MXPA06006206A - Biaryl sulfonamides and methods for using same - Google Patents

Abstract

The present invention relates to biaryl sulfonamides of the formula 1:wherein:R1 is H or Cl-.C6 a]kyl;R2 is H, C I -C6 alkyl, (CH2)nR2', phenyl, or benzyl;n is 0-6;R2'is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;R 3 is, independently with respect to each occurrence, H, halogen, OC(halogen)3,C(halogen)3, alkoxy, or C I -C 6 alkyl;X is selected from CH20, OCH2, C (R3)=(R3)2-C(R3)2, CH2NHC(=O), O(C=O)NH, O, C(=O)CH2, SO2CH2C(=O)NH, SO2NH, OC(=O), CH2S(O), and CH2S(O)2;and Z is at least one aryl or heteroaryl moiety, and their use as for example metalloproteinase inhibitors.

Description

BIARIL-SULFONAMIDAS AND METHODS FOR USE FIELD OF THE INVENTION The present invention relates to biaryl sulfonamides and their use as, for example, new metalloproteinase inhibitors.

BACKGROUND OF THE INVENTION Metalloproteinases, including matrix metalloproteinases and aggrecanases, are known to play a role in the disintegration of connective tissue. Matrix metalloproteinases ("MMPs") are a super family of genetically related proteolytic enzymes that are able to degrade almost all constituents of the extracellular matrix and the basement membrane that restrict cell movement. aggrecanases are members of the ADAMTS family of proteins (A disintegrin and metalloproteinase with thrombospondin configurations.) Aggrecanase-1 and aggrecanase-2 have been designated ADAMTS-4 and ADAMTS-5, respectively (Tang BL, Int J Biochem Cell Biol 2001, 33, 33-44) The ADAMTS family is implicated in the cleavage of aggrecan, a component of cartilage also known as the great proteoglycan of chondroitin sulfate. Adrepressant REP: 173289 (Abbaszade I et al., J Biol Chem 1999, 274, 23443-23450), in the processing of procollagen (Colige A et al., Proc Nati Acad Sci USA 1997, 94, 2374-2379), in angiogenesis (Vázquez F et al. collaborators, J Biol Chem 1999, 274, 23349-23357), in inflammation (Runo K et al., J Biol Chem 1997, 272, 556-562) and in tumor invasion (Masui T et al., J Biol Chem 1997, 272, 556-562). It has also been shown that MMPs break the aggrecan in the same way. The loss of aggrecan has been implicated in the degradation of articular cartilage in arthritic diseases; For example, osteoarthritis is a debilitating disease that affects at least 30 million Americans. The degradation of the articular cartilage and the resulting chronic pain can seriously reduce the quality of life. An early and important feature of the osteoarthritic process is the loss of aggrecan from the extracellular matrix, which results in deficiencies in the biomechanical characteristics of the cartilage. In the same way, it is known that MMPs and aggrecanases play a role in many disorders in which the degradation or destruction of the extracellular protein occurs, such as cancer, asthma, chronic obstructive pulmonary disease ("COPD"). , for its acronym in English), atherosclerosis, macular degeneration related to age, myocardial infarction, ulcer of the cornea and other ocular surface diseases, hepatitis, aortic aneurysms, tendinitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft disease against host, diabetes, inflammatory bowel disease, shock, degeneration of intervertebral discs, stroke, osteopenia and periodontal diseases. Therefore, metalloproteinase inhibitors, including inhibitors of MMPs and aggrecanases, are necessary.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the present invention provides novel biarylsulfonamide compounds. The preferred compounds of the invention are those of the formula I: wherein: R1 is H or alkyl of 1 to 6 carbon atoms; R2 is H, alkyl of 1 to 6 carbon atoms, (CH2)? V2 '/ phenyl or benzyl; n is 0-6; R2 'is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R3 is, independently in each of the occurrences, H, halogen, OC (halogen) 3, C (halogen) 3, alkoxy or alkyl of 1 to 6 carbon atoms; X is selected from CH20, OCH2, C (R3) = C (R3), C (R3) 2-C (R3) 2, CH2NHC (= 0), 0 (C = 0) NH, O, C (= 0 ) CH2, S02CH2C (= 0) NH, S02NH, OC (= 0), CH2S (0) and CH2S (0) 2; and Z is at least a portion of aryl or heteroaryl. In another aspect, the present invention provides methods for the use of biarylsulfonamide compounds to modulate and, preferably, inhibit metalloproteinases. Preferred methods include contacting in vitro and in vivo the metalloproteinase with a biarylsulfonamide. Preferred methods of this type are those in which the metalloproteinase activity is determined before or after this contact and, optionally, the determination is used to evaluate the extent to which the compound modulates the activity of the enzyme.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, it has been discovered that biaryl sulfonamide compounds can be used in the inhibition of metalloproteinases. Therefore, these compounds are useful in the treatment of cancer, osteoarthritis, reu atoid arthritis, asthma, COPD, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulcer and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft disease against host, diabetes, inflammatory bowel disease, shock, degeneration of intervertebral discs, stroke, osteopenia and periodontal diseases. The metalloproteinase is preferably Agrecanase-1 (also known as ADAMTS-4 and abbreviated herein as "Agg-1") or MMP-13. In one embodiment, the biaryl sulfonamide compound is of the formula I: where : R1 is H or alkyl of 1 to 6 carbon atoms; R2 is H, alkyl of 1 to 6 carbon atoms, (CH2) nR2 ', phenyl or benzyl; n is 0-6; R2 'is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R3 is, independently in each of the occurrences, H, halogen, OC (halogen) 3, C (halogen) 3, alkoxy or alkyl of 1 to 6 carbon atoms; X is selected from CH20, OCH2, C (R3) = C (R3), C (R3) 2-C (R3) 2, CH2NHC (= 0), 0 (C = 0) NH, 0, C (= 0) CH2, S02CH2C (= 0) NH, S02NH, 0C (= 0), CH2S (0) and CH2S (O) 2S (O) 2; and Z is at least one aryl or heteroaryl group. It has been found that the R configuration isomer in the alpha carbon is a better inhibitor of Agg-1, while both enantiomers are effective inhibitors of MMP. It will be understood that the following description includes pharmaceutically acceptable salts and prodrugs of these compounds. In one embodiment, Z is pyridine, pyrimidine, pyrazine, pyridazine, phenyl, naphthalene, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, benzothiazole, quinoline or isoquinoline, or wherein: U is selected from S, O, C (R3) = C (R3), C (R3) = N and N (R) W is selected from C (R) and N; M is selected from C (R3) and N; L is selected from S, O, C (R3) = C (R3), C (R3) = N and N (R4) R4 and R5 are, independently in each of the occurrences, a bond with the other, H, alkyl of 1 to 6 carbon atoms or phenyl; R7 is selected from a bond to R3, H, halogen, C (halogen) 3, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NRC (= 0) R5, NHC ( = 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONRR5, CN, phenyl, heteroaryl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl from 2 to 6 carbon atoms; and R8 is selected from H, phenyl, heteroaryl, and alkyl of 1 to 6 carbon atoms. R7, when substituted, is preferably substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R, CN, phenyl or heteroaryl. R8, when substituted, is preferably substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONRR5, CN, phenyl or heteroaryl. Preferred among the groups named above as R1 are H and branched alkyl and more preferably isopropyl. Preferred among the groups named above as R3 are halogen, CF3, OCH3 and CH3. Preferred among the groups named above as X are CH20, OCH2, C (R3) = C (R3) and CH2NHC (= 0). Preferred among the groups named above as R7 are CH3, ethyl, isopropyl, CF3, CN and 0CH3. Preferred among the groups named above as R8 are CH3, phenyl and benzyl. In one embodiment, X is CH20 and Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is 0CH and Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is C (R3) = C (R3) and Z is aryl or heteroaryl, preferably bicyclic. More preferably, X is a double bond of carbon-carbon trans. In one embodiment, X is C (R3) 2-C (R3) 2, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is CH2NHCO, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is carbamate 0-CO-NH, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is C0, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is 0, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is C (= 0) CH2, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is S0CH2, Z is aryl or heteroaryl, preferably bicyclic. In one embodiment, X is 0CH2, Z is aryl or heteroaryl, preferably bicyclic. Preferably, if substituted, the substitution is in the second phenyl ring. In one embodiment, X is 0CH2, Z is aryl or heteroaryl, preferably bicyclic. Preferably, if substituted, the substitution is on the first phenyl ring. In one embodiment, X is CH2OCH2, Z is aryl or heteroaryl, preferably bicyclic. Preferably, if substituted, the substitution is on the first phenyl ring.

The term "" alkyl ", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight chains and branched containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are included in the term "alkyl". The alkyl group of 1 to 6 carbon atoms includes straight or branched chain aliphatic groups possessing from 1 to 6 carbon atoms. Those aliphatic hydrocarbon chains that are optionally substituted are specifically included within the definition of "alkyl". The number of carbon atoms, as used in the definitions herein, refers to the structure of carbon atoms and the branching of carbon atoms, but does not include carbon atoms of substituents, such as alkoxy substitutions and Similar . The term "alkenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, a, straight and branched chains containing from 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl portion possesses 1 or 2 double bonds. These alkenyl portions may exist in the E or Z conformations and the compounds of this invention include both conformations. The alkenyl group of 2 to 6 carbon atoms includes a straight or branched chain of 1 to 6 carbon atoms possessing at least one carbon-carbon double bond. Those aliphatic hydrocarbon chains that are optionally substituted are specifically included within the definition of "alkenyl". The heteroatoms, such as O, S or N-R1, attached to an alkenyl group, must not be attached to a carbon atom participating in a double bond. The term "alkynyl" refers to a hydrocarbon portion containing at least one triple carbon-carbon bond. The alkynyl group of 2 to 6 carbon atoms includes a straight or branched chain of 1 to 6 carbon atoms possessing at least one triple carbon-carbon bond. The term "cycloalkyl" is a monovalent, monocyclic, bicyclic, tricyclic, fused, crosslinked or spiro monovalent hydrocarbon portion wherein the carbon atoms are located within or outside the ring system. Any appropriate position on the ring of the portion, cycloalkyl can be covalently bound to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl., cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spiro [4.5] decanyl and homologs, isomers and the like. The cycloalkyl group of 3 to 6 carbon atoms includes saturated, monocyclic rings of 3 to 6 carbon atoms optionally substituted with R 3. "Aryl" refers to an unsaturated carbon ring and may be fused to a carbocyclic or heterocyclic ring in any possible position. "Heteroaryl" refers to a 5 to 6 membered heterocyclic aryl ring containing from 1 to 3 heteroatoms in the ring, selected from the group consisting of oxygen, nitrogen and sulfur atoms and which may be fused with a carbocyclic ring or heterocyclic in any possible position. "Heterocycloalkyl" refers to a saturated 5- to 7-membered ring containing carbon atoms and from 1 to 2 heteroatoms selected from N, 0 and S. The term "phenyl", as used herein, either when used alone or as part of another group, refers to a phenyl group substituted or not replaced. An optionally substituted portion may be substituted with one or more substituents. Suitable optional substituents can be independently selected from H, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, NR4R5, N [(CH2) 2] , N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONRR5 and CN. When these portions are substituted, for example, they can typically be mono, di, tri or persubstituted. Examples for a halogen substituent include 1-bromovinyl, 1-fluorovinyl, 1,2-difluorovinyl, 2,2-difluorovinyl 1,2,2-trifluorovinyl, 1,2-dibromoethane, 1,2-difluoroethane, 1-fluoro -2-bromoethane, CF2CF3, CF2CF2CF3 and the like. The term "halogen" includes bromine, chlorine, fluorine and iodine. For simplicity, the connection points ("-") are not represented. When an atom or compound is described to define a variable, it is understood that it replaces the variable in order to satisfy the valence of the atom or compound. For example, when L is C (R3) = C (R3), both carbon atoms are part of the ring in order to satisfy their respective valences.

The term "pharmaceutically acceptable salt", as used herein, refers to salts derived from organic or inorganic acids such as, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic. , malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and acceptable acids that are similarly known, when a compound of this invention contains a basic portion. The salts can also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium or potassium, when a compound of this invention contains a carboxylate or phenolic portion or a similar portion which is capable of forming base addition salts. The term "patient", as used herein, refers to a mammal, preferably a human. The terms "administering", "administering" or "administration", as used herein, refer either to directly administering a compound or composition to a patient, or to administering a prodrug derivative or analogue of the compound to the patient, the which will give rise to an equivalent amount of compound or active substance within the body of the patient.

The term "vehicle", as used in this document, should encompass vehicles, excipients and diluents. The compounds of this invention may have an asymmetric carbon atom and some of the compounds of this invention may have one or more asymmetric centers and may, therefore, give rise to optical isomers and diastereomers. Although in formula I they are shown without regard to stereochemistry, the present invention includes these optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the stereoisomers R and S and pharmaceutically acceptable salts thereof. When a stereoisomer is preferred, in some embodiments it can be delivered substantially free of the corresponding enantiomer. In this way, a practically free enantiomer of the corresponding enantiomer refers to a compound that is isolated or separated, by separation techniques, or is prepared free of the corresponding enantiomer. "Practically free", as used herein, means that the compound is formed by a significantly greater proportion of a stereoisomer, preferably less than about 50%, more preferably less than about 75%, and even more preferably less than about 90. %.

The terms "effective amount", "therapeutically effective amount" and "effective dosage", as used herein, refers to the amount of a compound that, when administered to a patient, is effective to at least partially improve (and, in preferred embodiments, cure) a condition that is suspected of suffering the patient. It has been found that biaryl sulfonamide compounds act as metalloproteinase inhibitors. Therefore, they are useful in the treatment of cancer, osteoarthritis, rheumatoid arthritis, asthma, COPD, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulcer and other diseases of the body. ocular surface, hepatitis, aortic aneurysms, tendinitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft-versus-host disease, diabetes, inflammatory bowel disease, shock, degeneration of the intervertebral discs, stroke, osteopenia and periodontal diseases. The present invention thus provides pharmaceutical compositions comprising at least one biarylsulfonamide compound and one or more carriers, pharmaceutically acceptable excipients or diluents. Examples of these vehicles are well known to those skilled in the art and are prepared according to pharmaceutically acceptable methods, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety. The pharmaceutically acceptable vehicles are those compatible with the other ingredients of the formulation and biologically acceptable. The compounds of this invention can be administered orally or parenterally, alone or in combination with conventional pharmaceutical vehicles. Solid, applicable vehicles can include one or more substances that can also act as. flavoring agents, lubricants, solubilizers, suspension, filler, emollients, compression aids, binders or tablet disintegrating agents or encapsulating materials. These are formulated in a conventional manner, for example, in a manner similar to that used for antihypertensive agents, diuretics and known β-blocking agents. Oral formulations containing the active compounds of this invention may comprise any oral form conventionally used, including tablets, capsules, mouth shapes, troches, lozenges and liquids, suspensions or oral solutions. In powder form, the carrier is a finely divided solid, which is mixed with the finely divided active ingredient. In the form of tablets, the active ingredient is mixed with a vehicle having the necessary compression properties, in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. The capsules may contain mixtures of the active compound or compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg, corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, jellies, gums, et cetera. Useful tablet formulations can be formed by conventional methods of compression, wet granulation or dry granulation and can use diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), pharmaceutically acceptable suspending agents or stabilizers, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, gum arabic, xanthan gum, sodium citrate, silicate complexes, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate , lactose, kaolin, anitol, sodium chloride, low melting point waxes and ion exchange resins. Preferred surface modification agents include nonionic and anionic surface modification agents. Representative examples of surface modifying agents include, but are not imitated, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylisphate, sodium silicate, magnesium and aluminum and triethanolamine. The oral formulations of this document may use standard formulations of delayed or prolonged release to alter the absorption of the active compound or compounds. The oral formulation may also consist in the administration of the active ingredient in water or fruit juice, containing suitable solubilizers or emulsifiers if necessary. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or orregulators. Suitable examples of liquid carriers for parenteral or oral administration include water (particularly containing additives such as the above, for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric and polyhydric alcohols, eg, glycols) and its derivatives and oils (for example, coconut oil and fractionated peanut oil). For parenteral administration, the vehicle can also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile compositions in liquid form for parenteral administration. The liquid vehicle for pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions, which are Sterile solutions or suspensions can be used by injection, for example, intramuscular, intraperitoneal or subcutaneous. Sterile solutions can also be administered intravenously. The compositions for oral administration may be in liquid or solid form. Preferably, the pharmaceutical composition is in unit dosage forms, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In these forms, the composition is subdivided into unit doses containing suitable amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example, packaged powders, vials, ampoules, pre-filled syringes or seals containing liquids. The unit dosage form can be, for example, the same capsule or tablet, or it can be the appropriate number of any of these packaged compositions. This unit dosage form can contain from about 1 mg / kg to about 250 mg / kg and can be given in a single dose or divided into two or more doses. These doses may be administered in any manner useful for targeting the active compounds described herein to the bloodstream of the recipient, including orally, by means of implants, parenterally (including injections). intravenous, intraperitoneal and subcutaneous), rectal, vaginal and transdermal. These administrations can be carried out using the present compounds or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). When administered for the treatment or inhibition of a particular disease state or disorder, it is to be understood that the effective dose may vary depending on the particular compound used, the mode of administration, the condition and the severity, of the condition that is being treated, as well as the various physical factors related to the individual being treated. In the therapeutic application, the compounds of the present invention are provided to a patient who already suffers from a disease in an amount sufficient to cure or at least partially improve the symptoms of the disease and its complications. An adequate amount to accomplish this is defined as a "therapeutically effective amount". The dosage that is used in the treatment of a specific case must be determined sub-ethically by the attending physician. The variables involved include the specific condition and the patient's size, age and response pattern. In some cases, it is desirable to administer composed directly by the respiratory tract in the form of an aerosol. For administration by intranasal or intrabronchial inhalation, the compounds of this invention can be formulated into an aqueous or partially aqueous solution. The compounds of this invention can be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or as a pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms. The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the point of easy movement through the needle of a syringe. The form must be stable under the conditions of manufacture and storage and must be preserved from the contaminating action of microorganisms such as bacteria and fungi. He The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils. The compounds of this invention can be administered transdermally through the "use of a transdermal patch." For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the internal coatings of the body cavities, including epithelial and mucosal tissues, These administrations can be carried out using the present compounds or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). Transdermal can be achieved through the use of a transdermal patch containing the active compound and a vehicle that is inert with respect to the active compound, is not toxic to the skin and allows the distribution of the agent for systemic absorption into the bloodstream through the skin, the vehicle can take many forms, s as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be liquid or semisolid viscous emulsions, of the oil-in-water or water-in-oil type. They can also be Suitable pastes composed of absorbent powders dispersed in petrolatum or hydrophilic petrolatum containing the active ingredient. Various occlusive devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a vehicle or a matrix containing the active ingredient. Other occlusive devices are described in the literature. The compounds of this invention can be administered rectally or vaginally in the form of conventional suppositories. Formulations of suppositories can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the melting point of the suppository and glycerin. Water soluble suppository bases can also be used, such as polyethylene glycols of various molecular weights. In some embodiments, the present invention is directed to prodrugs of biaryl sulfonamide compounds. Various forms of prodrugs are known in the art as discussed, for example, in Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (Ed), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen et al. (Ed.), "Design and Application of Prodrugs", Textbook of Drug Design and Development, Chapter 5, 113-191 (1991): Bundgaard et al., Journal of Drug Deliver reviews, 8: 1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77: 285 et seq. (1998); and Higuchi and Stella (ed), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated as a reference in its entirety. It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the disease and the individual treated, and will be subject to the judgment of the physician involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and that it be increased until the desired effects are achieved. The compounds of the present invention were prepared according to the following general synthetic reaction scheme, starting from commercially available starting materials, the materials prepared as described in literature procedures or new intermediate products described in US Pat. reaction schemes and experimental procedures. This general reaction scheme covers most of the examples. For more detailed information, please refer to the reaction schemes in the Methods of Synthesis and Examples section.

General Reaction Scheme The bases used in this document are Et3N, 2C03, NaH, Hunig base, and so on. The link usually refers to Suzuki link or Stille link. The hydrolysis was carried out using trifluoroacetic acid (TFA), NaOH, LiOH, K2C03, et cetera. The compounds of the invention can be prepared using various methods starting from commercially available compounds, known compounds or compounds prepared by known methods. General synthetic routes to many of the compounds of the invention are included in the following reaction schemes. Those skilled in the art will understand that for these syntheses protection and deprotection steps may be needed that are not shown in the reaction schemes and that the order of the steps may be changed to accommodate functionalities in the target molecules.

In reaction scheme 1, the compounds of the invention, 1, are prepared in 4 steps. Sulfonylation of valine methyl ester with 4-bromo-benzenesulfonyl chloride was carried out under Hunig basic conditions to give the sulfonamide intermediate 1. This 4-bromo-benzenesulfonamide was further coupled with a boronate ester using a catalyst of palladium under Suzuki coupling conditions to give the biphenyl sulfonamide intermediate 2. The biphenyl sulphonamide intermediate 2 was then rented with various alkylating reagents to give the biphenyl sulphonamide ester (intermediate 3). The hydrolysis of intermediate 3 was carried out using bases such as NaOH or LiOH, to reach the final product 1.

Reaction Scheme 1 Intermediate Product 1 Intermediate Product 2 An alternative route for compounds 1 is shown in reaction scheme 2. The phenolic derivative was converted to Pinacolborane (intermediate 4) under basic conditions in DMF. The pinacolborane was then coupled with 4-bromo-benzenesulfonamide under Suzuki conditions to give the intermediate 5 of biphenylsulfonamide, which was hydrolyzed to the final product under basic conditions.

Reaction Scheme 2 Intermediate Product 4 Intermediate Product 5 The third option to achieve compounds of the invention, 1, is carried out based on reaction scheme 3. The synthesis sequence in reaction scheme 3 is similar to that of reaction scheme 1, but using a starting material different, tert-butyl ester of valina. Therefore, the final step to form product 1 was carried out using TFA to deprotect the tert-butyl ester group of intermediate 8.

Reaction Scheme 3 Intermediate Product 6 Intermediate Product 7 A slight modification of reaction scheme 3 resulted in another to obtain the compounds of the invention, 1. This is illustrated in reaction scheme 4.A. In this case, boronate esters are obtained with a suitable ether portion from commercial suppliers and used for Suzuki coupling to provide intermediate 8. The deprotection with TFA of the tert-butyl ester of intermediate 8 resulted in the desired final product 1.

Reaction Scheme 4A Intermediate Product 6 Intermediate Product 8 The compounds of the invention, 1, can also be made by the hydrolysis of an ester such as intermediate 10.

Reaction Scheme 4B PdCl2 (dppi, K2C03 Intermediate Product 9 Intermediate Product 10 Alkylation The phenolic derivative (4.14 mmol) is dissolved in methanol (6 mL) and treated with tetrabutylammonium hydroxide. (4.14 mmol). The mixture is stirred for 10 minutes and the solvent is removed under reduced pressure. The residue is dissolved in tetrahydrofuran (THF) (10 mL) and treated with a solution of benzyl bromide (4.14 mmol) in THF (5 mL). The reaction is stirred at room temperature overnight.

The solvent is removed under reduced pressure and redissolved in dichloromethane (5 mL) and ether (50 mL). The organic solution is washed with water (4 x 50 mL) and with saturated sodium chloride solution (50 mL) and dried over magnesium sulfate.

The organic solution is filtered and concentrated under reduced pressure. The crude material is purified by flash chromatography on silica gel to give the purified product in 53% yield.

Suzuki coupling The boronate ester (1.07 mmol) and the aryl bromide (1.07 mmol) are dissolved in ethylene glycol dimethyl ether (10 mL) and the resulting solution is treated with tetrakis (triphenylphosphine) palladium (0) (0.054 mmol) . A solution of potassium carbonate (2.14 mmol) in water (3.5 L) is added and the reaction is heated to reflux for 1 hour. The reaction is cooled, filtered to remove the solids, dilute with water (10 ml) and concentrate under reduced pressure. The residue is extracted with dichloromethane (3 x 25 mL) and the organic layers are washed with water (25 mL) and saturated sodium chloride solution (25 mL). The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel provides the product with a yield of 57%. In some cases, PdC12 (dppf) was used as a catalyst, instead of tetrakis (triphenylphosphine) -palladium (0).

