-butyl] -thiophenic acid (lH-tetrazol-5-ylmethyl) -amide. 2-carboxylic (Isomer 2) MS (RE): 573.8 [M + H] Example 28 5- (1- (2,6-Dimethyl-4 I-trifluoromethyl-biphenyl-4-ylsulfanyl) -pentyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide (Isomer 1) ) MS (RE): 559.8 [M + H] +.

Example 29 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -pentyl] -thiophene-2-carboxylic acid (l-tetrazol-5-ylmethyl) -amide (Isomer 2) MS (ER): 559.8 [M + H] The compound of Formula I is preferably formulated in a unit dosage form prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable carriers, diluents or excipients. In such form, the preparation is subdivided into appropriately sized unit doses containing appropriate amounts of the active components, for example, an effective amount to achieve the desired purpose. Such pharmaceutical compositions and processes for preparation thereof are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., Eds., 19th ed., Mack Publishing Co., 1995). The particular dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof required to constitute an effective amount in accordance with this invention, will depend on the particular circumstances of the conditions to be treated. Preferably the compound is administered orally. The amount of the active composition in a unit dose of preparation may be generally varied or adjusted from 0.01 milligrams to about 1,000 milligrams, preferably from about 0.01 to about 950 milligrams, more preferably from about 0.01 to about 500 milligrams, and typically from about 1 to about 250 milligrams, in accordance with the particular application. The current dosage used can be varied depending on the age, sex, weight and severity of the condition to be treated by the patient. Such techniques are well known to those skilled in the art. Generally, the oral to human dosage form contains the active ingredients that can be administered 1 or 2 times per day. Considerations such as dosage, route of administration and frequency of dosing are best decided by the attending physician. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. The compositions of the present invention can be formulated in sustained release form to provide the rate of controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e., glucagon receptor antagonist activity and the like. Suitable dosage forms for sustained release include stratified tablets containing layers of controlled release polymer matrices or varied disintegration ratios impregnated with the active components and formed in tablet or capsule form containing such impregnated or encapsulated porous polymer matrices. There is an evident increase that glucagon plays an important role in glucose homeostasis. The compounds of Formula I are effective as antagonists or inverse agonists of the glucagon receptor, and thus inhibit the activity of the glucagon receptor. More particularly, these compounds are selective antagonists or inverse agonists of the glucagon receptor. They are selective antagonist or inverse agonist, the compounds of Formula I are useful in the treatment of diseases, disorders or conditions responsible for the inactivation of the glucagon receptor, which includes but is not limited to diabetic disorders or related to another glucagon. It is expected that selective antagonists or inverse agonists of the glucagon receptor have lower plasma glucose levels and thus prevent or treat diabetic metabolic disorders or related to another glucagon.

PHARMACOLOGICAL METHODS In the following section, binding assays are described as well as useful assays to evaluate the efficacy of the compounds of the invention. The binding of compounds to the glucagon receptor can be determined in a competition binding assay using cloned human glucagon receptor, and selectively against the hGlpl receptor. Antagonism can be determined by the ability of the compounds to inhibit the amount of cAMP formed in the assay in the presence of 5 nM glucagon.