Deprotection with MgBr2 The 2- (trimethylsilyl) -ethyl ester (0.0621 mmol) is dissolved in dichloromethane (58 mL) and treated with magnesium bromide etherate (0.186 mmol). The mixture is stirred vigorously overnight or until the reaction is complete and then stirred with 10% HCl (3 x 25 mL) and saturated sodium chloride solution (25 mL). The organic solution is then dried over magnesium sulfate, filtered and concentrated under reduced pressure to deliver the product in 95% yield. The crude product could be purified by the HPLC when required. The Suzuki coupling can be carried out in the free acid with boronate ester. In this way, hydrolysis of the esters is avoided. This results in the direct preparation of the compounds, 1.

Reaction Scheme 4C Suzuki coupling with free acid Boronate ester (1.36 mmol) and bromine acid (1.36 mmol) are dissolved in ethylene glycol dimethyl ether (13.8 mL) and the resulting solution is treated with tetrakis (triphenylphosphine) palladium (0) ( 0.068 mmol). After stirring at room temperature for 10 minutes, a solution of potassium carbonate (4.08 mmol) in water is added. (4.8 mL). The solution is refluxed for 2 hours and then allowed to cool to room temperature overnight. The mixture is concentrated under reduced pressure to obtain an aqueous residue and ethyl acetate (50 mL) is added. The organic mixture is washed with 10% HCl (2 x 25 mL) and with saturated sodium chloride solution (25 mL). The organic solution is dried over magnesium sulfate, filtered and concentrated to a crude residue, which is purified by flash chromatography on silica gel to obtain the product in a yield of 64%. In the reaction scheme 5, the compounds of the invention, 2, are prepared in 3 steps. The boronate ester (intermediate 11) was prepared by alkylation under basic conditions. The intermediate product 11 obtained in this way can be easily coupled with a 4-bromo-benzenesulfonamide derivative to deliver a biphenyl-sulfonamide analog (intermediate 12). The ester functional group in intermediate 12 can be hydrolyzed under various conditions to give the desired biphenyl sulfonamide analog product, 2.

Reaction Scheme 5 Intermediate product 11 0 / = \ R, 0j -o, deprotection? FcCK * ^ R. Intermediate Product 12 An alternative route to obtain the compounds, 2, is shown in the reaction scheme 6. The starting material, a derivative of 4-hydroxybiphenylsulphonamide, can be obtained easily through a Suzuki coupling.

Alkylation of the 4-hydroxybiphenyl sulfonamide under basic conditions gives the intermediate 13 of biphenylsulphonamide with an ether linkage. The hydrolysis of the ester (intermediate 13) using aqueous NaOH delivers the final product of the desired invention, 2.

Reaction Scheme 6 Intermediate Product 13 Reaction Scheme 6B Deprotection of methyl esters: The methyl ester (0.294 mmol) is dissolved in THF: MeOH (2: 1) (2 mL) and 1 M LiOH (0.881 mmol) is added. The reaction is stirred for 3 days. The solvent was removed and the remaining white solid dissolved in H0. The H0 is extracted with ether. The ether layer is removed and the aqueous layer is acidified to pH 2 with HCl (conc.), Forming a cloudy solution. This is extracted with CH2C12. The aqueous layer is removed and the organic layer is washed with brine. The solvent is removed and the remaining solid dissolves at the minimum of CH2C12 and then hexanes are added, precipitating a white solid. The solid is filtered and dried under reduced pressure to deliver the desired product. The compounds of the invention, 3, are prepared based on the reaction scheme 7. A 4-vinylphenylboronic acid and a 4-bromobenzenesulfonamide derivative were subjected to Suzuki coupling catalyzed by a palladium catalyst to provide the intermediate product. The Heck reaction of product 14 with an aryl halide generated intermediate 15. Intermediate 15 is a biphenylsulfonamide derivative with a double bond as a linkage with the aryl ring. Normal deprotection with TFA of the tert-butyl ester of intermediate 15 provides the desired product 3 in high yield.

Reaction Scheme 7 Intermediate Product 14 Intermediate Product 15 The reaction scheme 8 shows the synthesis in multiple steps leading to the compounds of the invention, 4. A normal Suzuki coupling followed by alkylation with triflic anhydride yields triflate intermediate 16. Triflate 16 is converted to the alkynylation product 17 through a Sonagoshira reaction. The TBDMS protection group in product 17 was removed with TBAF followed by another Sonagoshira reaction to give the advanced intermediate 18 with a triple bond between the biphenyl group and the aryl portion. Intermediate 18 was then reduced by hydrogenation, followed by deprotection with TFA to give the desired product 4.

Reaction Scheme 8 Intermediate Product 16 Intermediate Product 17 Product | ntermed¡0 18 The pathways to the compounds of structure 5 are shown in the reaction scheme 9. A 4-aminomethyl-phenyl-boronic acid is used for the Suzuki coupling to provide the intermediate 19. The acylation of the product 19 with acetic anhydride, followed by deprotection with TFA gives compounds with the structure 5.

Reaction Scheme 9 An alternative route for synthesizing the compounds of structure 5 is presented in reaction scheme 10. Intermediate 21 is formed by coupling EDCI of 4-bromophenylacetic acid with phenylamine in DMF. The Stille coupling of the product 21 with the corresponding tin reagent, followed by deprotection with TFA, gives the product 5.

Reaction Scheme 10 Stille Intermediate Product 21 Intermediate Product 22 In reaction scheme 11, the compounds of the invention, 6, are prepared by reacting a 4-hydroxybiphenyl-sulfonamide derivative with several isocyanates in the presence of triethylamine. The carbamate (intermediate 24) obtained in this way is treated with TFA to remove tert-butyl ester and give compound 6.

Reaction Scheme 11 Intermediate Product 23 Intermediate Product 24 An alternative way to synthesize compounds 6 is shown in reaction scheme 12, by reacting the free acid of 4-hydroxybiphenyl-sulfonamide with isocyanate in the presence of triethylamine. The compounds 6 are obtained directly, without the step of deprotection.

Reaction Scheme 12 In reaction scheme 13, the pathways to compounds of structure 7 are shown. Intermediate 23 was coupled with a carboxylic acid using the DCC reagent, to obtain ester 24. Intermediate 24 was treated with TFA to selectively remove tere-butyl group and give compound 7.

Reaction Scheme 13 In reaction scheme 14, the compounds of the invention, 8, are prepared from intermediate 23 by alkylation followed by deprotection of the tere-butyl group with TFA.

Diagram of Reaction 14 Intermediate Product 23 Intermediate Product 25 In the reaction scheme 15, the compounds of the invention, 9, are prepared in a multi-step synthesis. Intermediate 26 is prepared based on methods known from the literature. A Stille coupling followed by a deprotection with TFA provides the desired product 9.

Reaction Scheme 15 Intermediate Product 26 Coupling Cl H) -S- ~ BuaSn de Stlle In reaction scheme 16, pathways to compounds of structure 10 are shown. Intermediate 28 (2- [1,2,3] thiazol-4-yl-phenol) was prepared according to literature procedures. Alkylation with a benzyl bromide derivative followed by a condensation resulted in the thioether intermediate 29. The Suzuki coupling of the product 29 with a 4-bromobenzenesulfonamide generated the intermediate 30. The oxidation with MCPBA followed by the hydrolysis afforded compound 10.

Reaction Scheme 16 P Deprotection with TFA of the t-butyl ester ester Reaction Scheme 7 The t-butyl ester (0.505 mmol) was dissolved in CH2C12 (2.5 mL). TFA (2.5 mL) was dissolved in CH2Cl2 (2.5 mL) and slowly added to the dissolved ester. It was stirred for 1.5 hours. The solvent was removed under reduced pressure, the remaining oil was dissolved in toluene and the toluene was removed. Finally, the oil was dissolved in a minimum amount of CHC1 and hexanes were added to precipitate a white solid. The solvent was removed under reduced pressure and the solid was dried in a vacuum chamber to give a 98% yield. MMPs and aggrecanases can degrade various connective tissue components, including collagen and proteoglycan. In the absence of natural controls on this activity, various pathologies and undesirable effects can occur. In fact, it is known that MMPs and aggrecanases play a role in many alterations in which the degradation / destruction of extracellular proteins takes place, such as cancer, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease. ("COPD"), atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulcer and other ocular surface diseases, hepatitis, aortic aneurysms, tendinitis, systemic diseases central nervous system, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft-versus-host disease, diabetes, inflammatory bowel disease, shock, degeneration of intervertebral discs, stroke, osteopenia and periodontal diseases. The preferred metalloproteinase is Agrecanase-1 (Agg-1). The molecular weight of the full-length Agg-1 is approximately 62 KD. The cDNA sequence contains 2511 base pairs encoding 837 amino acids (Tortorella, MD et al., Science 1999, 284, 1664-1666). The Agg-1 protein can be produced by culturing a cell transformed with the DNA sequence and recovering and purifying protein from the culture medium (Racie L A et al., International PCT Application). Analysis of the Agg-1 protein is carried out using standard techniques such as SDS-PAGE in acrylamide (Laemmli, Nature, 1970, 227, 680), silver staining (Oaklet et al., Anal. Biochem, 1980, 105, 361) and immunoblotting (To bin et al, Proc. Nati, Acad. Sci. USA 1979, 76, 4350). The biological activity of Agg-1 can be further characterized by the ability to demonstrate proteolytic activity on aggrecan in an assay that determines the presence of a molecule that degrades aggrecan. These tests or the development thereof are within the knowledge of those skilled in the art. These trials can involves contacting an aggrecan substrate with the aggrecanase molecule and monitoring the production of aggrecan fragments (Hughes et al., Biochem J, 1995, 305, 799-804). The invention includes methods for developing aggrecanase inhibitors and the inhibitors produced therefrom. The compounds are evaluated by their ability to inhibit the cleavage of a fluorescent peptide substrate (Abz-TEGARGSVI-Dap (Dnp) (Abz: o-aminobenzoyl; Dnp: 2, -dinitrophenyl) (Anaspec Inc.). The peptide sequence TEGARGSVI is Based on the amino acid sequence of the Glu373-Ala374 cleavage site of the aggrecan in osteoarthritis, the inhibitors are pre-incubated with recombinant, purified, full-length human aggrecanase-1 for 10 minutes, followed by the addition of substrate, at temperatures range from 25 ° C to 37 ° C, typically at 30 ° C. Cleavage of the Glu-Ala bond liberates the fluorophore from internal inactivation.This results in an increase in the fluorescence monitored at? ex 340 nm and? ex 420 nm for a period of 40 minutes The initial velocity (v) for each substrate concentration is adjusted to the following equation: V = Vmax-S? / (S? 0.5 + -S *), where h is Hill's constant and So.5 is the concentration of substr ato corresponding to half of Vmax. The percentage of activity remaining in the presence of the inhibitor is represents in function of the concentration of inhibitor and the IC50 value is determined by using the data to the following equation:% of activity = 100 IC50 / (lo + IC50) • In addition, the inhibitory activity of the candidate molecules is tested in a secondary assay such as a cell-based assay. Assays for the inhibitors involve contacting a mixture of aggrecan (proteoglycan from a cartilage cut) and the inhibitor with an aggrecanase molecule, followed by measurement of aggrecanase inhibition by, for example, the detection and measurement of fragments of aggrecan produced by cleavage at a site susceptible to aggrecanases. Therefore, another aspect of the invention provides pharmaceutical compositions containing a therapeutically effective amount of aggrecanase inhibitors, in a pharmaceutically acceptable carrier. The aggrecan-mediated degradation of aggrecan in cartilage has been implicated in osteoarthritis and other inflammatory diseases. Therefore, these compositions of the invention can be used in the treatment of diseases characterized by the degradation of aggrecan and / or a positive regulation of aggrecanase. The compositions can be used in the treatment of these conditions or in the prevention thereof.

Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, italic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and similarly acceptable known acids, when a compound of this invention contains a basic portion. Salts can also be formed from organic and inorganic bases, such as alkali metal salts (eg, sodium, lithium or potassium), alkaline earth metal salts, ammonium salts, alkylammonium salts containing from 1 to 6 carbon atoms. or dialkylammonium salts containing from 1 to 6 carbon atoms in each alkyl group and trialkylammonium salts containing from 1 to 6 carbon atoms in each alkyl group, when a compound of this invention contains an acid portion. The term "alkyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight chains and branched containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, unless explicitly specified otherwise way. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are included in the term "alkyl". The alkyl group of 1 to 6 carbon atoms includes straight and branched chain aliphatic groups possessing from 1 to 6 carbon atoms. Those aliphatic hydrocarbon chains that are optionally substituted are specifically included within the definition of "alkyl". The number of carbon atoms, as used herein in the definitions, refers to the structure of carbon atoms and the branches of carbon atoms, but does not include carbon atoms of substituents, such as alkoxy substitutions and Similar . The term "alkenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight chains and branched containing from 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl portion possesses 1 or 2 double bonds. These alkenyl portions may exist in the E or Z conformations and the compounds of this invention include both conformations. The alkenyl group of 2 to 6 carbon atoms includes a straight or branched chain of 1 to 6 carbon atoms that has at least one carbon-carbon double bond. Those aliphatic hydrocarbon chains that are optionally substituted are specifically included within the definition of "alkenyl". Heteroatoms, such as 0, S or N-R1 bound to an alkenyl group, should not be attached to a carbon atom participating in a double bond. The term "alkynyl" refers to a hydrocarbon portion containing at least one carbon-carbon triple bond The alkynyl group of 2 to 6 carbon atoms includes a straight or branched chain of 1 to 6 carbon atoms possessing at least one carbon-carbon triple bond. a triple carbon-carbon bond The term "cycloalkyl" refers to a monovalent monocyclic, bicyclic, tricyclic, fused, crosslinked or spiro monovalent hydrocarbon portion, wherein the carbon atoms are located within or outside the ring system. Any suitable position in the ring of the cycloalkyl portion may be covalently bound to the defined chemical structure Examples of cycloalkyl portions include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl. , cyclohexylethyl, cycloheptyl, norbomyl, adamantyl, spiro [4.5] decanyl and homologs, isomers and Similar. The cycloalkyl group of 3 to 6 carbon atoms includes monocyclic saturated rings of 3 to 6 carbon atoms, optionally substituted with R 3. "Heteroaryl" refers to a 5-6 membered heterocyclic, aromatic ring containing from 1 to 3 heteroatoms in the ring, selected from the group consisting of oxygen, nitrogen, and sulfur atoms and which may be fused to a carbocyclic ring or heterocyclic in any possible position. "Heterocycloalkyl" refers to a saturated 5- to 7-membered ring containing carbon atoms and from 1 to 2 heteroatoms selected from N, 0 and S. The term "phenyl", as used herein, either when used alone or as part of another group, refers to a substituted or unsubstituted phenyl group. An optionally substituted portion may be substituted with one or more substituents. Suitable optional substituents can be independently selected from H, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NRC (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5 and CN. When these portions are substituted, for example, they can typically be mono, di, tri or persubstituted Examples for a halogen substituent include 1-bromovinyl, 1-fluorovinyl, 1,2-difluorovinyl, 2,2-difluorovinyl, 1,2,2-trifluorovinyl, 1,2-dibromoethane, 1,2-difluoroethane, 1- fluoro-2-bromoethane, CF2CF3, CF2CF2CF3 and the like. The term halogen includes bromine, chlorine, fluorine and iodine. For simplicity, the connection points ("-") are not represented. When an atom or compound is described to define a variable, it is understood that it replaces the variable in order to satisfy the valence of the atom or compound. For example, when L is C (R3) = C (R3), both carbon atoms are part of the ring in order to satisfy their respective valences. The present invention is further described in the following examples.

EXAMPLES Examples IA and IB were prepared based on the Reaction Scheme 1 Example IA 3-Methyl-2- [4 # - (3-methyl-quinolin-2-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid Step IA [Intermediate Product 1]: They were placed in a dry-bottomed round-bottomed flask. 4-bromo-benzenesulfonyl (12.2 g, 47.7 mmol, 1 equiv.), Anhydrous methylene chloride (170 mL) and HD-Val-OMe (8.0 g, 47.7 mmol, 1 equiv.). The mixture was cooled to 0 ° C in an ice bath, then adding Hunig's base (19.11 mL, 109.7 mmol, 2.3 equiv.). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The determination by means of thin layer chromatography (CCD) indicated that the reaction was complete. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with brine. The organic layer was dried over anhydrous MgSO 4 and the solvent was evaporated to give the 2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester in 96% yield (16.0 g). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, J = 6.82 Hz, 3 H) 0.96 (d, .7 = 6.82 Hz, 3 H) 2.04 (m, 1 H) 3.49 (s, 3 H ) 3.74 (d, J = 14.40 Hz, 1 H) 5.10 (d, J = 9.85 Hz, 1 H) 7.66 (m, 4 H). Step IB [Intermediate Product 2]: 2- (4-Bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester (3.4 g, 9.71 mmol), 4-hydroxymethyl-phenyl-boronic acid (1.48 g, 9.71 g) was dissolved. mmol, 1 equiv.), Pd (PPh3) 4 (561 mg, 0. 48 mmol, 0.05 equiv.) In ethylene glycol dimethyl ether (90 mL) under an N2 atmosphere and stirred at room temperature for 30 minutes. Then, K2CO3 (2.68 g, 19.4 mmol, 2 equiv.) In H20 (30 mL) was introduced into the reaction mixture and heated to reflux overnight. After confirmation by the CCD of the reaction rate, the solvent was removed in a rotary evaporator, the residue was partitioned between EtOAc and brine.The organic layer was dried over MgSO 3, the solvent was removed and the residue was triturated with EtOAc to give 2- (4'-hydroxymethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester with a yield of 67% (2.46 g). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.90 (d, 7 = 7.07 Hz, 3 H) t 0.97 (d, 7 = 6.82 Hz, 3 H) 1.57 (s, 1 H) 2.04 (m, 1 H ) 3.43 (s, 3 H) 3.79 (dd, 7 = 10.11, 5.05 Hz, 1 H) 4.78 (s, 2 H) 5.11 (d, 7 = 10.36 Hz, 1 H) 7.49 (d, 7 = 8.34 Hz, 2 H) 7.60 (d, 7 = 8.34 Hz, 2 H) 7.70 (d, 7 = 8.84 Hz, 2 H) 7.88 (d, 7 = 8.59 Hz, 2 H). Step 1C [Intermediate Product 3]: 2- ('-hydroxymethyl-biphenyl-4-sulfonylamino) -3-methylbutyric acid methyl ester (1.2 g, 3.2 mmol, 1.0 equiv.) Was dissolved in DMF (30 mL) and 2-chloro-3-methyl-quinoline (2.26 g, 12.7 mmol, 4 equiv.), Followed by the addition of NaH (382 mg, 60% in oil, 9.54 mmol, 3 equiv.). The mixture was stirred at 100 ° C for 5 hours, then at room temperature during a night. Then, the reaction mixture was poured into cold water and the solid precipitated from the mixture was collected by filtration and washed with water. Regular column chromatography (silica gel, 1% MeOH / CH 2 Cl 2) yielded 203 mg of methyl 3-methyl-2- [4 '- (3-methyl-quinolin-2-yloxymethyl) -biphenyl-4-methyl ester. -sulfonylamino] -butyric in a yield of 12%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.89 (d, 7 = 6.82 Hz, 3 H) 0.97 (d, 7 = 6.82 Hz, 3 H) 2.04 (m, 1 H) 2.40 (s, 3 H) 3.43 (s, 3 H) 3.78 (dd, 7 = 10.11, 5.31 Hz, 1 H) 5.09 (d, 7 = 10.11 Hz, 1 H) 5.64 (s, 2 H) 7.37 (m, 1 H) 7.64 (m , 8 H) 7.86 (m, 4 H). Step ID: The methyl ester of 3-methyl-2- ['- (3-methyl-quinolin-2-yloxymethyl) -biphenyl-4-sulfonylamino] - was dissolved in THF (8 mL) and MeOH (4 mL). butyric (203 mg, 0.39 mmol, 1 equiv.) and hydrolyzed with 1 N NaOH (5.83 mL, 5.83 mmol, 13 equiv.). After stirring for 3 days the solvent was removed and the residue was dissolved in H20. The mixture was then acidified to pH 3 using 1 N HCl. The solid that was precipitated from the mixture was collected by filtration and washed with water. After drying in a vacuum oven, 101 mg of 3-methyl-2- [4 '- (3-methyl-quinolin-2-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid were obtained in a yield of 76.3 %. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.81 (d, 7 = 6.57 Hz, 3 'H) 0.84 (d, 7 = 6.82 Hz, 3 H) 1.95 (m, 1 H) 2.36 (s, 3 H) 3.56 (dd, 7 = 9.09, 5.81 Hz, 1 H) 5.61 (s, 2 H) ) 7.42 (t, 7 = 7.45 Hz, 1 H) 7.61 (t, "7 = 7.71 Hz, 1 H) 7.67 (d, 7 = 7.83 Hz, 2 H) 7.83 (m, 8 H) 8.08 (d, 7) = 8.34 Hz, '2 H) 12.58 (s, 1 H).

Example IB 3-Methyl-2- [4 '- (5-trifluoromethyl-pyridin-2-ylmethyl) -biphenyl-4-sulfonylamino] -butyric acid The title compound, 3-methyl-2- [4' - (5 -trifluoromethyl-pyridin-2-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those described in Example 1A. Step 1C: 2- (4'-Hydroxymethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (350 mg, 0.93 mmol, 1 equiv.) And the 2-methyl ester were dissolved in DMF (7 mL). -chloro-5-trifluoromethylpyridine (841 mg, 4.64 mmol, 5 equiv.), followed by the addition of NaH (111 mg, 2.78 mmol, 3 equiv.) under an atmosphere of N2. The mixture was heated at 100 ° C for 2 hours and cooled to room temperature. The reaction mixture was poured into cold water and the resulting solid was collected by filtration. A Further purification by column chromatography (silica gel, 20% EtOAc / hexane) provided 259 mg of G9058-182-2 in 54% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.90 (d, 7 = 6.82 Hz, 3 H) 1.98 (m, 1 H) 3.36 (s, 3 H) 3.72 (dd, 7 = 10.11, 5.05 Hz, 1 H) 5.02 (d, 7 = 10.11 Hz, 1 H) 5.43 (s, 2 H) 6.84 (d, 7 = 8.84 Hz, 1 H) 7.52 (m, 4 H) 7. 64 (d, 7 = 6.82 Hz, 2 H) 7.74 (d, 7 = 8.84 Hz, 1 H) 7.82 (, 2 H) 8.40 (s, 1 H). Step ID: 3-Methyl-2- [4 '- (5-trifluoromethyl-pyridin-2-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid was prepared (86.4% yield, 210 mg) in accordance with procedures of Step ID of Example 1A, using as starting material the methyl ester of 3-methyl-2- ['- (5-trifluoromethyl-pyridin-2-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid (250 mg). 1 H NMR (400 MHz, DMS0-D6) d ppm 0.81 (d, 7 = 6.82 Hz, 3 H) 0.84 (d, 7 = 6.57 Hz, 3 H) 1.95 (m, 1 H) 3.56 (m, 1 H) 5.51 (d, 2 H) 7.12 (d, 7 = 8.84 Hz, 1 H) 7.59 (d, 7 = 8.34 Hz, 2 H) 7.77 (d, 7 = 8.34 Hz, 2 H) 7.86 (m, 4 H) 8.11 (m, 2 H) 8.63 (m, 1 H) 12.57 (s, 1 H).

Examples 1C and ID were prepared based on Reaction Scheme 2.

IC Example 2- [4'- (2, 8-Bis-trifluoromethyl-quinolin-4-yloxymethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 2A [Intermediate Product 4, G9591-157-1]: A a solution of 2,8-bis-trifluoromethyl-quinolin-4-ol (3.85 g, 13.7 mmol, 1.1 equiv.) in DMF (40 mL) was added 2- (4-bromomethyl-phenyl) -4.4.5 , 5-tetramethyl- [1,3,2] dioxaborolane (3.7 g, 12.5 mmol, 1.0 equiv.) And K2C03 (3.45 g, 24.92 mmol, 2.2 equiv.) Under an atmosphere of N2. The reaction mixture was stirred at room temperature overnight. The reaction was determined to be complete by CCD. The reaction mixture was poured into cold water, the white precipitate formed was collected by filtration, washed with water and dried under vacuum to obtain 4- [4- (4,4,5,5-tetramethyl- [1 , 3,2] dioxaborolan-2-yl) -benzyloxy] -2,8-bis-trifluoromethyl-quinoline with a yield of 73% (4.95 g). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.36 (s, 12 H) . 38 (s, 2 H) 7.21 (s, 1 H) 7.51 (d, 7 = 8.34 Hz, 2 H) 7.65 (t, 7 = 7.83 Hz, 1 H) 7.90 (d, 7 = 8.08 Hz, 2 H) 8.14 (d, 7 = 7.33 Hz, 1 H) 8.50 (d, 7 = 8.59 Hz, 1 H). Step 2B [Intermediate Product 5, G9591-162]: A 4- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyloxy] -2, 8 Bis-trifluoromethyl-quinoline (1.5 g, 3.0 mmol, 1 equiv.) in 45 mL of ethylene glycol dimethyl ether was added 2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester (1.06 g, 3.0 mmol, 1.0 equiv.) and Pd (PPh3) 4 (174 mg, 0.15 mmol, 0.05 equiv.) under N2. The reaction mixture was stirred for 0.5 hour, then an aqueous solution of K2CO3 (834 mg, 6.0 mmol, 2 equiv.) Was added. The mixture was heated to reflux overnight. After cooling to room temperature, the solvent was removed in vacuo. The residue was diluted with EtOAc (100 mL) and washed with a brine solution. The organic layer was dried over anhydrous MgSO 4, the solvent was evaporated in vacuo and the crude product was purified on a column of silica gel (30% EtOAc / hexane) to give 1026 g of 2- [4 '] methyl ester. - (2,8-bis-trifluoromethyl-quinolin-4-yloxymethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric with a yield of 53%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.90 (d, 7 = 6.82 Hz, 3 H) 0.98 (d, 7 = 6.82 Hz, 3 H) 2.07 (m, 1 H) 3.45 (s, 3 H) 3.81 (dd, 7 = 10.11, 5.05 Hz, 1 H) 5.12 (d, 7 = 10.11 Hz, 1 H) . 44 (s, 2 H) 7.25 (s, 1 H) 7.70 (m, 7 H) 7.92 (d, 7 = 8.84 Hz, 2 H) 8.16 (d, 7 = 7.33 Hz, 1 H) 8.52 (d, 7 = 8.59 Hz, 1 H). Step 2C: 2- [4'- (2, 8-Bis-trifluoromethyl-quinolin-4-yloxymethyl) -biphenyl-4-sulfonylamino] methyl ester was dissolved in THF (15 mL) and MeOH (6 mL). 3-methyl-butyric acid (1.026 g, 1.6 mmol, 1 equiv.) And 1 N NaOH (17.6 mL, 11 equiv.) Was added. The reaction was monitored by the CCD. It was completed in 3 days. The solvent was removed in a rotary evaporator and the residue was dissolved in H0. The mixture was then acidified to pH 3 with 1N HCl. The resulting precipitated product was collected by filtration, washed with cold water and dried overnight. 460 mg of a white solid were obtained with a yield of 46%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.96 (m, 1 H) 3.57 (dd, 7 = 9.35 , 6.32 Hz, 1 H) 5.66 (s, 2 H) 7.83 (m, 10 H) 8.11 (d, 7 = 9.35 Hz, 1 H) 8.35 (d, 7 = 7.33 Hz, 1 H) 8.58 (d, 7 = 7.83 Hz, 1 H) 12.57 (s, 1 H).

Example ID D-3-Methyl-2- [4 '- (2-methyl-quinolin-4-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4'] acid - (2-methyl-quinolin-4-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those described in Example 1C. Step 2A: The alkylation of 2-methyl-quinolin-4-ol with 2- (4-bromomethyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] -dioxaborlane was carried out from according to the procedures of Step 2A of Example 1C to give 2-methyl-4- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyloxy] -quinoline with a yield of 28%. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 5.4 (s, 2 H) 7.0 (s, 1 H) 7.5 (m, 1 H) 7.6 (d , 7 = 8.1 Hz, 2 H) 7.7 (m, 1 H) 7.7 (d, 7 = 8.1 Hz, 2 H) 7.9 (d, 7 = 8.1 Hz, 1 H) 8.1 (dd, 7 = 8.3, 0.8 Hz , 1 HOUR) . Step 2B: The Suzuki coupling of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester with 2-methyl-4- [4- (4, 4, 5, 5-tetramethyl) - [1, 3, 2] dioxaborolan-2-yl) -benzyloxy] -quinoline was carried out according to the procedures of Step 2B of Example 1C with a yield of 80%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 15.0, 6.7 Hz, 6 H) 1.9 (m, 1 H) 2.6 (s, 3 H) 3.3 (s, 3 H) 3.6 (dd) , 7 = 9.3, 7.1 Hz, 1 H) 5.5 (s, 2 H) 7.1 (s, 1 H) 7.5 (t, 7 = 7.6 Hz, 1 H) 7.7 (m, 3 H) 7.8 (d, 7 = 7.6 Hz, 4 H) 7.9 (m, 1 H) 7.9 (, 2 H) 8.1 (d, "7 = 8.3 Hz, 1 H) 8.3 (d," 7 = 9.3 Hz, 1 H). Step 2C: The hydrolysis of D-3-methyl-2- [4 '- (2-methyl-quinolin-4-yloxymethyl) -biphenyl-4-sulfonylamino] -butyric acid methyl ester was carried out in accordance with procedures of Step 2C of Example 1C with a quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 6.8 Hz, 6 H) 2.0 (, 1 H) 2.6 (s, 3 H) 3.0 (s, 1 H) 5.4 (s, 2 H) 7.1 (s, 1 H) 7.5 (t, 7 = 8.1 Hz, 1 H) 7.7 (t, "7 = 7.7 Hz, 3 H) 7.8 (m, 7 H) 8.1 (d," 7 = 9.3 Hz, 1 H ).Example 1E was prepared based on Reaction Scheme 3. Example 1E Step 3A: To a round bottom flask was added 4-bromo-benzenesulfonyl chloride (24.37 g, 95.4 mmol, 1 equiv.), Anhydrous methylene chloride (350 mL) and HD-Val-OtBu (20 g, 95.4 mmol. , 1 equiv.). The mixture was cooled to 0 ° C followed by the addition of Hunig's base (38.2 mL, 219 mmol, 2.3 equiv.). The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature with stirring overnight. He starting material was consumed as determined by means of the CCD. The reaction mixture was then diluted with methylene chloride (200 mL) and washed with H20 (500 mL) and brine (250 mL). The organic cap was dried over anhydrous MgSO 4, evaporated in vacuo to obtain 2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester with a quantitative yield (35.0 g). 1 H NMR (400 MHz, DMSO-D6) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.84 (d, 7 = 6.82 Hz, 3 H) 1.19 (s, 9 H) 1.93 (m, 1 H) 3.46 (dd, 7 = 9.35, 6.06 Hz, 1 H) 7.69 (d, 7 = 8.59 Hz, 2 H) 7.79 (m, 2 H) 8.24 (d, 7 = 9.60 Hz, 1 H). Step 3B: 2- (4-Bromo-benzenesulfonylamino) -3-methyl-butyric acid tert -butyl ester (11.96 g, 30.47 mmol, 1 equiv.), 4- (hydroxymethylbenzene) -boronic acid (4.63 g) was charged. , 30.5 mmol, 1 equiv.) And Pd (PPh3) 4 (1.76 g, 1.52 mmol, 0.05 equiv.) In a reaction flask and ethylene glycol dimethyl ether (300 mL) was added. The mixture was stirred at room temperature for 10 minutes, then a solution of K2C03 (8.43 g, 60.9 mmol, 2 equiv.) Dissolved in 100 mL of H20 was introduced. The reaction mixture was heated to reflux overnight. After cooling to room temperature, the solvent was removed in a rotary evaporator and the residue partitioned between EtOAc and brine. The organic layer was separated and dried over MgSO4. After removing the solvent in a rotary evaporator, 8.3 g of a white ester solid were obtained 2- (4'-Hydroxymethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl with a 65% yield. 1 H-NMR (400 MHz, MeOD) d ppm 1.05 (d, 7 = 6.82 Hz, 3 H) 1.12 (d, 7 = 6.82 Hz, 3 H) 1.33 (s, 9 H) 2.16 (m, 1 H) 3.73 ( d, 7 = 5.56 Hz, 1 H) 4.81 (s, 2 H) 7.62 (d, 7 = 8.59 Hz, 2 H) 7.78 (d, 7 = 8.34 Hz, 2 H) 7.92 (d, 7 = 8.84 Hz, 2 H) 8.04 (m, 2 H). Step 3C: 2- (4'-Hydroxyruethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert -butyl ester (700 mg, 1.68 mmol, 1 equiv.) Was dissolved in DMF (20 mL) and 2-chloroquinoline (1.1 g, 6.7 mmol, 4 equiv.) And NaH (202 mg, in 60% oil, 5.04 mmol, 3 equiv.) Was added. The mixture was heated to 100 ° C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4C1 (aqueous). After stirring for 0.5 hours, a solid precipitated from the mixture. The solid was collected by filtration, washed with water and dried overnight to give 793 mg of the 2- [4 '- (isoquinolin-3-yloxymethyl) -biphenyl-4-sulfonylamino] - tert-butyl ester. 3- Ethyl-butyric with a yield of 87%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, 7 = 6.82 Hz, 3 H) 1.03 (d, 7 = 6.82 Hz, 3 H) 1.19 (s, 9 H) 2.05 (m, 1 H) 3.66 (dd, 7 = 9.85, 4.55 Hz, 1 H) 5.14 (d, 7 = 9.85 Hz, 1 H) 5.62 (s, 2 H) 6.98 (d, 7 = 8.84 Hz, 1 H) 7.40 (m, 1 H) 7.66 (, 9 H) 7.89 (m, 2 H) 8.03 (d, 7 = 8.59 Hz, 1 H).

Stage 3D: 2- [4 '- (Isoquinolin-3-yloxymethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert -butyl ester (480 mg, 0.88 mmol) was dissolved in 15 mL of dichloromethane . The solution was cooled to 0 ° C, followed by the addition of 5 mL of TFA. The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed in a rotary evaporator and the residue was washed with MeOH. The solid obtained in this way was dried overnight under vacuum to obtain 60 mg of 2- [4 '- (isoquinolin-3-yloxymethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid with a yield of 14%. % 1 H NMR (400 MHz, DMS0-D6) d ppm '0.81 (d, 7 = 6.82 Hz, 3 H) 0.84 (d, 7 = 6.82 Hz, 3 H) 1.95 (m, 1 H) 3.56 (dd, 7" = 9.35, 6.06 Hz, 1 H) 5.58 (s, 2 H) 7.11 (d, 7 = 8.84 Hz, 1 H) 7.46 (dd, 7 = 7.58, 6.32 Hz, 1 H) 7.79 (m, 11 H) 8.08 (d, 7 = 9.35 Hz, 1 H) 8.29 (d, 7 = 8.59 Hz, 1 H) 12.57 (s, 1 H).

Example 1F was prepared based on Reaction Scheme 4.

Example 1F 2- [4'- (Benzothiazol-2-yloxymethyl) -biphenyl-4-sulfonyl- amino] -3-methyl-butyric A 2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyloxy] -benzothiazole (300 mg, 0.604 mmol, 1 equiv.) In 9 mL of dimethoxyethane was added 2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester (237 g, 0.604 mmol, 1 equiv.) And Pd (PPh3) 4 (35 mg, 0.03 mmol, 0.05 equiv.). The mixture was stirred at room temperature for 20 minutes followed by the addition of K2CO3 (167 mg, 1,208 mmol, 2 equiv.) In H20 (3 L). The mixture was heated to reflux overnight. After cooling to room temperature, the solvent was removed in a rotary evaporator. The residue was dissolved in methylene chloride and washed with water and brine. The organic layer was dried over MgSO4, the solvent was removed in vacuo and the crude mixture was purified by column chromatography (30% EtOAc / hexane) to give 285 mg in 85% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.07 (d, 7 = 6.82 Hz, 3 H) 1.23 (d, 7 = 6.82 Hz, 3 H) 1.39 (s, 9 H) 1.47 (t, "7 = 7.20 Hz, 1 H) 3.86 (dd, J = 9.85, 4.55 Hz, 1 H) 5.42 (s, 2 H) 6.99 (s, 1 H) 7.22 (d, 7 = 7.07 Hz, 1 H) 7.39 (m, 2 H) 7.61 (d, 7 = 8.59 Hz, 2 H) 7.67 (d, 7 = 6.32 Hz, 1 H) 7.72 (m, 2 H) 7.84 (d, 7 = 8.84 Hz, 2 H) 8.09 (d, 7 = 8.59 Hz, 2 H). Step 4B: 2- [4 '- (Benzothiazol-2-yloxymethyl) -biphenyl-4-sulfonyl-amino] -3-methyl-butyric acid tert -butyl ester (140 mg, 0.25 mmol) in 6 mL was dissolved. from methylene chloride and then TFA (3 mL) was added. The reaction was completed in 6 hours, as determined by means of CCD. The solvent was removed and the residue was dissolved in? TOAc. N-Hexane was added to the solution and a solid precipitated from the mixture. The precipitated product was collected and dried to give 86 mg in 68% yield. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.83 (d, 7 = 6.82 Hz, 3 H) 1.93 (m, 1 H) 3.54 (dd, 7 = 9.35, 6.06 Hz, 1 H) 5.26 (s, 2 H) 7.21 (m, 1 H) 7.33 (m, 2 H) 7.44 (d, 7 = 8.59 Hz, 2 H) 7.71 (t, 7 = 8.46 Hz, 3 H) 7.82 (s, 4 H) 8. 07 (d, 7 = 9.35 Hz, 1 H) 12.55 (s, 1 H).

Examples 1G, 1H, 11, U, 1K, 1L, 1M, 1N, 10, 1P, 1Q and IR were prepared based on Reaction Scheme 4B. Example 1G ES-480.1 (M-H) -HRMS: 482.16311 (M + Na) +; 482.16319 Calculated Example 1H ES + 544.2 (M + H) + HRMS: 544.17694 (M + H); 544.17884 Calculated Example l ES-480.2 (M-H) -HRMS: 482.1635 (M + H) +; 482.16319 Calculated Example U ES- 495.2 (M-H) -HRMS: 497.17284 (M + H) +; 497.17409 Calculated Example 1K ES-468.2 (M-H) -HRMS: 470.16231 (M + H) +; 470.16319 Calculated Example 1L ES- 456.1 (M-H) -HRMS: 458.14323 (M + H) +; 458.1432 Calculated Example 1M ES- 551.2 (M-H) -HRMS: 553.19849 (M + H) +; 553.2003 Calculated Example 1N ES- 535.2 (M-H) -HRMS: 537.20469 (M + H) +; 537.20539 Calculated Example 10 ES- 456.1 (M-H) -HRMS: 458.14389 (M + H) +; 458.1432 Calculated Example 1P ES-468.2 (M-H) -HRMS: 470.16151 (M + H) +; 470.16319 Calculated Example 1Q ES + 539.1 (M + H) + HRMS: 539.22021 (M + H) +; 539.22104 Calculated Example IR ES-514.1 (M-H) -HRMS: 516.18313 (M + H) +; 516.18392 Calculated Examples 1S, 1T, 1U, IV, 1, IX, 1Y, 1Z, 1AA, 1AB, 1AC, 1AD, 1AE were prepared based on Reaction Scheme 4C.

Example 1S ES-495.1 (M-H) -HRMS: 497.17429 (M + H) +; 497.17409 Calculated Example 1T ES-488.1 (M-H) -HRMS: 490.16864 (M + H) +; 490.16827 Calculated Example 1TJ ES + m / z 452.1 (M-H) -HRMS: 454.16745 (M + H) +; 454.16827 Calculated NMR XH (400 MHz, CDC13): d 0.82 (d, 3H, 7 = 6.8 Hz), 0.94 (d, 3H, 7 = 6.8 Hz), 2.06 (m, 1H), 2.31 (s, 3H), 3.80 (dd, 1H, 7 = 4.4, 10 Hz), 5.13 (m, 3H), 6.90 (m, 2H), 7.17 (m, 2H), 7.55 (d, 2H, 7 = 8 Hz), 7.60 (d, 2H, 7 = 8 Hz), 7.66 (d, 2H, 7 = 8 Hz), 7.86 (d, 2H, 7 = 8 Hz).

Example IV ES + m / z 481.2 (M + H) + HRMS: 483.19410 (M + H) +; 483.19482 Calculated NMR XH (400 MHz, CD3OD): d 0.90 (d, 3H, 7 = 6.8 Hz), 0.99 (d, 3H, 7 = 6.8 Hz), 2.06 (m, 1H), 2.92 (s, 6H), 3.42 (s, 3H), 3.70 (d, 1H, 7 = 5.6, 10 Hz), 5.14 (s, 2H), 6.41 (m, 3H), 7.11 (m, 1H), 7.57 (d, 2H, 8 Hz), 7.71 (d, 2H, 7 = 8 Hz), 7.80 (d, 2H, «7 = 8 Hz), 7.92 (d, 2H, 7 = 8 Hz).

Ex ES + m / z 544.1 (M + H) + HRMS: 546.19448 (M + H) +; 546.19449 Calculated 1 H NMR (400 MHz, CD30D): d 0.93 (d, 3 H, "7 = 6.8.

Hz), 0.99 (d, 3H, 7 = 6.8 Hz), 2.07 (m, 1H), 3.70 (d, 1H, 7 = 5.6), 5.03 (s, 2H), 5.10 (s, 2H), 6.94 (s) , 4H), 7.31 (, 1H), 7. 37 (m, 2H), 7.43 (m, 2H), 7.55 (d, 2H, 8 Hz), 7.71 (d, 2H, 7 = 8 Hz), 7.80 (d, 2H, 7 = 8 Hz), 7.92 (d, 2H, J = 8 Hz).

Example IX ES + m / z 553.2 (M-H) -HRMS: 577.19777 (M + Na) +; 577.19789 Calculated NMR XH (400 MHz, CD30D): d 0. 1 (d, 3H, 7 = 6.8 Hz), 0. 97 (d, 3H, 7 = 6.8 Hz), 1.50 (s, 9H), 2.04 (m, 1H), 3.68 (d, 1H, J = 5.6 Hz), 5.10 (s, 2H), 6.92 (s, 2H) ), 7.28 (d, 2H, 7 = 8 Hz), 7.54 (d, 2H, 7 = 8 Hz), 7.70 (d, 2H, 7 = 8 Hz), 7. 79 (d, 2H, 7"= 8 Hz), 7.91 (d, 2H," 7 = 8 Hz).

Example 1Y ES + m / z 470.2 (M + H) + HRMS: 470.16364 (M + H) +; 470.16319 Calculated NMR XH (400 MHz, CDC13): d 0.89 (d, 3H, 7 = 6.8 Hz), 0.96 (d, 3H, 7 = 6.8 Hz), 2.10 (m, 1H), 3.82 (m, 1H), 3.90 (s, 3H), 5.07 (d, 1H, 7 = 9.6 Hz), 5.21 (s, 2H), 6.93 (m, 4H), 7.54 (d, 2H, 7"= 8 Hz), 7.58 (d, 2H, 7 = 8 Hz), 7.65 (d, 2H, 7 = 8 Hz), 7.89 (d, 2H, 7 = 8 Hz).

Example 1Z ES + m / z 466.2 (M-H) -HRMS: 468.18540 (M + H) +; 468.18392 Calculated NMR XH (400 MHz, CDC13): d 0.83 (d, 3H, 7 = 6.8 Hz), 0.95 (d, 3H, 7 = 6.8 Hz), 2.05 (m, 1H), 2.33 (s, 6H), 3.82 (dd, 1H, 7 = 5.2, 10 Hz), 4.88 (s, 2H), 5.07 (d, 1H, "7 = 10 Hz), 6.97 (m, 1H), 7.05 (, 2H), 7.64 (, 4H) ), 7.67 (d, 2H, 7 = 8 Hz), 7.87 (d, 2H, 7 = 8 Hz).

Example 1AA ES + m / z 454.1 (M-H) -HRMS: 456.14707 (M + H) +; 456.14754 Calculated 1 H NMR (400 MHz, acetone (d6)): d 0.92 (d, 3 H, J = 6.8 Hz), 0.98 (d, 3 H, 7 = 6.8 Hz), 2.10 (m, 1 H), 3.16 (m, 1H), 5.16 (s, 2H), 6.45 (d, 1H, 7 = 8 Hz), 6.53 (m, 2H), 7.10 (t, 1H, 7 = 8 Hz), 7.61 (d, 2H, 7 = 8 Hz), 7.76 (d, 2H, 7 = 8 Hz), 7.86 (d, 2H, 7 = 8 Hz), 7.94 (d, 2H, 7 = 8 Hz).

Example 1AB ES + m / z 530.1 (M-H) -HRMS: 532.17709 (M + H) +; 532.17884 Calculated XH NMR (400 MHz, CD30D): d 0.93 (d, 3H, 7 = 6.8 Hz), 0.99 (d, 3H, 7 = 6.8 Hz), 2.06 (m, 1H), 3.70 (d, 1H, 7 = 5.6) , Hz), 5.16 (s, 2H), 6.93 (m, 3H), 7.04 (, 3H), 7.31 (m, 2H), 7.58 (d, 2H, 7 = 8 Hz), 7.72 (d, 2H, 7 = 8 Hz), 7.81 (d, 2H, 7 = 8 Hz), 7.93 (d, 2H, 7 = 8 Hz).

Example 1AC ES + m / z 531.1 (M-H) -HRMS: 533.17293 (M + H) +; 533.17409 Calculated NMR XH (400 MHz, CDC13): d 0.88 (d, 3H, "7 = 6.8 Hz), 1.00 (d, 3H, 7 = 6.8 Hz), 2.13 (m, 1H), 3.83 (, 1H), 5.13 (m, 3H), 6.82 (m, 1H), 7.02 (m, 5H), 7.56 (m, 4H), 7.67 (m, 3H), 7.89 (, 2H), 8.16 (m, 1H).

Example 1AD ES + m / z 545.2 (M-H) -HRMS: 547.19006 (M + H) +; 547.18974 Calculated XH NMR (400 MHz, CDCl3): d 0.89 (d, 3H, 7 = 6.8 Hz), 1.01 (d, 3H, 7 = 6.8 Hz), 2.19 (m, 1H), 2.44 (s, 3H), 3.83 (, 1H), 5.04 (s, 2H), 6.39 (d, 1H, 7 = 8 Hz), 6.83 (m, 1H), 6. 90 (, 2H, 7 = 8 Hz), 6.97 (d, 2H, 7 = 8 Hz), 7.52 (m, 5H), 7. 60 (d, 2H, 7 = 8 Hz), 7.90 (d, 2H, 7 = 8 Hz).