Glucagon Receptor Linkage Assay (hGlucR) The receptor binding assay uses the cloned human glucagon receptor (Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH, Rosenberg GB, et al. Gene 140 (2), 203-209 (1994)) isolated from 293HEK membranes. In hGlucR cDNA it was subcloned into the expression of the phD plasmid (trans-activated expression of the completely gamma-carboxylated recombinant human protein C, an antithrombotic factor) Grinnell, BW, Berg, DT, Walls, J. and Yan, SB Bio / Technology 5: 1189-1192 (1987)). This plasmid DNA is transfected in 293 HEK cells and selected with 200 μg / ml Hygromycin. The crude plasma membranes were prepared using cells from the suspension culture. The cells were used in ice in hypotonic buffer containing 25 mM Tris HCl, pH 7.5, 1 mM MgCl2, DNAsal, 20 u / ml and EDTA without Roche Complete Inhibitors. The cell suspension was homogenized with a Dounce glass homogenizer using a Teflon pestle by 25 strokes. The homogenized is 7Í centrifuge at 4 degrees C at 1800 x g for 15 minutes. The supernatant is collected and the pellets are suspended again in hypotonic buffer and homogenized again. The mixture was centrifuged at 1800 x for 15 minutes. The second supernatant was combined with the first supernatant. The combined supernatants are centrifuged again at 1800 x g for 15 minutes to clarify. The clarified supernatant was transferred to high speed tubes and centrifuged at 25000 xg for 30 minutes at 4 degrees C. The membrane pellet was resuspended in homogenization buffer and stored as aliquots frozen at -80 ° C in freezing until necessary. The glucagon is radioiodinated by the I-125-lactoperoxidase procedure and purified by reverse phase HPLC in Perkin-Elmer / NEN (NEX207). The specific activity is 2200 Ci / mmol). The Kd determination is carried out by homologous competition instead of the binding to saturation due to the high content of propanol in the glucagon material 1-125. The Kd is estimated to be 3 nM and is used to calculate Ki values for all compounds tested. The binding assays are carried out using a Scintillation Proximity Assay (Amersham) with WGA pellets previously blocked with 1% free fatty acid BSA (ICN). The binding buffer contains 25 mM Hepes, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% fatty acid free BSA, (ICN), 0.003% tween-20, and EDTA without Roche Complete Inhibitors. Glucagon was dissolved in 0.01 N HCl at 1 mg / ml and immediately frozen at -80 degrees C in 30 μl aliquots. The aliquot of glucagon was diluted and used in binding assays within one hour. The test compounds were dissolved in DMSO and serially diluted in DMSO. 10 μl of the diluted compounds or DMSO are transferred to opaque clear bottom test plates, Corning 3632 containing 90 μl of assay binding buffer or cold glucagon (NSB to 1 μM final). Add 50 μl of 1-25 glucagon (0.15 nM reaction), 50 μl of membranes (300 μg / well), and 40 μl of WGA pellets (150 mgs / well), cover and mix until the end. The plates are read with a MicroBeta after 14 hours of settling time at room temperature. The results are calculated as a specific glucagon 1-125 binding percentage in the presence of the compound. The absolute EC50 dose of the compound is supplied by non-linear regression of the specific binding percentage of 1-125 glucagon against the dose of the added compound. The EC50 dose is converted to Ki using the Cheng-Prussoff equation (Cheng Y., Prusoff W.H., Biochem. Pharmacol. 22, 3099-3108, 1973).Glucagon-like Peptide 1 Receptor Binding Assay (Glpl-R) The receptor binding assay uses the cloned human glucagon-like peptide 1 receptor (hGlpl-R) (Graziano MP, Hey PJ, Borkowski D, Chicchi GG, Strader CD, Biochem Biophys Res Commun, 1993 Oct 15; 196 (1): 141-6) isolated from 293HEK membranes. The cDNA of hGlpl-R was subcloned into the expression of plasmid phD (trans-activated expression of protein C from fully gamma-carboxylated recombinant human, an antithrombotic factor Grinnell, BW, Berg, DT, Walls, J. and Yan, SB Bio / Technology 5: 1189-1192 (1987)). This plasmid DNA is transfected into 293 HEK cells and selected with 200 μg / ml Hygromycin. The crude plasma membrane is prepared using cells from the suspension culture. The cells are lysed on ice in hypotonic buffer containing 25 mM Tris.