Example 1AE ES + m / z 506.2 (M-H) -HRMS: 508.17782 (M + H) +; 508.17884 Calculated NMR XH (400 MHz, DMSO): d 0.81 (d, 3H, 7 = 6.8 Hz), 0.84 (d, 3H, 7 = 6.8 Hz), 1.98 (, 3H), 2.64 (d, 2H), 2.91 (t, 2H, 7 = 6 Hz), 3.56 (dd, 1H, 7 = 6, 9.2 Hz), 5.27 (s, 2H), 6.99 (d, 2H, 7 = 8 Hz), 7.59 (d, 2H, 7 = 8 Hz), 7.78 (d, 2H, - = 8 Hz), 7..85 (m, 4H), 8.08 (d, 1H, 8-Hz).

Examples 2A, 2B, 2C, 2D, 2 ?, 2F, 2G, 2H, 21, 2J were prepared based on Reaction Scheme 5. Example 2A D-3-Methyl-2- [4 '- (3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid Step 5A: A mixture of 2- was refluxed under a nitrogen atmosphere. chloromethyl-3-methyl-benzofuran (675.9 mg, 3.75 mmol), 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol (825 mg, 3.75 mmol, 1 equiv.) And K2C03 ( 2.1 g, 15.2 mmol, 4 equiv.) In 20 ml of CH3CN. The reaction was completed after 12 hours. Through the usual treatment and column purification (EtOAc al % / hexane) 3-methyl-2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran was obtained with a yield of 44% (601 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.3 (s, 12 H) 2.3 (s, 3 H) 5.2 (s, 2 H) 7.0 (d, 7 = 8.6 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, 7 = 21.6, 7.7 Hz, 2 H) 7.8 (d, «7 = 8.8 Hz, 2 H). Step 5B: A mixture of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester (568.07 g, 1.62 mmol), 3-methyl-2- [4] was refluxed for 12 hours. - (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran (590.7 mg, 1.62 mmol, 1 equiv.), Pd (PPh3) 4 (93.7 mg , 0.08 mmol, 0.05 equiv.) And K2C03 (448.35 mg, 3.24 mmol, 2 equiv.) In 5 mL of DME and 5 mL of H20. After cooling to room temperature, the mixture was charged to a column for purification. 616 mg of product G8475-146 were obtained with a yield of 75%. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (d, 7 = 6.8 Hz, 6 H) 1.9 (m,? H) 2.2 (s, 3 H) 3.2 (s, 3 H) 3.5 (d, 7 = 6.6 Hz, 1 H) 5.1 (s, 2 H) 7.0 (, 7 = 9.1 Hz, 2 H) 7.1 (m, 1 H) 7.2 (m, 1 H) 7.3 (m, 1 H) 7.4 (m, 1 H) 7.5 (d, 7 = 9.1 Hz, 2 H) 7.6 (d, 7 = 8.8 Hz, 2 H) 7.7 (m, 2 H). Step 5C: D-3-Methyl-2- [4 '- (3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid methyl ester (364 mg) in THF (10) was dissolved. mL) and MeOH (3 mL). 1 N LiOH (3 mL) was added and the mixture was stirred overnight. By normal treatment and column purification, D-3-methyl-2- [4 '- (3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid was obtained in quantitative yield. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, 7 = 30.3, 6..8 Hz, 6 H) 2.0 (m, 1 H) 2.2 (s, 3 H) 3.5 (d, 7 = 5.3 Hz, 1 H) 5.1 (s, 2 H) 7.1 (d, 7 = 9.1 Hz, 2 H) 7.1 (m, 1 H) 7.2 (m, 1 H) 7.3 (d, 7 = 8.3 Hz, 1 H) 7.5 (d, 7 = 8.3 Hz, 1 H) 7.5 (d, 7 = 9.1 Hz, 3 H) 7.6 (d, 7 = 8.6 Hz, 2 H) 7.8 (d, «7 = 8.8 Hz, 2 H).

Example 2B D-2- [4 '- (Benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, - D-2- [4' - (benzofuran-2-ylmethoxy acid ) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was prepared according to procedures similar to those of Example 2A. Step 5A: 2-Bromomethyl-benzofuran (1.5 g, 7.1 mmol, 1 equiv.), 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan- were dissolved in acetonitrile (50 mL). 2-yl) -phenol (1.56 g, 7.1 mmol, 1 equiv.), And potassium carbonate (1.96 g, 14.2 mmol, 2 equiv.) Under argon and heated at 70 ° C for 16 hours. After the usual work-up and flash column chromatography, 2- [4- (4,4,5,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran was obtained. Performance: 63%. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.1 (m, 3 H) 7.3 (, 1 H) 7.3 (m, 1 H) 7.6 (m, 4H). Step 5B: According to the procedures in Step 5B of Example 2A, 2- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl was coupled. ] -benzofuran with the d-2- [4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester to obtain the tert-butyl ester of D-2- [4'- (benzofuran-2- ilmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid. Performance: 33%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 8.3, 7.1 Hz, 6 H) 1.2 (s, 9 H) 1.9 (, 1 H) 3.5 (dd, 7 = 9.7, 6.2 Hz, 1 H) 5.3 (s, 2 H) 7.1 (s, 1 H) 7.2 (d, 7 = 8.6 Hz, 2 H) 7.3 (m, 1 H) 7.3 (, 1 H) 7.6 (dd, 7 = 8.2, 0.6 Hz, 1 H) 7.7 (m, 3 H) 7.8 (d, 7 = 3.3 Hz, 4 H) 8.1 (d, 7 = 9.9 Hz, 1 H). Step 5C: The D-2- [4'- (benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester (126 mg) was heated at 70 ° C for 16 hours. , 0.23 mmol, 1 equiv.), Cerium chloride heptahydrate (175 mg, 0.47 mmol, 2 equiv.) And potassium iodide (51 mg, 0.30 mmol, 1.3 equiv.) In acetonitrile (10 mL). After usual work-up and flash column chromatography, D-2- [4 '- (benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was obtained. Performance: 25%. NMR: 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 12.5, 6.7 Hz, 6 H) 2.0 (m, 1 H) 3.5 (dd, 7 = 9.2, 5.9 'Hz, 1 H) 5.3 (s, 2 H) 7. 1 (s, 1 H) 7.2 (d, 7 = 8.8 Hz, 2 H) 7.3 (dd, 7 = 8.1, 0.8 Hz, 1 H) 7.3 (, 1 H) 7.6 (d, 7 = 8.1 Hz, 1 H ) 7.7 (, 1 H) 7.7 (d, 7 = 8.8 Hz, 2 H) 7.8 (d, 4 H) 8.0 (d, 7 = 9.3 Hz, 1 H).

Example 2C D-3-Methyl-2- [4 '- (naphthalen-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4' - "(naphthalene -2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid, -was prepared according to procedures similar to those of Example 2A Step 5A: The alkylation of 2-bromomethyl-naphthalene with 4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol was carried out according to the procedures of Step 5A in Example 2A to give 4, 4, 5, 5-tetramethyl-2 - [4- (naphthalen-2-ylmethoxy) -phenyl] - [1,3,2] dioxaborlane with a yield of 85% 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, 7 = 8.6 Hz, 2 H) 7.5 (m, 2 H) 7.5 (dd, 7 = 8.3, 1.8 Hz, 1 H) 7.8 (d, 7 = 8.6 Hz, 2 H 7.9 (m, 4 H) Step 5B: The Suzuki coupling of 4,4,5,5-tetramethyl-2- [4- (naphthalen-2-ylmethoxy) -phenyl] - [1,3,2] - dioxaborolane with the methyl ester of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid was carried out according to the procedures of Step 5B in Example 2A to give the methyl ester of D-acid 3-methyl-2- ['- (naphthalen-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric in 44% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.9 (dd, 7 = 32.1, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.4 (s, 3 H) 3.8 (dd, 7 = 10.2, 5.2 Hz , 1 H) 5.1 (d, 7 = 10.1 Hz, 1 H) 5.3 (s, 2 H) 7.1 (d, "7 = 9.1 Hz, 2 H) 7.5 (m, 2 H) 7.6 (m, 3 H) 7.7 (d, 7 = 8.6 Hz, 2 H) 7.9 (m, 6 H). Step 5C: The hydrolysis of the methyl ester of D-3-methyl-2- [4 '- (naphthalen-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures of the Step 5C in Example 2A with a quantitative yield. 1 H-NMR (400 MHz, MeOD) d ppm 0.8 (dd, 7 = 32.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (d, 7 = 5.3 Hz, 1 H) 5.2 (s, 2 H) 7.1 (d, 7 = 8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (dd, 7 = 8.6, 1.8 Hz, 1 H) 7.5 (d, 7 = 8.8 Hz, 2 H) 7.6 (d, 7 = 8.8 Hz, 2 H) 7.8 (m, 5 H) 7.8 (s, 1 H).

Example 2D D-2- (4'-benzyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid The title compound, D-2- [4 '- (benzyloxy-biphenyl-4-sulfonylamino) -3-methyl acid -butyric, was prepared according to procedures similar to those of Example 2A. Step 5B: Suzuki coupling of 4-benzyloxyphenylboronic acid with D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester was carried out according to the procedures of Step 5B in Example 2A to give the tert-butyl ester of D-2- (4'-benzyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid in 73% yield. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, 7 = 29.7, 6.7 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (d, 7 = 5.8 Hz, 1 H) 5.0 (s, 2 H) 7.0 (d, 7 = 8.8 Hz, 2 H) 7.2 (t, "7 = 7.3 Hz, 1 H) 7.3 (m, 2 H) 7.4 (d, 7 = 6.8 Hz, 2 H ) 7.5 (d, 7 = 9.1 Hz, 2 H) 7.6 (d, 7 = 8.6 Hz, 2 H) 7.8 (d, 7 = 8.8 Hz, 2 H). Step 5C: D-2- ('-benzyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was prepared according to the procedures of Step 5C in Example 2A in quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 12.3, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, 7 = 9.3, 6.1 Hz, 1 H) 5.2 (s, 2 H) 7.1 (d, 7 = 9.1 Hz, 2 H) 7.4 (m, 3 H) 7.5 (m, 2 H) 7.7 (d, 7 = 8.8 Hz, 2 H) 7.8 (s, 4 H) 8.0 (d, 7 = 9.3 Hz, 1 H).

Example 2E D-3-methyl-2- [4 # - (quinolin-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4 '- (quinoline- 2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 2A. Step 5A: The alkylation of 2-chloromethyl-quinoline with 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol was carried out according to the procedures of Step 5A in Example 2A to give 2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -quinoline in 90% yield . 1 H NMR (400 MHz, MeOD) d ppm 1.2 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, 7 = 8.6 Hz, 2 H) 7.5 (m, 1 H) 7.6 (dd, 7 = 11.4, 8.6 Hz, 3 H) 7.7 (m, 1 H) 7.8 (dd, 7 = 8.1, 1.5 Hz, 1 H) 7.9 (d, "7 = 8.6 Hz, 1 H) 8.3 (d, 7 = 8.6 Hz, 1 H). Step 5B: The Suzuki coupling of 2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -quinoline with the tert-butyl ester of the D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid was carried out according to the procedures of Step 5B in Example 2A to give the tert-butyl ester of D-3-methyl-2- ['- (quinolin-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid in 70% yield. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, 7 = 29.8, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (d, 7 = 5.6 Hz, 1 H) 5.3 (s, 2 H) 7.1 (d, 7 = 8.8 Hz, 2 H) 7.5 (m, 3 H) 7.6 (t, «7 = 8.6 Hz, 3 H) 7.7 (m, 1 H) 7.8 (d, 7 = 8.8 Hz, 2 H) 7.9 (dd, 7 = 8.2, 0.9 Hz, 1 H) 8.0 (m, 1 H) 8.3 (d, 7 = 8.8 Hz, 1 H). Step 5C: The tert-butyl ester removal was performed according to the procedures of Step 5C in Example 2A with a quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 12.5, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, 7 = 9.3, 6.1 Hz, 1 H) 5.5 (s, 2 H) 7.2 (d, 7 = 8.8 Hz, 2 H) 7.7 (m, 1 H) 7.7 (dd, 7 = 8.7, 1.9 Hz, 3 H) 7.8 (s, 5 H) 8.0 (m, 3 H) 8.5 (d, 7 = 8.6 Hz, 1 H).

Example 2F D-3-Methyl-2- [4 '- (2-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4' - (2- nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 2A.

Step 5A: The alkylation of l-bromomethyl-2-nitro-benzene with 4- (4, 4, 5, 5-tetramethyl- [1,3, 2] dioxaborolan-2-yl) -phenol was carried out according to the procedures of Step 5A in Example 2A to give 4,4,5,5-tetramethyl-2- [4- (2-nitro-benzyloxy) -phenyl] - [1,3,2] -dioxaborolane with a 62% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.3 (s, 12 H) 5.5 (s, 2 H) 7.0 (d, 7 = 8.6 Hz, 2 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.8 (d, 7 = 8.6 Hz, 2 H) 7.9 (dd, 7 = 7.8, 1.0 Hz, 1 H) 8.2 (dd, 7 = 8.1, 1.3 Hz, 1 H). Step 5B: The Suzuki coupling of 4,4,5,5-tetramethyl-2- [4- (2-nitro-benzyloxy) phenyl] - [1,2,] -dioxaborlane with the tert-butyl ester of acid D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric was carried out according to the procedures of Step 5B for 2A to give the tert-butyl ester of D-3-methyl-2- [ 4'- (2-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric with a yield of 20%. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, 7 = 30.1, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (, 1 H) 3.5 (d, 7 = 5.6 Hz, 1 H) 5.4 (s, 2 H) 7.0 (d, 7 = 8.8 Hz, 2 H) 7.5 (m, 1 H) 7.5 (d, .7 = 8.8 Hz, 2 H) 7.6 (m, 3 H) 7.8 (d, 7 = 8.6 Hz, 3 H) 8.1 (dd, 7 = 8.1, 1.3 Hz, 1 H). Step 5C: The tert-butyl ester removal was performed according to the procedures of Step 5C in Example 2A with a quantitative yield. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, J = 24.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3. 6 (d, J = 5.8 Hz, 1 H) 5.4 (s, 2 H) 7.0 (d, J = 8.6 Hz, 2 H) 7.5 (t, J = 7.7 Hz, 1 H) 7.6 (d, J = 8.8 Hz, 2 H) 7.7 (m, 3 H) 7.8 (m, 3 H) 8.1 (d, J = 9.6 Hz, 1 H).

Example 2G D-2- [4 / - (2-chloro-benzyloxy) -biphenyl-4-sulfonylamino] -3-eti-butyric acid The title compound, D-2- ['- (2-chloro-benzyloxy) - biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 2A. Step 5A: The coupling of 2-chloro-benzyl bromide with 4-hydroxyphenyl-boronic ester to give 2- [4- (2-chloro-benzyloxy) phenyl] -4,4,5,5-tetramethyl- [1 , 3,2] -dioxaborolane was performed according to the procedures of Step 5A in Example 2A. Performance: 85%. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.3 (s, 12 H) 5.2 (s, 2 H) 7.0 (d, J = 8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.6 (d, J = 8.8 Hz, 2 H). Step 5B: The coupling of 2- [4- (2-chloro-benzyloxy) -phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborlane with the methyl ester of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid to obtain the methyl ester of the acid. D-2- [4 '- (2-chloro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed according to the procedures of Step 5B in Example 2A. Performance: 73%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 15.4, 6.6 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J = 9.3, 7.1 Hz, 1 H) 5.2 (s, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J = 8.8 Hz, 2 H ) 7.8 (d, J = 8.6 Hz, 2 H) 7.8 (m, 2 H) 8.3 (d, J = 9.3 Hz, 1 H). Step 5C: The hydrolysis of D-2- ['- (2-chloro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester to give D-2- [4' - ( 2-chloro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was carried out according to the procedures of Step 5C in Example 2A. Performance: 55%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.2, 5.9 Hz, 1 H) 5.2 (s, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.4 (, 2 H) 7.5 (m, 1 H), 7.6 (m, 1 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (s, 4 H) 8.0 (d, J = 9.3 Hz, 1 H) 12.6 (s, 1 H). Example 2H D-2- [4"- (2-Fluoro-6-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-2- [4 '- (2 -fluoro-6-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 2A. Step 5A: The coupling of 2-fluoro-6-nitrobenzyl bromide with the boronic ester of 4-hydroxyphenyl to obtain 2- [4- (2-fluoro-6-nitro-benzyloxy) -phenyl] -4, 5 , 5-tetramethyl- [1, 3, 2] dioxaborlane was performed according to the procedures of Step 5A in Example 2A. Yield: 95%. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.3 (s, 12 H) 5.3 (d, J = 1.3 Hz, 2 H) 7.0 (d, J = 8.8 Hz, 2 H) 7.6 (d, J = 8.8 Hz, 2 H) 7.7 (m, 2 H) 7.9 (m, 1 H). Step 5B: The coupling of 2- [4- (2-fluoro-6-nitro-benzyloxy) -phenyl] -4,5,5-tetramethyl- [1,3,2] -dioxaborlane with the methyl ester of acid D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid to obtain the methyl ester of D-2- [4'- (2-fluoro-6-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed < according to the procedures of Step 5B in Example 2A. Performance: 49%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 15.2, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J = 9.5, 7.2 Hz , 1 H) 5.4 (d, J = 1.3 Hz, 2 H) 7.1 (d, J = 8.8 Hz, 2 H) 7.8 (, 6 H) 7.8 (m, 2 H) 7.9 (m, 1 H) 8.3 ( , J = 9.3 Hz, 1 H).

Step 5C: Hydrolysis of D-2- [4 '- (2-fluoro-6-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester to give D-2- acid [4'- (2-Fluoro-6-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed according to the procedures of Step 5C in Example 2A, except that the purification was carried out through preparative CLAR. Performance: 30%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.2, 5.9 Hz, 1 H) 5.4 (d , J = 1. 3 Hz, 2 H) 7.1 (d, J = 8.8 Hz, 2 H) 7.7 (m, 4 H) 7.8 (d, J = 0.8 Hzr 4 H) 7.9 (m, 2 H) 8.0 ( d, J = 9.1 Hz, 1 H).

Example 21 D-3-Methyl-2- [4'- (quinolin-4-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4'- (quinoline- 4-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 2A. Step 5A: The coupling of 4-chloromethyl-quinoline with the boronic ester of 4-hydroxyphenyl for obtain 4- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -quinoline was carried out according to the procedures of Step 5A in Example 2A. Performance: 62%. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.3 (s, 12 H) 5.7 (d, J = 0.5 Hz, 2 H) 7.1 (d, J = 8.8 Hz, 2 H) 7.7 (m, 4 H) 7.8 (, 1 H) 8.1 (dd, J = 8.5, 0.9 Hz, 1 H) 8.2 (d, J = 8.3 Hz, 1 H) 8.9 (d, J = 4.5 Hz, 1 H). Step 5B: The coupling of 4- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -quinoline with the methyl ester of D-2 acid - (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid to obtain the methyl ester of D-3-methyl-2- [4 '- (quinolin-4-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid is performed in accordance with the procedures of Step 5B in Example 2A. Yield: 47%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 15.2, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J = 9.3, 7.1 Hz , 1 H) 5.8 (s, 2 H) 7.3 (d, J = 8.8 Hz, 2 H) 7.8 (m, 9 H) 8.1 (d, J = 8.6 Hz, 1 H) 8.2 (d, J = 8.6 Hz , 1 H) 8.3 (d, J = 9.3 Hz, 1 H) 8.9 (d, J = 4.3 Hz, 1 H). Step 5C: The hydrolysis of D-3-methyl-2- (4'- (quinolin-4-ylmethoxy) -biphenyl-4-sulfonylamino) -butyric acid methyl ester to give the acid D-3-methyl-2- [4 '- (quinolin-4-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric was carried out according to the procedures of Step 5C in Example 2A. Yield: 54%. 1 H NMR (400 MHz, DMSO- D6) d ppm 0.8 (dd, J = 43.6, 6.9 Hz, 6 H) 2.0 (m, 1 H) 3.0 (d, J = 3.0 Hz, 1 H) 5.8 (d, 2 H) 7.3 (d, J = 8.8 Hz, 2 H) 7.7 (, 4 H) 7.8 (m, 5 H) 8.1 (, 1 H) 8.2 (dd, J = 8.3, 0.8 Hz, 1 H) 8.9 (d, J = 4.5 Hz, 1 H ).

Example 2J D-2- [47- (2-Sianomethyl-bensyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-3-methyl-2- ['- (quinolin-4-) acid Imethoxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 2A. Step 5C: The hydrolysis of the methyl ester of D-2- [4 '- (2-cyanomethyl-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid (prepared according to step 3) to give the D-2- [4 '- (2-cyanomethyl-benzyloxy) -bipheni-4-sulfonylamino] -3-methyl-butyric acid was made according to the procedures of Step 5C in Example 2A. Preparative HPLC was used for purification. Performance: 75%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 23.7, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.8 (d, J = 6.6 Hz, 1 H) 4.1 (s, 2 H) 5.2 (s, 2 H) 7.2 (d, J = 9.1 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (, 1 H) ) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (d, J = 2.0 Hz, 4 H).

Examples 2K, 2L, 211, 2N, 20, 2P, 2Q, 2R were prepared based on Reaction Scheme 6. Example 2K D-3-Methyl-2- [4'- (2-methyl-quinolin-4-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid Step: A mixture of 4-chloromethyl-2-methyl-quinoline (165 mg) , 0.86 mmol, 1 equiv.), D-2- (4 '-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (314 mg, 0.86 mmol, 1 equiv.) And K2C03 (270 mg, 1.13 mmol, 1.3 equiv.) in 8 mL of DMF was heated under nitrogen at 90 ° C for 12 hours. After the usual treatment and column chromatography (30-60% EtOAc in hexane), the methyl ester of D-3-methyl-2- [4 '- (2-methyl-quinolin-4-ylmethoxy) was obtained. -biphenyl-4-sulfonylamino] -butyric with a yield of 34% (150 mg). 1 H NMR (400 MHz, DMS0-D6) d ppm 0. 8 (dd, 7 = 15.0, 6.7 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 3.3 (s, 3 H) 3.6 (dd, "7 = 9.2, 7.2 Hz, 1 H) 5.7 (s, 2 H) 7.3 (d, 7 = 8.8 Hz, 2 H) 7.6 (m, 2 H) 7.8 (m, 4 H) 7.8 (m, 2 H) 8.0 (d, 7 = 9.3 Hz, 1 H) 8.1 (d, 7 = 8.3 Hz, 1 H) 8.1 (none, 1 H) 8.3 (d, 7 = 9.6 Hz, 1 H). Step 6B: D-3-Methyl-2- [4 '- (2-methyl-quinolin-4-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid methyl ester (150 mg) in THF (8 mg) was dissolved. mL) and MeOH (4 mL) and 1 N LiOH (3 mL, 3 mmol) was added. The resulting solution was stirred at room temperature overnight. It was determined by means of the CCD if the reaction was over. The solvents were removed and the usual treatment and column chromatography allowed to obtain 148 mg with a quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 31.8, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.2 (s, 1 H) 5.7 (s, 2 H) 7.3 (d, J = 8.8 Hz, 2 H) 7.6 (m, 2 H) 7.8 (m, 7 H) 8.0 (d, J = 7.6 Hz, 1 H) 8.1 (d) , J = 6.8 Hz, 1 H).

Example 2L D-2- [4'- (3-siane-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyroic acid The title compound, D-2- [4 '- (3-cyano-benzyloxy)] -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, prepared according to procedures similar to those of Example 2. Step 6A: The coupling of a-bromo-m-tolunitrile with the methyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the methyl ester of D-acid 2- [4 '- (3-Cyano-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed according to the procedures of Step 6A in Example 2K. Performance: 25%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 14.9, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J = 9.5, 7.2 Hz , 1 H) 5.3 (s, 2 H) 7.2 (d, J = 9.1 Hz, 2 H) 7.6 (t, J = 8.0 Hz, 1 H) 7.7 (m, 4 H) 7.8 (m, 4 H) 8.0 (s, 1 H) 8.3 (d, J = 9.3 Hz, 1 H). Step 6B: Hydrolysis of D-2- ['- (3-cyano-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester to give D-2- [4' - ( 3-cyano-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was carried out according to the procedures of Step 6B in Example 2K. Performance: 24%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 26.0, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 1 H) 5.2 (s, 2 H) 7.2 (d , J = 8.8 Hz, 2 H) 7.6 (d, J = 7.6 Hz, 1 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (, 6 H) 8.0 (s, 1 H).