HCl, H 7.5, 1 mM MgCl2, DNase, 20 μl / ml and EDTA without Complete Roche Inhibitors. The cell suspension is homogenized with a glass dounce homogenizer using a hand of Teflon mortar for 25 strokes. The homogenate is centrifuged at 4 degrees C at 18000 x for 15 minutes. The supernatant is collected and the pellet is suspended again in hypotonic buffer and homogenized again. The mixture is centrifuged at 1800 x for 15 minutes. The second supernatant was combined with the first supernatant. The combined supernatants are centrifuged again at 1800 x g for 15 minutes to clarify. The clarified supernatant is transferred to high-speed tubes and centrifuged at 25,000 xg for 30 minutes at 4 degrees C. The membrane pellet is resuspended in homogenization buffer and stored as aliquots frozen at -80 degrees C in freezing until use. Glucagon-like peptide 1 (Glp-1) is radioiodinated by the I-125-lactoperoxidase method and purified by reverse-phase HPLC in Perkin-Elmer / NEN (NEX308). The specific activity is 2200 Ci / mmol). The Kd determination is performed by homologous competition instead of binding to saturation due to the high content of propanol in the 1-125 Glp-1 material. The Kd is estimated to be 3 nM and is used to calculate Ki values for all compounds tested. The binding assays are carried out using a Scintillation Proximity Assay (Amersham) with wheat germ agglutinin pellets (WGA) previously blocked with 1% free fatty acid BSA (ICN). The binding buffer contains 25 mM Hepes, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% fatty acid free BSA, (ICN), 0.003% of tween-20 and EDTA without complete inhibitors Roche. The glucagon-like peptide was dissolved in PBS at 1 mg / ml and immediately frozen at -80 degrees C in 30 ul aliquots. The aliquot of the glucagon-like peptide was diluted and used in binding assays within one hour. The test compounds were dissolved in DMSO and serially diluted in DMSO. 10 μl of the diluted compounds or DMS was transferred to light-background, opaque, Corning 3642 assay plates containing 90 μl of the assay binding buffer or cold glucagon-like peptide 1 (1 μM final NSB). Add 50 μl of peptide 1 similar to 1-125 glucagon (final 0.15 mM in reaction), 50 μl of membranes (600 μg / well, and 40 μl of WGA pellets (150 μg / well), cover and mix until The plates are read with MicroBeta after 14 hours of sedimentation time at room temperature.The results are calculated as a percentage of peptide 1 similar to specific I-125-glucagon bound in the presence of the compound. of the compound is derived by non-linear regression of the percentage of specific binding of peptide 1 similar to 1-125 glucagon against the dose of the added compound.The dose Ec50 is converted to Ki using the Cheng-Prusoff equation (Cheng Y., Prusoff WH , Biochem, Pharmacol., 22, 3099-3108, 1973).