Example 2M D-3-Methyl-2- [4 '- (naphthalen-1-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4'- (naphthalene- 1-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 2K. Step 6A: The alkylation of 1-chloromethyl-naphthalene with the methyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out in accordance with the procedures of Step 6A in Example 2K to give the methyl ester of D-3-methyl-2- [4 '- (naphthalen-1-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid in 34% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.9 (dd, 7 = 32.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.4 (s, 3 H) 3.8 (dd, 7 = 10.1, 5.1 Hz , 1 H) 5.1 (d, 7 = 10.1 Hz, 1 H) 5.6 (s, 2 H) 7.2 (d, 7 = 8.8 Hz, 2 H) 7.5 (dd, 7 = 8.2, 6.9 Hz, 1 H) 7.6 (m, 4 H) 7.6 (d, 7 = 6.6 Hz, 1 H) 7.-7 (d, 7 = 8.6 Hz, 2 H) 7.9 (m, 4 H) 8.1 (dd, 7 = 8.5, 1.4 Hz , 1 HOUR) . Step 6B: The hydrolysis of D-3-methyl-2- [4 '- (naphthalen-1-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid methyl ester was carried out in accordance with procedures of Step 6B in Example 2K with a quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0. 8 (dd, J = 15.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.5 (s, 1 H) 5.6 (s, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.6 (m, 3 H) 7.7 (m, 3 H) 7.8 (d, J = 2.8 Hz, 4 H) 8.0 (m, 3 H) 8.1 (m , 1 HOUR) .

Example 2N D-2- [4 # - (2-Fluoro-bensyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-2- [4 '- (2-fluoro-benzyloxy)] -biphenyl-sulphonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 2K. Step 6A: The coupling of 2-fluorobenzyl bromide with the methyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the methyl ester of D-2- acid [4'- (2-Fluorobenzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed according to the procedures of Step 6A in Example 2K. Yield: 47%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 15.2, 6.8 Hz, 6 H) 1.9 (dd, 1 H) 3.3 (s, 3 H) 3. 6 (dd, J = 9.3, 7.1 Hz, 1 H) 5.2 (s, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.3 (m, 2 H) 7.4 (m, 1 H) 7.6 (m , 1 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 8.3 (d, J = 9.3 Hz, 1 H). Step 6B: Hydrolysis of D-2- [4'- (2-fluoro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester to give D-2- acid [4'- (2-Fluoro-benzyloxy) -biphenyl-sulphonylamino] -3-methyl-butyric acid was made according to the procedures of Step 6B in Example 2K. Performance: 67%. 1 H-NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 43.7, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.9 (d, J = 2.8 Hz, 1 H) 5.2 (s, 2 H) 6.8 (s, 1 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.3 (m, 2 H) 7.4 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J = 8.8 Hz , 2 H) 7.8 (s, 4 H).

Example 20 D-2- [4'- (2,3-difluoro-benzyloxy) -biphenyl-4-sulfonyl-amino] -3-methyl-butyric acid The title compound, D-2- [4'- (2, 3-difluoro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 2K. Stage 6A: The coupling of 2,3- bromide difluorobenzyl with the methyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the methyl ester of D-2- (4 '- (2,3-difluorobenzyloxy) ) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was performed according to the procedures of Step 6A in Example 2K, but at room temperature for 16 hours Yield: 42% 1 H NMR (400 MHz, DMSO) -D6) d ppm (s, 2 H) 7. 2 (d, J = 8.8 Hz, 2 H) 7.3 (m, 1 H) 7.5 (, 2 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 8.3 (d, J = 9.3 Hz, 1 H ). Step 6B: Hydrolysis of D-2- [4'- (2,3-difluoro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester to give D-2- acid [4] '- (2,3-difluoro-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was carried out according to the procedures of Step 6B in Example 2K. Performance: 63%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.3, 6.1 Hz, 1 H) 5.3 (s) , 2 H) 7.2 (d, J = 9.1 Hz, 2 H) 7. 3 (m, 1 H) 7.5 (m, 2 H) 7.7 (d, J = 9.1 Hz, 2 H) 7.8 (d, J = 1.8 Hz, 4 H) 8.0 (d, J = 9.3 Hz, 1 H) 12.6 (s, 1 H).

Example 2P D-3-Methyl-2- [4 '- (2-methyl-3-nitro-bensyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4'] acid - (2-methyl-3-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 2K. Step 6A: Coupling of 2-methyl-3-nitrobenzyl bromide with D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain the methyl ester of acid D-3-methyl-2- [4 '- (2-methyl-3-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric was performed according to the procedures of Step 6A in Example 2K, but a room temperature for 16 hours. The product was further purified by recrystallization (EtOAc / hexane). Yield: 26%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 15.2, 6.8 Hz, 6 H) 1.9 (m, 1 H) 2.4 (s, 3 H) 3.3 (s, 3 H) 3.6 (m , 1 H) 5.3 (s, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.5 (t, J = 7.8 Hz, 1 H) 7.8 (m, 8 H) 8.3 (d, J = 9.3 Hz , 1 HOUR) . Step 6B: Hydrolysis of D-3-methyl-2- [4 '- (2-methyl-3-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric acid methyl ester to give D-3 acid Methyl-2- [4 '- (2-methyl-3-nitro-benzyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures of Step 6B in Example 2K. Performance: 33%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6 H) 1.9 (dd, 1 H) 3.5 (dd, «7 = 9.3, 6.1 Hz, 1 H) 5.3 (s, 2 H) 7.2 (d, J = 9.1 Hz, 2 H) 7.3 (m, 1 H) 7.5 (m, 2 H) 7.7 (d, J = 9.1 Hz, 2 H) 7.8 (d, J = 1.8 Hz, 4 H) 8.0 (d, J = 9.3 Hz, 1 H) 12.6 (s, 1 H).

Example 2Q D-2- [47- (2-iodo-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-2- [4 '- (2-iodo-benzyloxy) - biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 2K. Step 6A: The alkylation of l-chloromethyl-2-iodo-benzene with the methyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out in accordance with the procedures of Step 6A in Example 2K to give the methyl ester of D-2- [4 '- (2-iodo-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid with a yield of 55%. %. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 15.3, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, "7 = 9.5, 7.2 Hz, 1 H) 7.1 (m, 3 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (m, 4 H) 7.8 (, 2 H) 7.9 (dd, 7 = 8.0, 1.1 Hz, 1 H) 8.3 (d, 7 = 9.3 Hz, 1 H).

Step 6B: Hydrolysis of D-2- [4'- (2-iodo-benzyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester was carried out according to the procedures of Step 6A in Example 2K with a quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.3, 6.1 Hz, 1 H) 5.1 (s, 2 H) 7.1 (d, J = 8.8 Hz, 2 H) 7.5 (m, 1 H) 7.6 (d, J = 7.6 Hz, 1 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (s, 4 H) 7.9 (dd, J = 7.8, 1.3 Hz, 1 H) 8.0 (d, J = 9.3 Hz, 1 H).

Example 2R D-2- [4'- (Benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-2- [4'- (benzothiazol-2-ylmethoxy) acid -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 2K. Step 6A: The alkylation of 2-bromomethyl-benzothiazole with the methyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to the procedures of Step 6A in Example 2K to give the methyl ester of D-2- [4 '- (benzothiazole- 2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric with a yield of 20%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 15.0, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, 7 = 9.5, 7.2 Hz, 1 H) 5.7 (s) , 2 H) 7.2 (m, 7 = 8.8 Hz, 2 H) 7.5 (, 1 H) 7.6 (m, 1 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 8.0 (d, 7 = 7.3 Hz, 1 H) 8.1 (d, 7 = 7.8 Hz, 1 H) 8.3 (d, 7 = 9.6 Hz, 1 H). Step 6B: The hydrolysis of D-2- [4'- (benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester was carried out according to the procedures of the Step 6B in Example 2K with a quantitative yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.3, 5.8 Hz, 1 H) 5.7 (s, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (d, J = 2.3 Hz, 4 H) 8.0 (dd, J = 9.1, 4.5 Hz, 2 H) 8.1 (d, J = 8.6 Hz, 1 H).

Examples 2S, 2T, 2U, 2V, 2W, 2X, 2Y were prepared based on Reaction Scheme 6B. Example 2S Acid 2- [47- (2,3-di-idro-benzo [1,4] dioxin-6-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid XH NMR (400 MHz, DMSO): d 0.778 (d, 3H), 0.845 (d, 3H), 1.99 (dd, 1H), 3.17 (broad s, 1H), 4.24 (s, 4H), 5.04 (s, 2H), 6.91 (, 3H), 7.10 ( d, 2H), 7.68 (d, 2H); ES + m / z 496.0 (M-H); HRMS (C26H27N07S): calculated; 520.14004; found; 520.13995 (M + Na). Example 2T 3-Methyl-2- [4'- (pyridin-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid XK-NMR (400 MHz, DMSO): d 0.800 (d, 3H), 0.803 (d, 3H), 1.94 (m, 1H), 3.51 (broad s, 1H), 5.25 (s, 2H), 7.15 (d, 2H), 7.36 (m, 1H), 7.54 (d, 2H), 7.71 (d, 2H), 7.83 (m, 3H), 8.59 (d, 2H); ES + m / z 441.2 (M + H); HRMS (C23H24N205S): calculated; 440.14004; found; 440.14037 (M + H). Example 2U 3-Methyl-2- [4 '- (pyridin-3-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid NMR aH (400 MHz, DMSO): d 0.800 (d, 3H), 0.803 (d, 3H ), 1.95 (m, 1H), 3.49 (broad s, 1H), 5.23 (s, 2H), 7.16 (d, 2H), 7.45 (m, 1H), 7.71 (d, 2H), 7.80 (m, 3H) ), 7.90 (d, 2H), 8.56 (d, 1H), 8.70 (broad s, 1H); ES + m / z 441.1 (M + H); HRMS (C23H24N205S): calculated; 441.14787; found; 441.14617 (M + H).

Example 2V 2- [4'- (lH-Benzoimidazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyroxy acid NMR XH (400 MHz, DMSO): d 0.802 (d, 3H), 0.833 (d, 3H), 1.94 (, 1H), 3.54 (m, 1H), 5.51 (s, 2H), 6.88 (d, 2H), 7.24 (d, 1H), 7.34 (m, 1H), 7.58 (d, 2H) , 7.66 (m, 1H), 7.78 (m, 4H), 8.03 (d, 1H); ES + m / z 480.1 (M + H); HRMS (C25H25N305S): calculated; 480.15877; found; 480.15787 (M + H).

Example 2W 2- [4'- (3-Methoxy-bensyloxy) -b-phenyl-4-sulfonylamino] -3-methyl-butyric acid XH-NMR (400 MHz, DMSO): d 0.804 (d, 3H), 0.835 (d, 3H ), 1.95 (m, 1H), 3.54 (, 1H), 3.77 (s, 3H), 5.15 (s, 2H), 6.89 (m, 2H), 7.04 (m, 2H), 7.13 (m, 2H), 7.32 (m, 1H), 7.58 (d, 1H), 7.69 (d, 2H), 7.80 (m, 1H), 8.01 (d, 1H); ES + m / z 470.1 (M + H); HRMS (C25H27N06S): calculated; 470.16319; found; 470.16183 (M + H). Example 2X 2- [4 '- (4-Methoxy-benzyloxy) -bxphenyl-4-sulfonylamino] -3-methyl-butyric acid XH NMR (400 MHz, DMSO): d 0.805 (d, 3H), 0.836 (d, 3H), 1.94 (m, 1H), 3.54 (m, 1H), 3.76 (s, 3H), 5.09 (s, 2H), 6. 96 (d, - 2H), 7.12 (d, 2H), 7.40 (d, 2H), 7.69 (d, 2H), 7.80 (s, 3H), 8.01 (d, 1H); ES + m / z 468.2 (M-H); HRMS (C25H27N06S): calculated; 470.16319; found; 470.16248 (M + H). Example 2Y (Abs) 2- [4'- (3,5-Dimethoxy-bensyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid or XH-NMR (400 MHz, DMSO): d 0.804 (d, 3H), 0.835 (d , 3H), 1.95 (m, 1H), 3.55 (m, 1H), 3.75 (s, 6H), 5.11 (s, 2H), 6. 45 (broad s, 1H), 6.62 (broad s, 2H), 7.12 (d, 2H), 7.70 (d, 2H), 7.80 (s, 3H), 8.01 (d, 1H); ES + m / z 498.2 (M-H); HRMS (C26H29N07S): calculated; 500.17375; found; 5 500.17223 (M + H). Example 3A was prepared based on Reaction Scheme 7. Example 3A 3-Methyl-2- (4'-vinyl-biphenyl-4-sulfonylamino) -butyric acid tert-butyl ester Step 7A: 4-Vinylphenylboronic acid 5 (1.89, 12.7 mmol, 1 equiv.) And the ester were dissolved tert-butyl 2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid (5 g, 12.7 mmol, 1 equiv.) in ethylene glycol dimethyl ether (180 mL) and Pd (Ph3) (736.0 mg, 0.64 mmol) was added. and stirred at room temperature for 20 minutes. Then an aqueous solution of KC03 (3.52 g, 25.5 mmol, 2 equiv.) Was added to the reaction mixture and heated to reflux overnight. After cooling to room temperature, the solvent was evaporated and the residue was partitioned between EtOAc and H0. The organic layer was washed with brine, dried over MgSO4 and purified by column chromatography (silica gel, 10% EtOAc / hexane), to yield 808 mg of G9058-169 in 15.2% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.95 (d, 7 = 6.82 Hz, 3 H) 1.12 (s, 9 H) 1.99 (m, 1 H) 3.59 (dd, 7 = 9.85, 4.55 Hz, 1 H) 5.06 (d, 7 = 10.11 Hz, 1 H) 5.25 (d, 7 = 10.86 Hz, 1 H) 5.75 (d, 7 = 16.93 Hz, 1 H) 6.70 (m, 1 H) 7.45 (m, 4 H) 7.61 (d, 7 = 8.84 Hz, 2 H) 7.82 (d, 7 = 8.84 Hz, 2 H). Step 7B: 3-Methyl-2- (4'-vinyl-biphenyl-4-sulfonylamino) -butyl acid tert-butyl ester was placed (300 mg, 0.72 mmol, 1.2 equiv.), Pd2 (dba) 3 (11 mg, 0.012 mmol, 0.02 equiv.), Tris-t-butyl phosphonium tetrafluoroborate (14 mg, 0.048 mmol, 0.08 equiv.) And dioxane (1.5 mL), in a microwave tube under N. 2-Bromo-l-benzofuran (118 mg, 0.6 mmol, 1 equiv.) And dicyclohexyl- were injected. methyl-amine (0.15 mL, 0.72 mmol, 1.2 equiv.). Then, the mixture was irradiated in a microwave reactor at 180 ° C for 30 minutes. The mixture was partitioned between EtOAc and H0 and the organic layer was dried over MgSO4. The crude residue was purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 80 mg of the 2- [4 '- (2-benzofuran-2-yl-vinyl) tert-butyl ester) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid (G9058-171) with a yield of 25%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.96 (d, 7 = 6.82 Hz, 3 H) 1.14 (s, 9 H) 2.01 (m, 1 H) 3.60 (dd, 7 = 9.98, 4.42 Hz, 1 H) 5.07 (d, 7 = 9.85 Hz, 1 H) 6.66 (s, 1 H) 7.01 (d, 7 = 15.92 Hz, 1 H) 7.14 (m, 1 H) 7. 25 (m, 2 H) 7.42 (d, 7 = 8.08 Hz, 1 H) 7.52 (m, 5 H) 7.64 (d, 7 = 8.59 Hz, 2 H) 7.84 (d, 7 = 8.59 Hz, 2 H). Step 7C: TFA (1.5 mL) was added to the 2- [4 '- (2-benzofuran-2-yl-vinyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert -butyl ester (80 mg ) in dichloroethane (4.5 mL) and stirred at room temperature. The reaction was completed after 3 hours, as determined by means of CCD. After removing the solvent, the crude residue was purified by column chromatography (5-10% MeOH / CH 2 Cl 2) to give 22 mg of 2- [4 '- (2-benzofuran-2-yl-vinyl) - biphenyl-4-sulfonylamino] -3-methyl-butyric G9058-172 with a yield of 30.7%. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.79 (d, 7 = 6.82 Hz, 3 H) 0.86 (d, 7 = 6.82 Hz, 3 H) 1.23 (s, 2 H) 2.02 (m, 1 H) 3.18 (, 1 H) 7.01 (s, 1 H) 7.25 (t, 7 = 7.07 Hz , 1 H) 7.33 (m, 1 H) 7.38 (d, 7 = 14.65 Hz, 1 H) 7.59 (d, 7 = 8.08 Hz, 1 H) 7.64 (d, 7 = 8.08 Hz, 1 H) 7.79 (d , 7 = 6.57 Hz, 4 H) 7.83 (d, 7 = 8.59 Hz, 2 H) 7.90 (m, 2 H).

Example 4A was prepared based on Reaction Scheme 8. Example 4A N- ( {4 - [2-4-Methylisoquinolin-3-yl) ethyl] -l, 1-biphenyl-4-yl} sulfonyl) -D-valine Step 8A: 2- (4-Bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester (10.65 g, 27.1 mmol, 1 equiv.), 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenol (5.97 g, 27.1 mmol, 1 equiv.), Pd (PPh3) (1.57 g, 1.4 mmol, 0.05 equiv.) In ether Ethylene glycol dimethyl (210 mL) under an N2 atmosphere and stirred at room temperature for 30 minutes. Then K2C03 (7.5 g, 54.3 mmol, 2 equiv.) In H20 (70 mL) was introduced into the reaction mixture and heated to reflux overnight. It was determined by means of the CCD if the reaction was over. The solvent was removed using a rotary evaporator and the The residue was partitioned between dichloromethane and brine. The organic layer was dried over MgSO, the solvent was removed and the crude product was purified by column chromatography (silica gel, 30% EtOAc / n-hexane) to give 7.1 g of the tert-butyl ester of 2-acid. (4 '-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric with a 65% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.79 (d, 7 = 6.82 Hz, 3 H) 0.95 (d, 7 = 6.57 Hz, 3 H) 1.13 (s, 9 H) 1.51 (s, 1 H) 1.99 (m, 1 H) 3.59 (dd, 7 = 10.11, 4.55 Hz, 1 H) 5.06 (d, 7 = 9.85 Hz, 1 H) 6.86 (d, 7 = 8.84 Hz, 2 H) 7.38 (d, 7 = 8.84 Hz, 2 H) 7.55 (d, 7 = 8.59 Hz, 2 H) 7.79 (d, 7 = 8.59 Hz, 2 H). Step 8B: 2- (4'-Hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester was dissolved (330 mg, 0.81 mmol) in 20 mL of dry methylene chloride and cooled to 0 ° C. NaH (83 mg, 60% in oil, 2.0 mmol, 2.5 equiv.) Was added under N2 and the mixture was stirred for 15 minutes. Triflic anhydride (251 mg, 0.89 mmol, 1.1 equiv.) Was injected and the mixture allowed to warm to room temperature for 1 hour. The CCD indicated that the reaction had been completed. The reaction mixture was diluted with methylene chloride and neutralized with 1 N HCl. The mixture was washed with water and brine and dried over MgSO4. 314 mg of the desired product was obtained from a usual column chromatography (40% EtOAc / hexane) in a yield of 72%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, 7 = 6.82 Hz, 3 H) 1.03 (d., 7 = 6.82 Hz, 3 H) 1.21 (s, 9 H) 2.01-2.20 (m, 1 H) 3.68 (dd, 7 = 9.85, 4.55 Hz, 1 H ) 5.18 (d, 7 = 10.11 Hz, 1 H) 7.39 (d, 7 = 8.84 Hz, 2 H) 7.64 (dd, 7 = 13.52, 8.72 Hz, 4 H) 7.93 (d, 7 = 8.59 Hz, 2 H ). Stage: The reaction tube was filled with triflate (300 mg, 0.56 mmol) from Step 8B, lithium chloride (24 mg, 0.56 mmol, 1 equiv.), Cul (11 mg, 0.05 mmol, 10%) and PdCl 2 (PPh 3) 2 (19.6 mg, 0.028). mmol, 5%) under nitrogen followed by the addition of DMF (5 mL). T-butyldimethylacetylene (235 mg, 1.68 mmol, 3 equiv.) And diethylamine (409 mg, 5.6 mmol, 10 equiv.) Were injected. The tube was irradiated in a microwave reactor at 125 ° C for 10 minutes. The starting materials were consumed, as determined by means of the CCD. The mixture was partitioned between ethyl acetate and water. The organic phase was collected and subjected to the usual workup process and column chromatography to give 270 mg of the desired acetylenic product, N- [(4 '-. {[[Tert -butyl (dimethyl) silyl] ethynyl}. -l, 1'-biphenyl-1-yl) -sulfonyl] -D-valinate of tere-butyl, with a yield of 92%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.00 (s, 6 H) 0.66 (d, 7 = 6.82 Hz, 3 H) 0.81 (s, 9 H) 0.82 (d, 7 = 6.82 Hz, 3 H) 0.98 (s, 9 H) 1. 75-1.98 (m, 1 H) 3.46 (dd, 7 = 9.85, 4.55 Hz, 1 H) 4.93 (d, 7 = 9.85 Hz, 1 H) 7.27-7.32 (m, 2 H) 7.33-7.39 (m, 2 H) 7.47 (d, 7 = 8.84 Hz, 2 H) 7.70 (d, 7 = 8.84 Hz, 2 H). Stage 8D: The N- [(4 '- { [Tere- butyl (dimethyl) silyl] ethynyl} -l, 1'-biphenyl-4-yl) -sulfonyl] -D-valinate from tere-butyl (600 mg, 1.14 mmol) in THF (8 mL) and TBAF (1.7 mL, 1 M, 1.7 mmol, 1.5 equiv.). The solution was stirred at room temperature for half an hour to complete the reaction. The solvent was removed and the residue was purified with column chromatography (silica gel, 20% EtOAc / hexane). 469 mg of the product, N- [(4'-ethynyl, 1-biphenyl-4-yl) sulfonyl] -D-valinate of tere-butyl, were isolated in a quantitative yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.86 (d, 7 = 6.82 Hz, 2 H) 1.02 (d, 7 = 6.82 Hz, 2 H) 1.20 (s, 9 H) 1.88-2.29 (m, 1 H) 3.17 (s, 1 H) 3.67 (dd, 7 = 9.85, 4.55 Hz, 1 H) 5.14 (d, 7 = 10.11 Hz, 1 H) 7.52 (d, 7 = 8.59 Hz, 2 H) 7.56-7.62 (m, 2 H) 7.67 (d, 7 = 8.84 Hz, 2 H) 7.91 (d, 7 = 8.59 Hz, 2 H). Stage 8E: Placed in a low reaction tube N2 the N- [(4'-etiyl-1,1'-biphenyl-4-yl) sulfonyl] -D-valinate tere-butyl ester (117 mg, 0.28 mmol), 2-chloro-3-methylisoquinoline (60 mg, 0.34 mmol, 1.2 equiv.), Cul (5.3 mg, 0.028 mmol, al %) and PdC12 (PPh3) 2 (9.8 mg, 0.014 mmol, 5%) and DMF (4 mL) and 10 equiv. of diethylamine. The mixture was irradiated at 125 ° C for 10 minutes. The reaction was completed as determined by LC-MS. The mixture was diluted with EtOAc and washed 3 times with water, once with brine and then dried over MgSO4. Column chromatography (silica gel, 30% EtOAc / hexane) gave 120 mg of the desired product, N- (. {4 '- [(4-methylisoquinolin-3-yl) ethynyl] -1,1' -biphenyl-4-yl.} Sulfonyl) -D-valinate tere-butyl, with a yield of 76%. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.86 (dd, 7 = 8.59, 6.82 Hz, 6 H) 1.17 (s, 9 H) 1.94 (m, 1 H) 2.67 (s, 3 H) 3.50 (dd) , 7 = 10.61, 7.33 Hz, 1 H) 7.62 (t, 7 = 7.45 Hz, 1 H) 7.69-7.78 (m, 1 H) 7.80-7.85 (, 4 H) 7.87 (d, 7 = 8.59 Hz, 2 H) 7.90-7.97 (m, 2 H) 8.00 (d, 7 = 8.59 Hz, 1 H) 8.20 (d, 7 = 9.60 Hz, 1 H) 8.30 (s, 1 H). Step 8F: N- (. {4 '- [(4-methylisoquinolin-3-yl) ethynyl] -l, 1-biphenyl-4-yl.} Sulfonyl) -D-valinate from terephthalate was dissolved. butyl (46 mg, 0.08 mmol) in 25 ml of methanol and a catalytic amount of Pd / C (8.5 mg, 10% by weight on carbon, 0.008 mmol) was added. Hydrogenation was carried out in a Parr shaker bottle under H2 (3.511 kg / cm2 (50 PSD) .The reaction was terminated after 5 hours and analysis by LC-MS indicated that the reaction had been completed. Mix through Celite and concentrate to the desired product, G8594-178, with a quantitative yield (46 mg). 1 H NMR (400 MHz, DMSO-D6) d ppm 0.77-0.93 (m, 6 H) 1.15 (s) , 9 H) 1.85-2.06 (m, 1 H) 2.51 (s, 3 H) 3.13-3.28 (m, 2 H) 3.25-3.39 (m, 2 H) 3.47 (d, 7 = 8.84 Hz, 1 H) 7.47 (d, 7 = 8.08 Hz, 2 H) 7.52 (t, 7 = 7.45 Hz, 1 H) 7.59-7.71 (m, 3 H) 7.76-7.90 (m, 4 H) 7.97 (d, 7 = 8.34 Hz , 1 H) 8.06 (s, 1 H) 8.15 (s, 1 H) Step 8G: N- (. {4 '- [2- (4-Methylisoquinolin-3-yl) ethyl] -1 was dissolved, 1'-biphenyl-4-yl.}. Sulfonyl-D-valinate of tere- butyl (46 mg, 0.08 mmol) in 5 ml of dry methylene chloride, followed by the addition of 2.5 ml of TFA. The mixture was stirred at room temperature for 3 hours and analysis by means of the CCD indicated that the reaction had been completed. The solvent was removed using a rotary evaporator and the product dried in a vacuum oven overnight. 44 mg of product were obtained, N- ( {4'- [2- (4-methylisoquinolin-3-yl) ethyl] -1, 1'-biphenyl-4-yl.} Sulfonyl) -D-valinate with a 95% yield. 1 H NMR (400 MHz, MeOD) d ppm 0.83 (d, 7 = 6.82 Hz, 3 H) 0.88 (d, 7 = 6.82 Hz, 3 H) 1.80-2.13 (m, 1 H) 2.57 (s, 3 H) 3.15 (t, 7 = 7.83 Hz, 2 H) 3.45-3.55 (m, 2 H) 3.60 (d, 7 = 5.56 Hz, 1 H) 7.25 (d, 7 = 8.08 Hz, 2 H) 7.53 (d, 7 = 8.08 Hz, 2 H) 7.65 (d, 7 = 8.34 Hz, 2 H) 7.81 (d, 7 = 8.59 Hz, 3 H) 7.98 (t, 7 = 7.58 Hz, 1 H) 8.02-8.09 (m, 1 H) 8.13 (d, 7 = 8.08 Hz, 1 H) 8.83 (s, 1 H).

Example 5A was prepared based on Reaction Scheme 9. Example 5A D-2- [4, - (acetylamino-methyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 9A: 4-aminomethyl-phenyl- boronic (143 mg, 0.77 mmol, 1 equiv.), D-2- (bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester (300 mg, 0.77 mmol, 1 equiv.) and palladium tetrakis ( 44 mg, 0.038 mmol, 0.05 equiv.) In dimethoxyethane (10 mL) and stirred at room temperature for 10 minutes. Potassium carbonate (212 mg, 1.53 mmol, 2 equiv.) In 4 mL of water was added to the reaction mixture and heated at 88 ° C for 4 hours. Then, the reaction was cooled to room temperature and diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and extracted to dryness. The residue was purified by flash chromatography on silica gel, eluting with 4-10% MeOH in methylene chloride with 2% Et3N to obtain 200 mg of the tert-butyl ester of D-2- (4 '-aminomethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid. Performance: 63%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, J = 8.1, 7.1 Hz, 6 H) 1.1 (s, 9 H) 1.9 (, 1 H) 3.5 (d, J = 6.3 Hz, 2 H) 3.8 (s, 2 H) 7.5 (d, J = 8.3 Hz, 2 H) 7.6 (d, J = 8.3 Hz, 2 H) 7.8 (d, J = 2.0 Hz, 4 H). Step 9B: To the acetic anhydride (71 uL, 0.75 mmol, 1.05 equiv.) In CH2C1 (5 mL) was added pyridine (70 uL, 0. 86 mmol, 1.2 equiv.) Under argon and stirred for 5 minutes; After the acid tert-butyl ester was added D-2- (4'-Aminomethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric (300 mg, 0.72 mmol, 1 equiv.) And stirred for 16 h. After treatment and instant chromatography in column, D-2- [4'- (acetylamino-methyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester was obtained. Performance: 32%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 9.1, 6.8 Hz, 6 H) 0.9 (t, J = 7.3 Hz, 3 H) 1.2 (s, 9 H) 1.3 (m, 2 H) 1.5 (m, 2 H) 1.9 (, 1 H) 2.5 (m, 2 H) 3.4 (dd, J = 9.6, '6.3 Hz, 1 H) 7.0 (dd, 4 H) 7.1 (, 2 H) 7.5 (d, J = 8.8 Hz, 2 H) 7.7 (d, 7 = 9.6 Hz, 1 H) 8.6 (s, 1 H). Step 9C: To a solution of the d-2- [4 '- (acetylamino-methyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester (300 mg, 0.65 mmol) in 6 ml of dichloroethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 hours and determined by means of the CCD if the reaction had been completed. The solvent was removed and the residue was dried in a vacuum oven to obtain 250 mg of D-2- [4 '- (acetylamino-methyl) -biphenyl-4'-sulfonylamino] -3-methyl-butyric acid. Yield: 94%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 12.5, 6.7 Hz, 6 H) 1.9 (s, 3 H) 2.0 (, 1 H) 3.6 (dd, 7 = 9.3, 5.8 Hz, 1 H) 4.3 (d, 7 = 5.8 Hz, 2 H) 7.4 (d, 7 = 8.1 Hz, 2 H) 7.7 (d, 7 = 8.3 Hz, 2 H) 7.8 (s, 4 H) 8.1 (d, 7 = 9.3 Hz, 1 H) 8.4 (t, 7 = 5.8 Hz, 1 H) 12.6 (s, 1 H) .

Examples 5B and 5C were prepared based on Reaction Scheme 10. Example 5B D-3-methyl-2- (4'-phenylcarbamoylmethyl-biphenyl-4-sulfonylamino) -butyric acid Step 10A: A mixture of 4-bromofacetylacetic acid (1.5 g, 7.0 mmol, 1 equiv.), EDC (2.67 g, 14.0 mmol, 2 equiv.), DMAP (846 mg, 7.0 mmol, 1 equiv.) And phenylamine (0.765 mL, 8.4 mmol, 1.2 equiv.) in 15 mL of DMF was stirred under nitrogen at room temperature for 3.5 hours. After the aqueous work-up and recrystallization, 2- (4-bromofenyl) -N-f-enylacetamide was obtained in a yield of 69% (1.4 g). 1 H NMR (400 MHz, DMS0-D6) d ppm 3.6 (s, 2 H) 7.0 (m, 1 H) 7.3 (m, 4 H) 7.5 (m, 2 H) 7.6 (dd, 7 = 8.7, 1.1 Hz , 2 H) 10.2 (s, 1 H). Step 10B: A mixture of 2- (4-bromophenyl) -N-phenylacetamide (107 mg, 0.37 mmol, 1.1 equiv.), Tert-butyl ester of D-3-methyl-2 acid was heated to reflux or nitrogen. - (4-Tributylstannyl-benzenesulfonylamino) -butyric (202 mg, 0. 34 mmol, 1 equiv.) And Pd (PPh3) 4 (38.5 mg, 0.033 mmol, 0.1 equiv.) In 5 mL of toluene. The reaction was completed after 5 hours. After the usual treatment and column purification, the D-3-methyl-2- ('-phenylcarbamoylmethyl-2-phenyl-4-sulfonylamino) -butyric acid tert-butyl ester was obtained in a yield of 34% (60 mg ). 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, 7 = 8.3, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (, 1 H) 3.5 (dd, 7 = 9.6, 6.3 Hz, 1 H) 3.7 (s, 2 H) 7.0 (t, 7 = 7.3 Hz, 1 H) 7.3 (m, 2 H) 7.5 (d, 7 = 8.3 Hz, 2 H) 7.6 (dd, 7 = 8.6, 1.0 Hz, 2 H) 7.7 (d, 7 = 8.3 Hz, 2 H) 7.8 (d, 7 = 2.5 Hz, 4 H) 8.1 (d, 7 = 9.6 Hz, 1 H) 10.2 (s, 1 H). Step 10C: The removal of the t-butyl ester of the tert-butyl ester of D-3-methyl-2- (4'-phenylearbamoylmethyl-2-phenyl-sulfonylamino) -butyric acid was carried out using TFA in dichloroethane (1: 1) . After evaporation of the solvent, D-3-methyl-2- (4'-phenyl-4-phenylaminoethyl-biphenyl-4-sulfonylamino) -butyric acid was obtained in quantitative yield. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, J = 27.0, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (d, J = 5.6 Hz, 1 H) 3.6 (s, 2 H) 7.0 (m, 1 H) 7.2 (, 2 H) 7.4 (d, J = 8.3 Hz, 2 H) 7.5 (dd, J = 8.7, 1.1 Hz, 2 H) 7.6 (d, J = 8.3 Hz, 2 H) 7.7 (dd, J = 48.0, 8.6 Hz, 4 H).

Example 5C D-2- [4'- (Benzylsarbamoyl-methyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 10A: The coupling of the amide of 4-bromophenylacetic acid with benzylamine was carried out according to the procedures of Step 10A in Example 5B, to obtain N-benzyl-2- (4-bromo-phenyl) -acetamide in 82% yield. 1 H NMR (400 MHz, DMSO-D6) d ppm 3.5 (s, 2 H) 4.3 (d, 7 = 5.8 Hz, 2 H) 7.2 (dd, 7 = 7.8, 5.6 Hz, 5 H) 7.3 (m, 2 H) 7.5 (d, 7 = 8.3 Hz, 2 H) 8.6 ( t, 7 = 5.9 Hz, 1 H). Step 10B: The Stille coupling between N-benzyl-2- (4-bromo-phenyl) -acetamide and the tert-butyl ester of D-3-methyl-2- (4-tributylstannyl-benzenesulfonylamino) -butyric acid is carried out according to the procedures of Step 10B in Example 5B to obtain the d-2- [4 '- (benzylcarbamoylmethyl) -biphenyl-4-sulfonylamino] -3-methyl- tert -butyl ester. Butyric with a yield of 31%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.9 (d, 7 = 6.8 Hz, 3 H) 1.0 (d, 7 = 6.6 Hz, 3 H) 1.2 (s, 9 H) 2.1 (m, 1 H) 3.7 (m, 3 H) 4.5 (d, 7 = 5.8 Hz, 2 H) 5.1 (d, 7 = 9.9 Hz, 1 H) 5.7 ( s, 1 H), 7.3 (m, 5 H) 7.4 (d, 7 = 8.1 Hz, 2 H) 7.5 (d, 7 = 8.3 Hz, 2 H) 7.7 (d, 7 = 8.3 Hz, 2 H) 7.9 (d, 7 = 8.3 Hz, 2 H). Step 10C: Removal of the t-butyl ester was performed according to the procedures of Step 10C in Example 5B with a quantitative yield. 1 H NMR (400 MHz, MeOD) d ppm 0.8 (dd, J = 26.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.5 (s, 2 H) 3.6 (d, J = 5.6 Hz, 1 H) 4.3 (d, J = 5.6 Hz, 2 H) 7.2 (m, 5 H) 7.3 (d, J = 8.3 Hz, 2 H) 7.5 (d, J = 8.3 Hz, 2 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (d, J = 8.8 Hz, 2 H) 8.5 (s, 1 H). Examples 6A, 6B, 6C, 6D, 6E, 6F, 6G, 6H, 61, 6J, 6K, 6L, 6M, 6N, 60, 6P, 6Q, 6R, 6S were prepared based on Reaction Scheme 11. Example 6A 2- ['- (4-Fluoro-phenylcarba oyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step HA: 2- (4'-Hydroxy-biphenyl-4-tert-butyl ester was dissolved -sulfonylamino) -3-methyl-butyric (300 mg, 0.74 mmol, 1 equiv.) In diethyl ether (7.5 mL), followed by the addition of 4-fluorophenylisocyanate (101 mg, 0.74 mmol, 1 equiv.) And Et3N (1 mL). The reaction mixture is stirred at room temperature for 50 minutes. The solid was precipitated from the reaction mixture. The solid was collected by filtration and washed with ether to give the 2- [4 '- (4-fluoro-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester with a yield of 57% (228 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, 7 = 6.82 Hz, 3 H) 1.03 (d, 7 = 6.82 Hz, 3 H) 1.20 (s, 9 H) 2.05 (m, 1 H) 3.67 (dd, 7 = 9.98, 4.42 Hz, 1 H) 5.13 (d, 7 = 9.85 Hz, 1 H) 6.95 (s, 1 H) 7.05 (d, 7 = 9.09 Hz, 2 H) 7.30 (d, 7 = 8.59 Hz, 2 H) 7.43 (, 2 H) 7.57 (d, 7 = 8.59 Hz, 2 H) 7.67 (s, 2 H) 7.90 (d, 7 = 8.34 Hz, 2 H). Step 11B: 2- [4 '- (4-Fluoro-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester (223 mg) was dissolved in dichloroethane (7.5 mL) and added TFA (2.5 L). The mixture was stirred at room temperature for 5 hours and analysis by means of the CCD indicated that the reaction had been completed. After the usual treatment and column chromatography, 2- [4 '- (4-fluoro-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was obtained in 89% yield (178 mg). . 1 H NMR (400 MHz, DMSO-D6) d ppm 0.81 (d, 7 = 6.57 Hz, 3 H) 0.84 (d, 7 = 6.82 Hz, 3 H) 1.96 (m, 1 H) 3.56 (dd, 7 = 9.35 , 6.06 Hz, 1 H) 7.19 (t, 7 = 8.84 Hz, 2 H) 7.37 (d, 7 = 8.59 Hz, 2 H) 7. 54 (dd, 7 = 9.09, 4.80 Hz, 2 H) 7.79 (d, 7 = 8.84 Hz, 2 H) 7.86 (d, 7 = 4.29 Hz, 4 H) 8.08 (d, 7 = 9.35 Hz, 1 H) 10.34 (s, 1 H). Example 6B D-3-Methyl-2- [4 '- (4-phenoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4' - (4- phenoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 6A. Step 11A: The reaction of 4-phenoxyphenyl-isocyanate with D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester to obtain the tert-butyl ester of D-acid 3-methyl-2- [4 '- (4-phenoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures described in Step 11A of Example 6A. Performance: 36%. 1 H NMR (400 MHz, DMS0-D6) D ppm 0.9 (dd, J = 8.2, 6.9 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.6, 6.3 Hz, 1 H) 7.0 (dd, J = 8.6, 1.0 Hz, 2 H) 7.0 (d, J = 9.1 Hz, 2 H) 7.1 (m, 1 H) 7.4 (m, 4 H) 7.5 (d, J = 8.8 Hz, 2 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J = 9.6 Hz, 1 H) 10.3 (s, 1 H). Step 11B: The conversion of D-3-methyl-2- ['- (4-phenoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino) -butyric acid tert-butyl ester to D-3-methyl-2- acid [4'- (4-Phenoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures described in Step 11B of Example 6A. Performance: 87%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J = .3, 6.1 Hz, 1 H) 7.0 ( m, 2 H) 7.0 (d, J = 9.1 Hz, 2 H) 7.1 (t, J = 7.3 Hz, 1 H) 7.4 (, 4 H) 7.5 (d, J = 8.8 Hz, 2 H) 7.8 (d , J = 8.8 Hz, 2 H) 7.9 (d, J = .8 Hz, 4 H) 8.1 (d, J = 9.3 Hz, 1 H) 10.3 (s, 1 H). Example 6C D-3-methyl-2- [4'- (naphthalen-2-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4 '- (naphthalene- 2-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 6A. Step HA: The reaction of 2-naphthyl-isocyanate with tert-butyl ester of D-2- (4 '-hydroxy-biphenyl-4-acid) sulphonylamino) -3-methyl-butyric acid to obtain the tert-butyl ester of D-3-methyl-2- [4 '- (naphthalen-2-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out in accordance with the procedures described in Step HA of Example 6A. Performance: 16%. 1 H NMR (400 MHz, DMSO-D6) D ppm 0.9 (dd, J = 8.2, 6.9 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz, 1 H) 7.4 (m, 3 H) 7.5 (m, 1 H) 7.6 (dd, J = 8.8, 2.3 Hz, 1 H) 7.8 (d, J = 8.8 Hz, 2 H) 7.9 (m, 7 H) 8.1 (s, 1 H) 8.2 (d, J = 9.9 Hz, 1 H) 10.5 ( s, 1 H). Step 11B: The conversion of D-3-methyl-2- [4 '- (naphthalen-2-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid tert-butyl ester to D-3-methyl-2 acid - [4 '- (Naphthalen-2-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures described in Step IIB of Example 6A. Performance: 40%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6 H) 2. 0 (, 1 H) 3.6 (dd, J = 9.1, 5.8 Hz, 1 H) 7.4 (m, 3 H) 7.5 (m, 1 H) 7.6 (dd, J = 8.8, 2.3 Hz, 1 H) 7.9 (m, 9 H) 8.1 (m, 2 H) 10.5 (s, 1 H) 12.6 (s, 1 H). Example 6D D-2- [4'- (4-benzyloxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyrisoic acid The title compound, D-2- [4'- (4-benzyloxy-phenylcarbamoyloxy)] -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 6A. Stage HA: The reaction of 4-benzyloxyphenyl-isocyanate with tert-butyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the tert-butyl ester of acid D-2- [4'- (4-benzyloxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed according to the procedures described in Step 11A of Example 6A. Yield: 37%. NMR: G8701-142. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, J = 8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz , 1 H) 5.1 (s, 2 H) 7.0 (d, J = 9.1 Hz, 2 H) 7.4 (m, 9 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J = 9.6 Hz, 1 H) 10.1 (s, 1 H). Step llB: The conversion of D-2- [4 '- (4-benzyloxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester to D-2- [4'] acid - (4-benzyloxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was made according to the procedures described in Step IIB of Example 6A. Yield: 60%. NMR: G8701-151. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J = 9.3, 6.1 Hz, 1 H) 5.1 (s, 2 H) 7.0 (d, J = 9.1 Hz, 2 H) 7.4 (m, 9 H) 7.8 (d, J = 8.8 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J = 9.3 Hz, 1 H) 10.1 (s, 1 H).

Example 6E D-2- (4'-Sislopentylcarbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyroic acid The title compound, D-2- (4'-cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl- butyric, was prepared according to procedures similar to those in Example 6A. Step HA: The reaction of cyclopentyl-isocyanate with the tert-butyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the tert-butyl ester of D-acid 2- (4'-Cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to the procedures described in Step HA of Example 6A. Yield: 70%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, J = 8.1, 7.1 Hz, 6 H) 1.2 (s, 9 H) 1.5 (m, 4 H) 1.7 (m, 2 H) 1.8 (m , 2 H) 1.9 (, 1 H) 3.5 (dd, J = 9.6, 6.3 Hz, 1 H) 3.9 (m, 1 H) 7.2 (d, J = 8.6 Hz, 2 H) 7.7 (d, J = 8.6 Hz, 2 H) 7.8 (m, 5 H) 8.2 (d, J = 9.6 Hz, 1 H). Step llB: The conversion of the tert-butyl ester of D-2- ('-cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to D-2- (4'-cyclopentylcarbamoyloxy-biphenyl-4) acid sulfonylamino) -3-methyl-butyric acid was carried out according to the procedures described in Step IIB of Example 6A. Yield: 91%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (, 6 H) 1.5 (m, 4 H) 1.7 (d, J = 4.5 Hz, 2 H) 1.8 (m, 2 H) 1.9 (m, 1 H ) 3.6 (dd, J = 9.3, 6.1 Hz, 1 H) 3.9 (m, 1 H) 7.2 (d, J = 8.6 Hz, 2 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (s, 5 H) 8.1 (d, J = 9.3 Hz, 1 H) 12.6 (s, 1 H).

Example 6F D-2- [4'- (4-dimethylamino-phenylsarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-2- [4'- (4-dimethylamino-phenylcarbamoyloxy)] -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 6A. Step HA: The coupling of 4- (dimethylamino) -phenyl-isocyanate with the tert-butyl ester of D-2- acid (4'- hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the d-2- [4'- (4-dimethylamino-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-tert-butyl ester butyric was performed according to the procedures described in Step HA of Example 6A. Yield: 28%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd), J = 8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 2.8 (s, 6 H) 3.5 (dd, J = 9.6, 6.3 Hz, 1 H) 6.7 (d, J = 9.1 Hz, 2 H) 7.3 (d, J = 8.6 Hz, 4 H) 7.7 (d, J = 8.6 Hz, 2 H) 7.8 (m, 4 H) 8.2 (d, J = 9.9 Hz, 1 H 9.9 (s, 1 H). Step llB: The conversion of D-2- (4 '- (4-dimethylamino-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester to D-2- [4'] acid - (4-dimethylamino-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was carried out according to the procedures described in Step llB of Example 6A Yield: 99% NMR: G8701-161. (400 MHz, MeOD) d ppm 0.8 (dd, J = 23.7, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.1 (s, 6 H) 3.6 (d, J = 5.6 Hz, 1 H) 7.2 ( d, J = 8.8 Hz, 2 H) 7.4 (d, J = 9.1 Hz, 3 H) 7.6 (m, 6 H) 7.8 (d, J = 8.8 Hz, 2 H).

Example 6G Acid D-2- I47- (4-isopropyl-f-enylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid The title compound, D-2- [4 '- (4-isopropyl-f-enylcarbamoyloxy) ) -bifinyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 6A. Step HA: The reaction of 4-isopropyl-enyl-isocyanate with tert-butyl ester of D-2- (4'-hydroxy) -bifinyl-4-sulfonylamino] -3-methyl-butyric acid to obtain the tertiary ester -butyl acid of D-2- [4 '- (4-i-sopropi-1-f-enylcarbamoyloxy) -bifinyl-4-sulfonylamino] -3-methyl-butyric acid was carried out according to the procedures described in Step HA of the Example 6A Performance: 38%. NMR: G8701-158. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.9 (dd, J = 8.3, 6.8 Hz, 6 H) 1.2 (m, 15 H) 1.9 (m, 1 H) 2.8 (, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz, 1 H) 7.2 (d, J = 8.6 Hz, 2 H) 7.4 (d, J = 8.6 Hz, 2 H) 7.4 (d, J = 8.6 Hz, 2 H) 7. 7 (d, J = 8.6 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J = 9.9 Hz, 1 H) 10.2 (s, 1 H). Step llB: The conversion of D-2 - [4 '- (4-isopropyl-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester to D-2 - [4'] acid - (4-isopropyl-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl- butyric was performed according to the procedures described in Step llB of Example 6A. Yield: 34%. NMR: G8701-165. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6 H) 1.2 (d, J = 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.8 (m, 1 H) 3.6 (dd, J = 9.3, 6.1 Hz, 1 H) 7.2 (d, J = 8.6 Hz, 2 H) 7.4 (d, J = 8.8 Hz, 2 H) 7.4 (d, J = 8.6 Hz, 2 H) 7.8 (d, J = 8.8 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J = 9.3 Hz, 1 H) 10.2 (s, 1 H) 12.6 (s, 1 H).