Test of Functional Antagonism Stimulated by Glucagon cAMP The cAMP functional assay uses the same cloned human glucagon receptor cell line isolated for the hGlucR binding assay described above. The cells are stimulated with a mixture of an EC80 dose of glucagon in the presence of the compound. The cAMP generated within the cell is quaternized using a Homogeneous Amplified Proximity Assay, Alpha Screen, by Perkin Elmer (6760625R). Briefly, the cAMP with the competent cell for biotinylated cAMP binding of the kit to an anti-cAMP coated antibody acceptor and a strepavidin coated donor bead. As the cAMP level within the increased cells, an interruption of the complex perlilla cAMP-Donor biotinylated-Perlilla Acceptor occurs and the signal decreases. Glucagon is dissolved in 0.01N HCl at 1 mg / ml and immediately frozen at -80 degrees C in aliquots of 30 ul. The glucagon aliquot is diluted and used in the functional assay within one hour. Cells are collected from the sub-confluent tissue culture discs with Enzyme-free Cell Dissociation Solution, (Especially medium 5-400-B). Cells are pelleted at low speed and washed 3 times with assay buffer [25 mM Hepes in HBSS with Mg and Ca (GIBCO, 14025-092) with 1% free fatty acid BSA (ICN)] then diluted at a final concentration of 250,000 cells per ml. The compounds are serially diluted in DMSO, then diluted in assay buffer with a 3X concentration of glucagon and 3% DMSO. The EC80 of glucagon is pre-determined from a full glucagon response dose and represents the dose at which glucagon produces 80% of the maximum glucagon response. A mixture of biotinylated cAMP (1 unit / final cavity) of the Alpha Selection Kit and 3X IBMX (1500 μM) in Test Buffer is prepared. The functional test is carried out on Platar Costar Plates, white, with a low volume of 96 cavities (3688). The biotinylated cAMP / IBMX mixture, 0.02 ml is placed in each well, followed by the addition of 0.02 ml of glucagon dose response, standard cAMP curve or compound / glucagon mixture. The reaction is initiated by the addition of 0.02 ml of cells (5000 / final cavity). After 60 minutes at room temperature, the reaction is stopped by the addition of 0.03 ml of Lysis Buffer [10 mM Hepes, pH 7.4, 1% NP40 and 0.01% fatty acid free BSA (ICN) containing 1 each unit / cavity of the Perlillas Acceptoras and Donadores of the Alfa Selection Kit]. The addition of lysis buffer is performed under a green light to prevent bleaching of the detection pellets. The plates are wrapped in aluminum and left to equilibrate overnight at room temperature. The plates are read in an Instrument -OÍ of Packard Fusion ™. The alpha selection units are converted to pmoles of cAMP generated by cavity, based on the standard curve of cAMP. The cAMP pmoles produced in the presence of the compound are converted to% of a maximum response with the EC80 dose of glucagon alone. With each experiment, the dose of glucagon needed to produce a 50% response of cAMP pmoles is determined. This dose of EC50 is used to normalize results to a Kb using a modified Cheng-Prusoff equation (Cheng Y., Prusoff WH, Biochem Pharmacol, 22, 3099-3108, 1973), where Kb = (EC50 of compound) / [1 + (pM glucagon used / EC50 in pM by glucagon dose response)]. The compounds according to the invention, preferably have a Ki value of not more than 50 μM as determined by the Glucagon Receptor Linkage Assay (hGlucR) described herein. More preferably, the compounds according to the invention have a Ki value of less than 5 μM, preferably less than 500 nM and even more preferred of less than 100 nM, as determined by the Glucagon Receptor Binding Assay ( hGlucR) described in this document. In general, the compounds according to the invention show a higher affinity for the glucagon receptor compared to the GLP-1 receptor, and preferably, they have a higher binding affinity to the glucagon receptor than to the GLP-1 receptor. All the examples provided in this document have a Ki value of less than 10 μM.

The results are given below for the indicated compound.

Table 1: From the above description, a person skilled in the art can determine the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions. Thus, other embodiments are also within the claims.

Claims (16)

1. A compound characterized in that it is structurally represented by Formula I (i) or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are independently -H- or halogen; R3 is -alkyl (Cj-Cß) (optionally substituted with 1 to 3 halogens), -cycloalkyl (C3-C7), -alkyl (d-C6) -cycloalkyl (C3-C7), or -cycloalkyl (C3-C7) -alkyl (C? ~ 6) (optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen, -hydroxy, hydroxymethyl, -CN, (C? -C7) alkoxy, (C2-C7) alkenyl, or -alkyl (Ci-Ce), (optionally substituted with 1 to 3) halogens); R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are independently -H, -halogen, -alkyl (C? -C6) (optionally substituted with 1 to 3 halogens), -alkoxy (Ci-Cß), cycloalkyl (C3-C7), -C (O) R10 , -COOR10, -OC (O) R10, -OS (O) 2R10, -SR10, -S (O) R10, -S (O) 2R10, or -O (C2-C7) alkenyl; R9 is independently -H, -halogen, -CN, -cycloalkyl (C3-C7), C (O) R10,

-COOR10, -OC (O) R10, -OS (O) 2R10, -SR10, -S (O) R10, -S (O) 2R10, or -O (C2-C7) alkenyl, -alkoxy (C? ~ C3) ) (optionally substituted with 1 to 3 halogens, or -alkyl (Ci-Ce) (optionally substituted with 1 to 3 halogens), and RIO is independently in each case -hydrogen or -alkyl (Ci-Cd) (optionally substituted with 1) to 3 halogens) 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are H; R3 is -alkyl (C6-8) (optionally substituted with 1 to 3 halogens); ), -cycloalkyl (C3-Cd), -alkyl (C? -C6) -cycloalkyl (C3-C6), or -cycloalkyl (C3-C6) -alkyl (Ci-e) (optionally substituted with 1 to 3 halogens) R4 and R5 are independently -H, halogen, or -alkyl (C? -C6), (optionally substituted with 1 to 3 halogens); R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are independently -H, -halogen, -alkyl (Ci-Cd) (optionally substituted with 1 to 3 halogens), -alkoxy (C? -C6), and R9 is independently -H, -halogen, or -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens). 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are -H; R3 is -alkyl (Ci-Cs) (optionally substituted with 1 to 3 halogens), -cycloalkyl (C3-Cd), -alkyl (C_-C6) -cycloalkyl (C3-C-7), or -cycloalkyl (C3- C6) -alkyl (C? -6) (optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen or -CH3 (optionally substituted with 1 to 3 halogens);

R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are independently -H, or -halogen; Y

R9 is independently -alkyl (C? -C6) (optionally substituted with 1 to 3 halogens). 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are -H; R3 is -alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens), -cycloalkyl (C3-C6), -alkyl (Ci-Cß) -cycloalkyl (C3-C6), or -cycloalkyl (C3-C6) -alkyl (Ci-Cd) (optionally substituted with 1 to 3 halogens); R4 and R5 are -CH3 (optionally substituted with 1 to 3 halogens) and each occupies a position adjacent to R6 in the phenyl ring in which R6 is attached; R6 is , wherein the zig-zag mark shows the point of attachment to the precursor molecule; R7 and R8 are -H; and R9 is independently alkyl (Ci-Cß) (optionally substituted with 1 to 3 halogens).

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are independently hydrogen or halogen; R3 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, 3, 3-dimethylbutyl, 2-methylpropyl, 3-methyl-butyl, tertbutyl, 4-methylpentyl, 2,2-dimethylpropyl, 3, 3,3-trifluoropropyl, 4, 4, 4-trifluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R4 and R5 are independently hydrogen, methyl, ethyl, tertbutyl, cyclohexyl, pentyl, isopropoxy, chloro, fluoro, bromo, hydroxy, trifluoromethyl, -CN, methoxy, hydroxymethyl, 4-methylpentyloxy, or pentyloxy; R7 and R8 are independently hydrogen, fluoro, chloro, methyl, ethyl, pentyl, isopropyl, tertbutyl, trifluoromethyl, acetyl, 2-methylpropyl, methoxy, cyclohexyl, or trifluoromethoxy; and R9 is hydrogen, bromine, fluoro, methyl, terbutyl, trifluoromethyl, or isopropyl.