Example 6H D-3-Methyl-2- [4 '- (2-thiophen-2-yl-ethylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4'] acid ~ (2-thiophen-2-yl-ethylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 6A. Step HA: The reaction of 2- (2-thienyl) ethyl-isocyanate with the d-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester to obtain the ester D-3-methyl-2- [4 '- (2-thiophen-2-yl-ethylcarbamoyloxy) -bifeni-1-sulfonylamino] tert-butyl ester butyric was performed according to the procedures described in Step HA of Example 6A. Performance: 63%. NMR: G8701-169. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.9 (dd, J = 8.3, 7.1 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.0 (t, J = 7.1 Hz, 2 H) 3.3 (m, 2 H) 3.5 (dd, J = 9.6, 6.3 Hz, 1 H) 7.0 (m, 2 H) 7.2 (d, J = 8.8 Hz, 2 H) 7.4 (dd, J = 5.1, 1.3 Hz, 1 H) 7.7 (d, J = 8.6 Hz, 2 H) 7.8 (d, J = 2.3 Hz, 4 H) 8.0 (t, J = 5.7 Hz, 1 H) 8.2 (d, J = 9.9 Hz , 1 HOUR) . Step llB: The conversion of D-3-methyl-2- [4 '- (2-thiophen-2-yl-ethylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid tert-butyl ester to D-3 acid -methyl-2- [4'- (2-thiophen-2-yl-ethylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures described in Step IIB of Example 6A. Performance: 43%. NMR: G8701-175. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, 7 = 12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.0 (t, 7 = 7.1 Hz, 2 H) 3.3 (, 2 H) ) 3.6 (dd, 7 = 9.2, 5.9 Hz, 1 H) 6.9 (d, 7 = 3.3 Hz, 1 H) 7.0 (dd, 7 = 5.1, 3.3 Hz, 1 H) 7.2 (d, 7 = 8.8 Hz, 2 H) 7.4 (dd, 7 = 5.1, 1.3 Hz, 1 H) 7.7 (d, 7 = 8.6 Hz, 2 H) 7.8 (s, 4 H) 8.0 (t, 7 = 5.8 Hz, 1 H) 8.1 ( d, 7 = 9.3 Hz, 1 H).

Example 6 D-3-Methyl-2- [4 '- (4-trifluoromethoxy-phenylsarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4'- (4- trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 6A. Step HA: The reaction of 4-methoxyphenyl-isocyanate with tert-butyl ester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain the tert-butyl ester of acid D-2- [4'- (4-methoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric was performed according to the procedures described in Step 11A of Example 6A. Performance: 49%. NMR: G8701-199. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, J = 8.3, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz, 1 H) 3.7 (s, 3 H) 6.9 (d, J = 9.1 Hz, 2 H) 7.4 (d, J = 8.8 Hz, 2 H) 7.4 (d, J = 8.8 Hz, 2 H) 7.7 (d, J = 8.6 Hz , 2 H) 7.9 (m, 4 H) 8.2 (d, J = 9.9 Hz, 1 H) 10.1 (s, 1 H). Step 11B: The reaction of tert-butyl ester of D-2- [4'- (4-methoxy-phenylcarbamoyloxy) -biphenyl-4- acid sulfonylamino] -3-methyl-butyric acid to give the acid D-3-methyl-2- [4 '- (4-trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to the procedures described in Step llB of Example 6A. Yield: 91%. NMR: G9241-4. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J = 9.3, 5.8 Hz, 1 H) 3.7 (s) , 3 H) 6.9 (d, J = 9.1 Hz, 2 H) 7.4 (d, J = 8.8 Hz, 2 H) 7.4 (d, J = 8.8 Hz, 2 H) 7.8 (d, J = 8.6 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J = 9.3 Hz, 1 H) 10.1 (s, 1 H) 12.6 (s, 1 H).

Example 6 D-3-Methyl-2- [4 '- (4-trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid The title compound, D-3-methyl-2- [4' - (4- trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid, was prepared according to procedures similar to those of Example 6A. Step 11A: To a solution of the d-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester (300 mg, 0.74 mmol, 1 equiv.) In diethyl ether ( 10 mL) was added 4- (trifluoromethoxy) phenyl isocyanate (123 uL, 0.81 mmol, 1.1 equiv.) and triethylamine (124 uL, 0.89 mmol, 1.2 equiv.) under argon and stirred at room temperature. After the reaction was complete, standard treatment and flash column chromatography afforded D-3-methyl-2- [4 '- (4-trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino tert-butyl ester. ] -butyric with a yield of 37%. NMR: G8701-200. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.9 (dd, J = 8.1, 0 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz, 1 NMR: G8701-200. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, J = 8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz, 1 H) 7.4 (m, 4 H) 7.6 (d, J = 9.3 Hz, 2 H) 7.8 (d, J = 8.8 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J = 9.6 Hz, 1 H) 10.5 (s, 1 H). Step llB: The conversion of D-3-methyl-2- [4 '- (4-trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric acid tert-butyl ester to D-3-methyl-2 acid - [4'- (4-trifluoromethoxy-phenylcarbamoyloxy) -biphenyl-4-sulfonylamino] -butyric was carried out according to the procedures described in Step llB of Example 6A.

Yield: 76%. NMR: G9241-5. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (dd, - J = 9.3, 5.8 Hz, 1 H) 7.4 (m, 4 H) 7.6 (d, J = 9.1 Hz, 2 H) 7.8 (d, J = 8.6 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J = 9.3 Hz, 1 H) 10.5 (s, 1 H).

Example 6K D-2- (4-carbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid The title compound, D-2- (4'-carbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid , was prepared according to procedures similar to those of Example 6A. Step HA: To a solution of the D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester (500 mg, 1.23 mmol, 1 equiv.) In CH2C12 (2) mL) chlorosulfonyl isocyanate (107 uL, 123 mmol, 1 equiv.) was added under argon and stirred at room temperature for 16 hours. It was determined by means of the CCD that the reaction had been completed. After treatment and flash column chromatography, D-2- (4'-carbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester was obtained. Performance: 45%. NMR: G9241-38. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.9 (dd, J = 8.3, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J = 9.9, 6.3 Hz , 1 H) 7.2 (d, J = 8.8 Hz, 2 H) 7. 7 (d, J = 8.8 Hz, 2 H) 7.8 (d, J = 1. O Hz, 4 H) 8.2 (d, J = 9.6 Hz, 1 H). Step llB: The conversion of D-2- (4 '-carbamoyloxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester to D-2- (' -carbamoyloxy-biphenyl-4-acid) sulfonylamino) -3-methyl-butyric acid was carried out according to the procedures described in Step IIB of Example 6A. Performance: 85%. NMR: G9241-46. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (dd, J = 9.3, 5.8 Hz, 1 H) 7.0 (s) , 1 H) 7.2 (m, 3 H) 7.7 (d, J = 8.8 Hz, 2 H) 7.8 (s, 4 H), 8.1 (d, J = 9.3 Hz, 1 H).

Example 6L 3-Methyl-2- (4'-phenylcarbamoyloxy-biphenyl-4-sulfonylamino) -butyric acid ester-butylism 3-Methyl-2- (4'-phenylcarbamoyloxy-biphenyl) tert-butyl ester -4-sulfonylamino) -butyric acid, was prepared according to procedures similar to those of Example 6A. Stage HA: 2- (4'-Hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butyl ester was dissolved (300 mg, 0.74 mmol, 1 equiv.) In diethyl ether (7.5 mL) and phenylisocyanate (0.08 mL, 0.74 mmol, 1 equiv.) Was added, followed by EtN (1 mL). The reaction mixture was stirred for 4 hours. The solid precipitated from the reaction mixture was collected by filtration and washed with ether to give the product in 76% yield (295 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, 7 = 7.07 Hz, 3 H) 1.03 (d, 7 = 6.82 Hz, 3 H) 1.20 (s, 9 H) 2.07 (m, 1 H) 3.67 (dd, 7 = 9.98, 4.42 Hz, 1 H) 5.13 (d, 7 = 9.85 Hz, 1 H) 6.96 (s, 1 H) 7.14 (m, 1 H) 7.31 (d, 7 = 8.59 Hz, 2 H) • 7.36 (m, 2 H) 7.47 (d, 7 = 8.34 Hz, 2 H) 7.58 (d, 7 = 8.59 Hz, 2 H) 7.66 (d, 7 = 8.34 Hz, 2 H) 7.91 (m, 2 H). Step llB: The tert-butyl ester of 3-methyl-2- (4'-phenylcarbamoyloxy-biphenyl-4-sulfonylamino) -butyric acid (200 mg) was hydrolyzed according to the procedures described in Step IIB of Example 6A for provide 3-methyl-2- (4'-phenylcarbamoyloxy-biphenyl-4-sulfonylamino) -butyric acid in 88% yield (158 mg). 1 H NMR (400 MHz, DMSO-D6) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.57 Hz, 3 H) 1.95 (m, 1 H) 3.56 (dd, 7 = 9.22, . 94 Hz, 1 H) 3.90 (s, 1 H) 7.07 (m, 1 H) 7.35 (m, 4 H) 7.53 (d, 7 = 7.83 Hz, 2 H) 7.80 (d, 7 = 8.59 Hz, 2 H) 7.86 (d, 7 = 22.23 Hz, 4 H) 8.08 (d, 7 = 9.35 Hz, 1 H) 10.29 (s) , 1 HOUR) .

Example 6M 2- [4 # - (Benzo [b] thiophen-3-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyroic acid ester-butyl ester The title compound, tert-butyl ester of 2- [-] acid 4'- (Benzo [b] thiophen-3-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid, was prepared according to procedures similar to those of Example 6A. Step 11A: 2- (4'-Hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert -butyl ester (300 mg, 0.74 mmol, 1 equiv.) In diethyl ether (7.5 L) was dissolved. , added with l-benzothiophen-3-yl isocyanate (129.6 mg, 0.74 mmol, 1 equiv.), followed by 0.5 mL of Et3N. A solid was precipitated from the reaction mixture in 5 minutes. The reaction mixture was continued stirring at room temperature for 2 hours, the precipitate was collected by filtration and washed with ether to give a 43% yield (187 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, '7 = 6.82 Hz, 3 H) 1.03 (d, 7 = 6.82 Hz, 3 H) 1.20 (s, 9 H) 2.08 (m, 1 H ) 3.68 (m, 1 H) 5.15 (d, 7 = 10.11 Hz, 1 H) 7.35 (d. 7 = 8.34 Hz, 2 H) 7.43 (m, 2 H) 7.60 (d, 7 = 8.59 Hz, 2 H) 7.67 (d, 7 = 8.34 Hz, 3 H) 7.74 (s, 1 H) 7.90 (t, 7 = 9.09 Hz, 3 H). Step llB: The 2- [4'- (benzo [b] thiophen-3-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester (180 mg, 0.31 mmol) was dissolved in Methylene chloride under an N2 atmosphere, TFA (2 mL) was added at 0 ° C and stirred for 4 hours. The solvent was evaporated and the product was dried under high vacuum to give 2- [4'- (benzo [b] thiophen-3-ylcarbamoyloxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid in a yield 66% (108 mg). 1 H NMR (400 MHz, MeOD) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.89 (d, 7 = 6.82 Hz, 3 H) 1.20 (s, 1 H) 3.54 (d, 7 = 5.05 Hz, 1 H) 7.30 (m, 2 H) 7.35 (m, 2 H) 7.58 (s, 1 H) 7.66 (d, 7 = 8.59 Hz, 2 H) 7.71 (d, 7 = 8.59 Hz, 2 H) 7.78 ( d, 7 = 7.83 Hz, 1 H) 7.84 (d, 7 = 8.59 Hz, 2 H) 7.92 (d, 7 = 8.08 Hz, 1 H).

Example 6N N- [(4 '- { [2, 3-dihydro-l-benzofuran-5-ylamino) carbonyl] oxy} -1,1 '-biphenyl-4-yl) sulfonyl] -D-valine The title compound, N- [(4' - { [2, 3-dihydro-l-benzofuran-5-ylamino) carbonyl] oxy } -l, 1'-biphenyl-4-yl) sulfonyl] -D-valine, was prepared in accordance with procedures similar to those of Example 6A. Stage HA and llB: Performance: 40%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.98 (m, 1 H) 3.17 (t, 7 = 8.97 Hz, 2 H) 3.39 (s, 1 H) 4.50 (t, 7 = 8.59 Hz, 2 H) 6.72 (d, 7 = 8.34 Hz, 1 H) 7.19 (d, 7 = 8.84 Hz, 1 H) 7.34 ( d, 7 = 8.59 Hz, 2 H) 7.40 (s, 1 H) 7.78 (d, 7 = 8.59 Hz, 2 H) 7.85 (d, 7 = 1.77 Hz, 4 H) 10.05 (s, 1 H). Example 60 N - [(4'- { [(2,3-dihydro-l, 4-benzodioxin-6-ylamino) carbonyl] -oxi.]. -l, l-bxphenyl-4-yl) sulfonyl] - D-valine The title compound, N- [(4 '-. {[[(2,3-dihydro-l, -benzodioxin-6-ylamino) carbonyl] -oxi.] -1, 1'-biphenyl- 4-yl) sulfonyl] -D-valine, was prepared according to procedures similar to those of Example 6A. Stage 11A and llB: Yield: 62%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.98 (m, 1 H) 3.42 (s, 1 H) 4.21 (m, 4 H) 6.81 (d, 7 = 8.84 Hz, 1 H) 6.94 (d, 7 = 10.86 Hz, 1 H) 7.09 (s, 1 H) 7.34 (d, 7 = 8.84 Hz, 2 H) 7.78 (d, 7 = 8.84 Hz, 3 H) 7.85 (d, 7 = 1.77 Hz, 4 H) 10.11 (s, 1H).

Example 6P N- [(4 - { [(3,4-Dihydro-2H-1, 5-benzodioxepin-7-ylamino) -carbonyl] oxy}. -l, lf-biphenyl-4-yl) sulfonyl] - D-Valine The title compound, N- [(4 '-. {[[(3,4-dihydro-2H-1, 5-benzodioxepin-7-ylamino) carbonyl] oxy}.-1, 1' - biphenyl-4-yl) sulfonyl] -D-valine, was prepared according to procedures similar to those of Example 6A. Stage HA and llB: Yield: 55%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.80 (d, 7 = 6.82 Hz, '3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.97 (m, 1 H) 2.08 (m, 2 H) 3.45 (s, 1 H) 4.08 (, 4 H) 6.94 (d, 7 = 8.59 Hz, 1 H) 7.06 (d, 7 = 2.53 Hz, 1 H) 7.18 (d, 7 = 2.27 Hz, 1 H ) 7.35 (d, 7 = 8.59 Hz, 2 H) 7.79 (d, 7 = 8.59 Hz, 2 H) 7.85 (d, 7 = 3.79 Hz, 4 H) 7.88 (s, 1 H) 10.21 (s, 1 H) ). Example 6Q N- [(4'- { [(5-methyl-3-phenylisoxazol-4-yl) amino) carbonyl] oxy} -l # l -biphenyl-4-yl) sulfonyl] -D-valine The title compound, N- [(4 '- { [(5-methyl-3- phenylisoxazol-4-yl) amino) carbonyl] oxy} -l, 1-biphenyl-4-yl) sulfonyl] -D-valine, was prepared according to procedures similar to those of Example 6A. Stage 11B: Performance: 75%. 1 H-NMR (400 MHz, ACETONYRTHYL-D3) d ppm 0.63 (d, 7 = 6.82 Hz, 3 H) 0.74 (d, 7 = 6.57 Hz, 3 H) 1.83-1.88 (m, 1 H) 2.20 (s, 1 H) 2.34 (m, 3 H) 3.81 (s, 1 H) 6.56 (s, 1 H) 6.66 (s, 1 H) 7.12 (d, 7 = 7.83 Hz, 1 H) 7.45 (d, 7 = 4.80 Hz , 4 H) 7.59 (m, 4 H) 7.68 (d, 7 = 3.54 Hz, 2 H) 7.80 (d, 7 = 8.08 Hz, 2 H).

Example 6R N - [(4'-. {[[(Methylamino) carbonyl] oxy} -1,1 '-biphenyl-4-yl) -sulfonyl] -D-valine The title compound, N - [(4' - { [(Methylamino) carbonyl] oxy} -l, 1'-biphenyl-4-yl) sulfonyl] -D-valine, was prepared according to procedures similar to those of Example 6A. Stage 11B: Yield: 90%. 1 H-NMR (400 MHz, MeOD) d ppm 0.80 (d, 7 = 8.34 Hz, 3 H) 0.87 (d, 7 = 6.82 Hz, 3 H) 1.91- 2.02 (m, 1 H) 2.71 (s, 3 H) 3.52 (d, 7 = 5.05 Hz, 1 H) 7.11 (d, 7 = 8.84 Hz, 2 H) 7.58 (d, 7 = 8.84 Hz, 2 H) 7.66 (d, 7 = 8.59 Hz, 2 H) 7.81 (d, 7 = 8.59 Hz, 2 H) Example 6S N- [(4'-. {[[(1-benzofuran-2-ylamino) carbonyl] oxy] -1,1 '-biphenyl-4-yl) sulfonyl] -D-valine Step 12A: The 2- (4'-Hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid (314 mg, 0.9 mmol) in methylene chloride (10 mL) and diethyl ether (20 mL) and benzofuran isocyanate ( 143 mg, 0.9 mmol, 1 equiv.) And triethylamine (363 mg, 3.6 mmol, 4 equiv.). The mixture was stirred at room temperature overnight. The solid precipitated from the reaction mixture was collected by filtration followed by column chromatography (silica gel, 5% MeOH / CH2Cl2). 76 mg of a white solid was obtained with a yield of 16%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.74-1.00 (m, 6 H) 1.90-2.07 (m, 1 H) 3.22-3.48 (, 1 H) 6.86 (d, 7 = 8.59 Hz, 2 H) 7.10-7.28 (m, 2 H) 7.33-7.62 (m, 4 H) 7.69-7.83 (m, 4 H) 7.86 (s, 1 H).

Examples 7A and 7B were prepared based on Reaction Scheme 13. Example 7A Ester 4'- (l-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-xlico acid of D-3-methyl-benzofuran-2-sarboxylic acid Stage 13A: A mixture of the tert-butyl ester of D-2- acid (4 '-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid (305 mg, 0.75 mmol, 1 equiv.), 3-methyl-benzofuran-2-carboxylic acid (131 mg, 0.74 mmol, 1 equiv.), 4-dimethylaminopyridine (DMAP, 95 mg, 0.77 mmol, 1 equiv.) And 1, 3-dicyclohexylcarbodiimide (DCC, 240 mg, 1.17 mmol, 1.6 equiv.) Dissolved in 5 mL of dichloromethane under a nitrogen atmosphere was allowed to react at room temperature for 3.5 hours. Usual treatment and column chromatography (10% EtOAc in hexane) provided the 4'- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-3-methyl-benzofuran -2-carboxylic acid (300 mg) with a yield of 71%. NMR: G8475-101. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.9 (d, 7 = 7.1 Hz, 3 H) 1.0 (d, 7 = 6.8 Hz, 3 H) 1.2 (s, 9 H) 2.1 (m, 1 H) 2.7 (s, 3 H) 3.7 (dd, 7 = 10.0, 4.4 Hz, 1 H) 5.1 (d, 7 = 9.9 Hz, 1 H) 7.4 (m, 3 H) 7.5 (m, 1 H) 7.6 (t , 7 = 8.0 Hz, 3 H) 7.7 (m, 3 H) 7.9 (d, 7 = 8.3 Hz, 2 H).