6. The compound according to claim 1, characterized in that it is selected from the group consisting of Formula XI through Xll: or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1, characterized in that it is selected from the group consisting of: (R, S) -5- [l- ('-ter-) - (2H-tetrazol-5-ylmethyl) -amide. butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid; (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -propyl] -thiophen-2-(2H-tetrazol-5-ylmethyl) -amide. carboxylic; (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophen-2-(2H-tetrazol-5-ylmethyl) -amide. carboxylic; (+) - 5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenylylsylsulfanyl) -pentyl] -thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl) -amide.; (±) -5- [1- (4'-Tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl] - (2H-tetrazol-5-ylmethyl) -amide] - thiophene-2-carboxylic acid; ((±) -5- [l- ('-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -3,3-dimethyl-butyl (2H-tetrazol-5-ylmethyl) -amide. ] -thiophene-2-carboxylic acid (±) -5- [l- (4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) (2H-tetrazol-5-ylmethyl) -amide) -2, 2-dimethyl-propyl] -thiophene-2-carboxylic acid; (±) -5- [1- (2,6-Dimethyl-4,4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide; (±) -5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenyl-4-ylsulfanyl) -2-methyl-propyl] -thiophene- (lH-tetrazol-5-ylmethyl) -amide. 2-carboxylic; (±) -5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenylylsylsulfanyl) -2,2-dimethyl-1-propyl] -thiophene (1H-tetrazol-5-ylmethyl) -amide. -2-carboxylic; (±) -5- [1- (2,6-Dimeti-4'-trifluoromethyl-bipheni-4-ylsulfanyl) -3-methyl-1-butyl] -thiophenol- (1H-tetrazol-5-ylmethyl) -amide. 2-carboxylic; (±) -5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenyl- -ylsulfanyl) -3,3-dimethyl-butyl] -thiophene (lH-tetrazol-5-ylmethyl) -amide. -2-carboxylic; (±) -5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -pentyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide; 5- [1- (4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophenic acid (2H-tetrazol-5-ylmethyl) -amide. 2-carboxylic acid (Isomer 1); 5- [1- (4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -2,2-dimethyl-propyl] -thiophenic acid (2H-tetrazol-5-ylmethyl) -amide. 2-carboxylic acid (Isomer 2); 5- [1- (1-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -propyl] -thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl) -amide (Isomer 1); 5- [1- (4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl) -propyl] -thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl) -amide (Isomer 2) ); 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophene-2-carboxylic acid (l-tetrazol-5-ylmethyl) -amide (Isomer 1); 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -butyl] -thiophen-2-carboxylic acid (l-tetrazol-5-ylmethyl) -amide (Isomer 2); 5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-bipheni-4-ylsulfanyl) -2-methyl-propyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide ( Isomer 1); 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -2-methylpropyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide (Isomer 2) ); 5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-lysulfanyl) -2, 2-dimethyl-propyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide ( Isomer 1); 5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-4-ylsulfanyl) -2, 2-dimethyl-propyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide. (Isomer 2); 5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl] -thiophen-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide (Isomer) 1); 5- [1- (2,6-Dimethyl-1-trifluoromethyl-biphenyl-4-ylsulfanyl) -3-methyl-butyl] -thiophen-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide (Isomer) 2); 5- (1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenyl-4-ylsulfanyl) -3,3-dimethyl-butyl] -thiophen-2- (lH-tetrazol-5-ylmethyl) -amide. carboxylic (Isomer 1); 5- [1- (2,6-Dimethyl-4 '-trifluoromethyl-biphenyl-4-ylsulfanyl) -3,3-dimethyl-butyl] -thiophen-2- (lH-tetrazol-5-ylmethyl) -amide. carboxylic (Isomer 2); 5- [1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -pentyl] -thiophene-2-carboxylic acid (l-tetrazol-5-ylmethyl) -amide (Isomer 1); and 5- (1- (2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl) -pentyl] -thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl) -amide (Isomer 2); or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-7, and a pharmaceutically acceptable carrier.

9. A method for inhibiting the glucagon receptor in a mammal, characterized in that it comprises administering to a mammal in need thereof, a dose that inhibits the glucagon receptor of a compound of formula I, or a salt thereof, as described in any of claims 1-8. A method for selectively reducing the glycemic level in a mammal, characterized in that it comprises administering to a mammal in need thereof, a dose that inhibits the glucagon receptor of a compound of formula I, or a salt thereof, as described in any of claims 1-8. 11. A method for the treatment of a diabetic or other metabolic disorder related to glucagon, characterized in that it comprises administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to any of claims 1-8. . 12. A method for the treatment of a metabolic disorder diabetic or other related to glucagon, characterized in that it comprises administering to a mammal in need of such treatment or prevention, an effective amount of a pharmaceutical composition according to claim 8. 13. A method for the treatment of a disorder or disease in which, inhibition of the glucagon receptor has a beneficial effect, characterized in that it comprises administering to a subject in need of such treatment, an effective amount of a compound in accordance with any of the Claims 1-8. A method for the treatment or prevention of a disorder or disease in which, the inhibition of the glucagon receptor has a beneficial effect, characterized in that it comprises administering to a subject in need of such treatment or prevention, an effective amount of a composition Pharmaceutical according to claim 8. 15. A compound of formula I, or a salt thereof, as claimed in any of claims 1-7, for use in the treatment of a diabetic metabolic disorder or other related to the glucagon. 16. The use of a compound of formula I, or a salt thereof, as claimed in any of claims 1-8, for use in the manufacture of a medicament for the treatment of a diabetic metabolic disorder or other related with glucagon.