Step 13B: Removal of the t-butyl ester was carried out according to the procedures described in Step llB of Example 6A with a quantitative yield. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J = 9.2, 5.9 Hz , 1 H) 7.4 (t, J = 7.6 Hz, 1 H) 7.5 (d, J = 8.8 Hz, 2 H) 7.6 (t, J = 8.2 Hz, 1 H) 7.8 (d, J = 8.3 Hz, 1 H) 7.9 (m, 7 H) 8.1 (d, J = 9.3 Hz, 1 H). Example 7B Ester '- (l-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -biphenyl-4-yl of benzofuran-2-sarboxylic acid The title compound, 4' - (l-tert-butoxycarbonyl-2-methyl-propylsulfamoyl ester ) -biphenyl-4-yl of benzofuran-2-carboxylic acid, was prepared according to procedures similar to those of Example 7A. Step 13A: 2-Benzofuran-carboxylic acid (400.5 mg, 2.47 mmol, 1 equiv.) Was dissolved in dry CH2C12 (50 mL), DCC (1.019 g, 4.94 mmol, 2 equiv.) Was added and stirred under N during 15 minutes. Then the 2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert -butyl ester (1.0 g, 2.47 mmol, 1 equiv.) Was introduced into the reaction mixture, followed by the addition of DMAP (50 mg, 0.41 mmol). The mixture was stirred at room temperature during one night. The reaction mixture was then diluted with CH2C12 and washed with H2O and brine. The organic layer was dried over MgSO4 and the solvent was removed to obtain the crude product. The residue was dissolved in EtOAc and purified by column chromatography (silica gel, 20% EtOAc / n-hexane) to give G9058-53-1 in 30.5% yield (325 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.87 (d, 7 = 6.82 Hz, 3 H) 1.03 (d, 7 = 6.82 Hz, 3 H) 1.21 (s, 9 H) 2.07 (m, 1 H) 3.68 (dd, 7 = 9.85, 4.55 Hz, 1 H) 5.15 (d, 7 = 9.85 Hz, 1 H) 7.37 (m, 3 H) 7.53 (t, 7 = 7.83 Hz, 1 H) 7.66 (m, 5 H) 7.77 (, 2 H) 7.92 (d, 7 = 8.34 Hz, 2 H). Step 13B: The 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of benzofuran-2-carboxylic acid (325 mg) was dissolved in dichloromethane (15 mL) and TFA was added. . The solution was stirred at room temperature for 7 hours. The solvent was removed in a rotary evaporator and the crude product was purified by column chromatography (5-20% MeOH / EtOAc) to obtain the ester 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4 - benzofuran-2-carboxylic acid ethyl ester with 76% yield (241 mg). 1 H NMR (400 MHz, DMSO-D6) d ppm 0.80 (d, 7 = 6.57 Hz, 3 H) 0.87 (d, 7 = 6.82 Hz, 3 H) 2.04 (m, 1 H) 3.24 (m, 1 H) 7.43 (t, 7 = 7.58 Hz, 1 H) 7.49 (d, 7 = 8.84 Hz, 2 H) 7.60 (t, 7 = 7.96 Hz, 1 H) 7.70 (d, 7 = 9.85 Hz, 1 H) 7.85 (m, 7 H) 8.08 (s, 1 H). Examples 8A, 8B, 8C, 8D, 8E, 8F, 8G were prepared based on Reaction Scheme 14. Example 8A 3-Methyl-2- [4 '- (5-trifluoromethyl-pyridin-2-yloxy) -biphenyl-4-sulfonylamino] -butyric acid ester-butyl ester Step 14A: Tert-butyl ester of 2-acid was mixed (4 '-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid (100 mg, 0.25 mmol, 1.0 equiv.), 2-chloro-5-trifluoromethyl-pyridine (45.4 mg, 0.25 mmol, 1 equiv.) and 2C03 (86.4 mg, 0.63 mmol, 2.5 equiv.) in DMF (8 mL) and heated at 110 ° C for 4.5 hours. It was determined by means of the CCD that the reaction had been completed. The reaction mixture was then cooled to room temperature, diluted with EtOAc, washed with brine and dried over MgSO4. After removing the solvent, the crude product was purified by column chromatography (silica gel, 20% EtOAc / n-hexane) to obtain G9058-109-1 in a yield of 74% (100 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.96 (d, 7 = 6.82 Hz, 3 H) 1.14 (s, 9 H) 2.01 (, 1 H) 3.61 (m, 1 H) 5.07 (d, 7 = 9.85 Hz, 1 H) 7.03 (d, 7 = 8.59 Hz, 1 H) 7.19 (s, 1 H) 7.21 (s, 1 H) 7.55 (d, 7 = 8.59 Hz, 2 H) 7.62 (d, 7 = 8.59 Hz, 2 H) 7.85 (d, 7 = 2.02 Hz, 2 H) 7.88 (d, 7 = 6.06 Hz, 1 H) 8.40 (s, 1 H). Step 14B: 3-Methyl-2- [4 '- (5-trifluoromethyl-pyridin-2-yloxy) -biphenyl-4-sulfonylamino] -butyric acid tert-butyl ester (97 mg) was dissolved in CH2C12 (6). mL) and TFA (2 mL) was added. The reaction was completed in 6 hours as determined by means of CCD. After removing the solvent, the residue was purified by column chromatography (10% MeOH / CH2C12) to obtain 3-methyl-2- [4 '- (5-trifluoromethyl-pyridin-2-yloxy) -biphenyl acid. -4-sulfonylamino] -butyric with a yield of 66% (54.5 mg). 1 H NMR (400 MHz, MeOD) d ppm 0.81 (d, 7 = 6.82 Hz, 3 H) 0.88 (d, 7 = 6.82 Hz, 3 H) 1.97 (m, 1 H) 3.55 (d, 7 = 5.31 Hz, 1 H) 7.09 (d, 7 = 8.59 Hz, 1 H) 7.19 (d, 7 = 8.59 Hz, 2 H) 7.68 (dd, 7 = 14.65, 8.59 Hz, 4 H) 7.83 (d, 7 = 8.34 Hz, 2 H) 8.02 (d, 7 = 11.37 Hz, 1 H) 8.35 (d, 7 = 2.53 Hz, 1 H). Example 8B 3-Methyl-2- [4 '- (quinolin-2-yloxy) -biphenyl-4-sulfonylamino] -butyric acid tert-butyl ester The title compound, tert-butyl 3-methyl-2- [-] 4 '- (quinolin-2-yloxy) -biphenyl-4-sulfonyl-amino] -butyric acid, was prepared according to procedures similar to those of Example 8A. Step 14A [9058-120-1]: 2- (4'-Hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert -butyl ester (200 mg, 0.49 mmol, 1 equiv.) Was mixed. , 2-chloroquinoline (242 mg, 1.48 mmol, 3 equiv.) And Cs2CO3 (402 mg, 1.235 mmol, 2.5 equiv.) In DMF (8 mL) and the mixture was stirred at 100 ° C for 7 hours. The reaction mixture was cooled to room temperature, then placed in an ice bath and water was added. The solid precipitated from the mixture was collected by filtration and washed with water. After drying, 174 mg of a yellow solid was obtained with a yield of 66%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.88 (d, 7 = 6.82 Hz, 3 H) 1.03 (d, 7 = 6.82 Hz, 3 H) 1.22 (s, 9 H) 2.07 (m, 1 H) 3.68 (dd, 7 = 9.85, 4.55 Hz, 1 H) 5.15 (d, 7 = 9.85 Hz, 1 H) 7.15 (d, 7 = 8.84 Hz, 1 H) 7.38 (d, 7 = 8.84 Hz, 2 H) 7.45 (, 1 H) 7. 63 (m, 3 H) 7.71 (d, 7 = 8.84 Hz, 2 H) 7.81 (t, 7 = 8.72 Hz, 2 H) 7.91 (d, 7 = 8.59 Hz, 2 H) 8.17 (d, 7 = 8.34 Hz, 1 H). Step 14B [9058-121-2]: 3-Methyl-2- [4 '- (quinolin-2-yloxy) -biphenyl- tert -butyl ester was dissolved 4-Sulfonylamino] -butyric (164 mg) in dichloroethane • (12 mL) and hydrolyzed with TFA (4 mL) at room temperature over a period of 4 hours. The solvent was removed and the crude residue was purified by column chromatography (eluent 10% MeOH / DCE) to obtain 3-methyl-2- [4 '- (quinolin-2-yloxy) -biphenyl-4-acid. sulfonylamino] -butyric with a yield of 58% (84.8 mg). 1 H NMR (400 MHz, MeOD) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.88 (d, 7 = 6.82 Hz, 3 H) 1.97 (m, 1 H) 3.60 (d, 7 = 5.56 Hz, 1 H) 7.10 (d, 7 = 8.84 Hz, 1 H) 7.25 (d, 7 = 8.84 Hz, 2 H) 7.39 (t, 7 = 6.82 Hz, 1 H) 7.56 (t, 7 = 7.71 Hz, 1 H ) 7.63 (d, 7 = 0.51 Hz, 1 H) 7.65 (d, 7 = 1.26 Hz, 1 H) 7.68 (m, 1 H) 7.69 (d, 7 = 2.27 Hz, 1 H) 7.72 (m, 1 H ) 7.74 (m, 1 H) 7.79 (dd, 7 = 7.83, 1.26 Hz, 1 H) 7.82 (m, 1 H) 7.85 (m, 1 H) 8.23 (d, 7 = 8.84 Hz, 1 H). Example 8C N- ( {4 '- [(5-nitropyridin-2-yl) oxy] -l, 1-biphenyl-4-yl.}. Sulfonyl) -D-valine The title compound, N- ( {4 '- [(5-Nitropyridin-2-yl) oxy] -1,1' -biphenyl-4-yl}. Sulfonyl) -D-valine, was prepared according to procedures similar to those of Example 8A . Stage 14A and 14B: Yield 60%. 1 H NMR (400 MHz, MeOD) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.88 (d, 7 = 6.82 Hz, 3 H) 1.96 (m, 1 H) 3.58 (d, 7 = 5.31 Hz, 1 H) 7.11 (d , 7 = 9.09 Hz, 1 H) 7.22 (d, 7 = 8.84 Hz, 2 H) 7.70 (dd, 7 = 11.87, 8.84Hz, 4 H) 7.83 (d, 7 = 8.59 Hz, 2 H) 8.52 (dd) , 7 = 9.09, 2.78 Hz, 1 H) 8.91 (d, 7 = 3.28 Hz, 1 H). Example 8D N- ( { 4 '- [(2, 6-d ___ petc_sd.piri_pddi_n-4-yl) oxy] -1, 1' -bif enyl-4-yl.}. Sulfonyl) -D-valine The title compound , N- (. {4 '- [(2,6-shmetoxipir_im.din-4-yl) oxy] -l, 1-biphenyl-4-yl.} Sulfonyl) -D-valine, was prepared from according to procedures similar to those of Example 8A. Stage 14A and 14B: Yield 82%. 1 H NMR (400 MHz, MeOD) d ppm 0.81 (d, 7 = 6.82 Hz, 3 H) 0.88 (d, 7 = 6.82 Hz, 3 H) 1.97 (m, 1 H) 3.56 (d, 7 = 5.31 Hz, 1 H) 3.78 (s) , 3 H) 3.85 (s, 3 H) 5.73 (s, 1 H) 7.18 (d, 7 = 8.84 Hz, 2 H) 7.66 (d, 7 = 8.84 Hz, 3 H) 7.70 (d, 7 = 8.84 Hz , 3 H) 7.81 (s, 1 H) 7.83 (s, 1 H). Example 8E N- ( { 4 '- [(4-sloropyrimidin-2-yl) oxy] -l, 1-biphenyl-4-yl.}. Sulfonyl) -D-valine The title compound, N- ( {4 '- [(4-chloropyrimidin-2-yl) oxy] -1,1' -biphenyl-4-yl}. Sulfonyl) -D-valine, was prepared according to procedures similar to those of Example 8A . Stage 14A and 14B: Yield 59%. 1 H NMR (400 MHz, DMS0-D6) d "ppm 0.80 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.97 (m, 1 H) 3.47 (s, 1 H 7.24 (d, 7 = 5.81 Hz, 1 H) 7.42 (d, 7 = 8.84 Hz, 2 H) 7.87 (d, 7 H) 8.66 (d, 7 = 5.56 Hz, 1 H).

Example 8F N- [4 '- (pyridin-2-yloxy) -1, 1' -biphenyl-4-yl] sulfonyl} -D-valina The title compound, N-. { [4 '- (pyridin-2-yloxy) -1, 1' -biphenyl-4-yl] sulfonyl} -D-Valine, was prepared according to procedures similar to those of Example 8A. Stage 14A and 14B: Yield: 83%. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.85-2.02 (m, 1 H) 3.57 (dd, 7 = 10.48, 4.67 Hz, 1 H) 7.10 (d, 7 = 9.85 Hz, 1 H) 7.17 (dd, 7 = 7.20, 4.93 Hz, 1 H) 7.26 (d, 7 = 8.84 Hz, 2 H) 7.79 (d, 7 = 8.84 Hz, 2 H) 7.82-7.95 (m, 4 H) 8.09 (d, 7 = 9.35 Hz, 1 H) 8.13-8.28 (m, 1 H) .

Example 8G N-. { ['- (1,3-benzoxazol-2-yloxy) -1,1' -biphenyl-4-yl] sulfonyl} -D-valine The title compound, N-. { [4 '- (1,3-benzoxazol-2-yloxy) -1, 1' -biphenyl-4-yl] sulfonyl} -D-valine was prepared according to procedures similar to those of Example 8A. Stage 14A and 14B: Yield: 85%. 1 H NMR (400 MHz, DMS0-D6) d ppm 0.82 (d, 7 = 6.82 Hz, 3 H) 0.85 (d, 7 = 6.82 Hz, 3 H) 1.86-2.05 (m, 1 H) 3.58 (dd, 7 = 9.22, 5.94 Hz, 1 H) 7.32 (d, 7 = 9.35 Hz, 1 H) 7.53 (d, 7 = 7.33 Hz, 1 H) 7.61-7.73 (m, 3 H) 7.81-7.99 (m, 6 H) 8.10 (d, 7 = 9.35 Hz, 1 HOUR) .

Example 9A was prepared based on the Reaction Scheme . Example 9A N- ( {4 '- [2- (1-benzofuran-2-yl) -2-oxoethyl] -l, 1-biphenyl-4-yl}. Sulfonyl) -D-valine Step 15A: The (4-bromophenyl) -acetic acid (5.0 g, 23. 2 mmol, 1 equiv.) Dissolved in thionyl chloride (50 mL) was heated at reflux for 1 hour under a nitrogen atmosphere. The solution was cooled to room temperature and the solvent was evaporated. The residue obtained in this way was dissolved in anhydrous methylene chloride and used in Step 15B. Step 15B: Benzofuran-2-yltrimethylsilane (3.4 g, 17.86 mmol) was dissolved in methylene chloride (40 mL) and cooled to -78 ° C. At this temperature 4-bromophenyl-acetyl chloride (19.65 mmol, 1.1 equiv.) Was added. Under heavy stirring, a solution of TiCl4 (23 mL 1 M, 23.2 mmol, 1.3 equiv.) In CHC12 was added dropwise and stirring was continued for 20 minutes. Then, the reaction was stopped with H0 (100 L), the cooling bath was removed and the mixture was allowed to warm to room temperature. It was then diluted with H20 (100 mL) and extracted with CH2Cl2 (3x). The organic layers were combined, washed with brine, dried over MgSO4 and the solvent was evaporated. The crude product obtained in this way was subjected to column purification (silica gel, 10% EtOAc / hexane). 980 mg of l-benzofuran-2-yl-2- (4-bromo-phenyl) -ethanone was obtained in a yield of 17%. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 4.34 (s, 2 H) 7.34 (d, 7 = 8.59 Hz, 2 H) 7.44 (d, 1 H) 7.58 (d, 7 = 8.59 Hz, 2 H) 7.62 (d, 7 = 5.81 Hz, 1 H) 7.67 (s, 1 H) 7.71 (m, 1 H) 7.84 (t, 7 = 6.19 Hz, 1 H). Step 15C: A solution of 3-methyl-2- (4-tributylstannyl-benzenesulfonylamino) -butyric acid tert-butyl ester (347.5 mg, 0.58 mmol, 1.0 equiv.), 1-benzofuran-2-yl-2- ( 4-bromo-phenyl) -ethanone (200 mg, 0.64 mmol, 1.1 equiv.) And Pd (PPh3) 4 (66 mg, 0.06 mmol, 10%) in anhydrous toluene (10 mL) was heated to reflux for 7 hours. It was determined by means of the CCD that the reaction had been completed. The solvent was removed in a rotary evaporator and the crude product was purified by column chromatography (silica gel, 20% EtOAc / n-hexane) to obtain the tert-butyl ester of 2- [4 '- (2 -benzofuran-2-yl-2-oxo-ethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric in a yield of 20% (62 mg). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.79 (d, 7 = 6.82 Hz, 3 H) 0.95 (d, 7 = 6.82 Hz, 3 H) 1.11 (s, 9 H) 3.58 (dd, 7 = 9.85, 4.55 Hz, 1 H) 4.26 (s, 2 H) 5.05 ( d, 7 = 9.85 Hz, 1 H) 7.26 (t, 7 = 7.07 Hz, 1 H) 7.43 (m, 5 H) 7.56 (m, 4 H) 7.65 (d, 7 = 7.83 Hz, 1 H) 7.81 ( d, 7 = 8.59 Hz, 2 H). Step 15D: 2- [4 '- (2-Benzofuran-2-yl-2-oxo-ethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid tert-butyl ester (62 mg) was dissolved in anhydrous CH2C12 (6 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed and the crude product was purified by chromatography on column (10% MeOH / CH2C1) to obtain 2- [4 '- (2-benzofuran-2-yl-2-oxo-ethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid with a yield 19% (10.7 mg). 1 H NMR (400 MHz, DMSO-D6) d ppm 0.79 (d, 7 = 6.82 Hz, 3 H) 0.84 (m, 7 = 6.82 Hz, 3 H) 1.97 (m, 1 H) 3.33 (s, 1 H) 4. 42 (s, 2 H) 7.39 (t, 7 = 7.07 Hz, 1 H) 7.47 (d, 7 = 8.34 Hz, 2 H) 7.57 (t, 7 = 8.59 Hz, 1 H) 7.73 (m, 3 H) 7.83 (d, 4 H) 7.88 (d, 7 = 8.84 Hz, 1 H) 8.13 (s, 1 H) 10.08 (s, 1 H).

Example 10A was prepared based on Reaction Scheme 16. Example 10A D-2- [4'- (Benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 16A: The starting material, 2- [1, 2, 3] thiadiazole-4- il-phenol was prepared according to a procedure of the literature (MA Abramov, Dehaen, B. D'hooge, ML Petrov, S. Smeets, S. Toppet and M. Voets, Tetrahedron 2000, 56, 3933-3940) . 2 - [1, 2, 3] thiadiazol-4-yl-phenol (241 mg, 1.35 mmol), 2- (4-bromomethyl-phenyl) -4,4,5,5-tetramethyl- [ 1, 3, 2] dioxaborlane (406 mg, 137 mmol, 1 equiv.) and K2C03 (396 mg, 2.87 mmol, 1.9 equiv.) in 8 mL of CH3CN and heated to 90 ° C under a nitrogen atmosphere. After completion of the reaction, as monitored by means of the CCD, the mixture was cooled to room temperature and the solvent was evaporated. The resulting crude material was subjected to column chromatography (20% EtOAc in hexane) for 2- [4- (4,, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzylsulphane ] benzofuran (198 mg) with a yield of 40%. NMR: G8475-125. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.3 (s, 12 H) 4.1 (s, 2 H) 6.6 (d, 7 = 1.0 Hz, 1 H) 7.2 (m, 4H) 7.4 (d, 7 = 7.8 Hz, 2 H) 7.7 (d, 7 = 8.1 Hz, 2 H). Step 16B: The Suzuki coupling of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester with 2- [4- (4, 4, 5, 5-tetramethyl- [1] 3, 2] dioxaborolan-2-yl) benzylsulfane] -benzofuran was carried out according to the procedures of Step 5B of Example 2A, to obtain the methyl ester of D-2- [4 '- (benzofuran-2 -ylsulfanylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric with a yield of 54%. NMR: G8475-165. 1 H NMR (400 MHz, BENZEN-D6) d ppm 0.7 (d, 7 = 6.8 Hz, 3 H) 0.9 (d, 7 = 6.8 Hz, 3 H) 1.9 (m, 1 H) 3.0 (s, 3 H) 4.0 (m, 3 H) 5.0 (d, 7 = 10.1 Hz, 1 H) 6.6 (d, 7 = 1.0 Hz, 1 H) 7.1 (m, 4H) 7.3 (m, 6H) 7.3 (s, 1H) 7.4 ( , 1 HOUR) . Step 16C: A solution of the methyl ester of D-2- [4'- (benzofuran-2-ylsulfanylmethyl) -biphenyl-4-methyl ester sulfonylamino] -3-methyl-butyric acid (75 mg, 0.15 mmol, 1 equiv.) in 4 mL of THF 'was placed in an ice bath. 125 mg of MCPBA (77%, 0.55 mmol, 3.7 equiv.) In 3 mL of THF were added dropwise. After completing the addition, the ice bath was removed and the reaction was allowed to warm to room temperature with stirring for 12 hours. The CCD indicated that the reaction was complete. By normal treatment and column chromatography (20% EtOAc in hexane) provided the methyl ester of D-2- [4'- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid. (56 mg) with a yield of 70%. NMR: G8475-166. 1 H NMR (400 MHz, CHLOROFORM-D) D ppm 0.9 (dd, 7 = 33.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.4 (s, 3 H) 3.8 (dd, 7 = 10.1, 5.3 Hz , 1 H) 4.6 (s, 2 H) 5.1 (d, 7 = 10.1 Hz, 1 H) 7.4 (m, 4 H) 7.5 (m, 3 H) 7.6 (m, 1 H) 7.7 (m, 3 H ) 7.9 (d, 7 = 8.8 Hz, 2 H). Step 16D: The hydrolysis of the methyl ester of D-2- [4 '- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was carried out according to the procedures of the Step ID of Example IA, with a quantitative yield. 1 H NMR (400. MHz, DMSO-D6) d ppm 0.8 (dd, "7 = 12.1, 6.8 Hz, 6 H) 1.9 (, 1 H) 3.5 (dd, J = 9.3, 6.1 Hz, 1 H) 5.0 (s, 2 H) 7.4 (d, J = 8.3 Hz, 2 H) 7.4 (m, 1 H) 7.6 (, 1 H) 7.7 (d, J = 1 .0 Hz, 1 H) 7.7 (d, J = 8.3 Hz, 2 H) 7.8 (m, 6 H) 8.1 (d, J = 9.1 Hz, 1 H) .

The following compounds (11A-11B) were prepared according to Reaction Scheme 6B. Example HA 3-Methyl-2- [4'- (naphthalen-2-ylmethoxy) -3'-methoxy-biphenyl-4-sulfonylamino] -butyric acid NMR X ?. (400 MHz, DMSO): d 0.806 (d, 3H), 0.837 (d, 3H), 1.94 (m, 1H), 3.53 (t, 1H), 3.90 (s, 3H), 5.33 (s, 2H), 7. 20 (d, 1H), 7.27 (m, 1H), 7.34 (s, 1H), 7.54 (d, 2H), 7.61 (d, 1H), 7.89 (m, 8H); ES + m / z 518.2 (M-H); HRMS (C29H29N06S): calculated; 520.17884; found; 520.17839 (M + H). Example 11B 2- [4 '- (3,5-Dimethoxy-benzyloxy) -3' -methoxy-biphenyl-4-sulfonylamino] -3-methyl-butyric acid X H NMR (400 MHz, DMSO): d 0. 808 (d, 3H), 0. 838 (d, 3H), 1.94 (m, 1H), 3.74 (s, 6H), 3.89 (s, 3H), 5.09 (s, 2H), 6.45 (t, 1H), 6.62 (d, 2H), 7.11 (d, 1H) ), 7.25 (d, 1H), 7.32 (d, 1H), 7.79 (d, 2H), 7.85 (d, 2H), 8.02 (d, 1H); ES + m / z 528.2 (M-H); HRMS (C27H31N08S): calculated; 530,18432; found; 530.18367 (M + H).

The following compounds (12A-12R) were prepared using the procedures described in Reaction Scheme 17. Example 12A 2- (4'-Hydroxy-3-trifluoromethoxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid XR-NMR (400 MHz, DMSO): d 0.825 (d, 3H), 0.875 (d, 3H), 2.04 (, 1H), 3.70 (m, 1H), 6.89 (d, 2H), 7.59 (, 2H), 7. 75 (dd, 1H), 7.94 (d, 1H), 8.16 (d, 1H); ES + m / z 432.1 (M-H); HRMS (C18H18F3N06S): calculated; 451.11451; found; 451. 11461 (M + NH4).

Example 12B 2- (4'-Hydroxy-3-trifluoromethyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid NMR aH (400 MHz, DMSO): d 0.850 (m, 6H), 2.02 (m, 1H), 3.60 (m, 1H), 6.90 (d, 2H), 7.67 (d, 2H), 8.10 (m, 3H); ES + m / z 416.0 (M-H); HRMS (C18H18F3N05S): calculated; 435.11960; found; 435.11966 (M + NH4).

Example 12C 2- ('-hydroxy-3-methyl-biphenyl-4-sulfonylamino) -3-methyl-butyric acid NMR (400 MHz, DMSO): d 0.810 (t, 6H), 1.93 (, 1H), 2.64 (s, 3H), 3.39 (m, 1H), 6.87 (m, 2H), 7.56 (m, 3H), 7. 81 (d, 1H), 8.00 (d, 1H); ES + m / z 362.1 (M-H); HRMS (C18H21N05S): calculated; 381.14786; found; 381.14808 (M + NH4).

Example 12D 2- (3-Fluoro-4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid XH NMR (400 MHz, DMSO): d 0.850 (, 6H), 2.02 (m, 1H), 3.63 ( m, 1H), 6.87 (d, 2H), 7.61 (m, 3H), 7.76 (t, 1H), 8.22 (d, 1H); ES + m / z 366.0 (M-H); HRMS (C17H18FN05S): calculated; 385.12279; found; 385.12276 (M + NH4).

Example 12? (Abs) 2- (2,5-Difluoro-4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid XH NMR (400 MHz, DMSO): d 0.880 (m, 6H), 2.04 (m, 1H) , 3.69 (, 1H), 6.89 (d, 1H), 7.45 (m, 2H), 7.58 (m, 2H), 8.45 (d, 1H); ES + m / z 384.1 (M-H); HRMS (C17H17F2N05S): calculated; 403.1137; found; 403.11328 (M + NH4).

Example 12F 3-Methyl-2- [4 '- (naphthalen-2-ylmethoxy) -3-trifluoromethyl-biphenyl-4-sulfonylamino] -butyric acid NMR XH (400 MHz, DMSO): d 0.900 (d, 3H), 0.960 ( d, 3H), 2.06 (m, 1H), 3.70 (d, 1H), 4.19 (s, 2H), 6.95 (d, 1H), 7. 43 (m, 6H), 7.69 (s, 1H), 7.75 (m, 3H), 7.88 (m, 1H), 7.97 (s, 1H), 8.15 (d, 1H); ES + m / z 556.1 (M-H); HRMS (C29H26F3N05S): calculated; 558.15566; found; 558.15484 (M + H).

Example 12G 2- [3-Fluoro-4'- (naphthalen-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid XH-NMR (400 MHz, MeOH): d 0.920 (d, 3H), 0.980 ( d, 3H), 2.10 (m, 1H), 3.76 (d, 1H), 4.19 (s, 2H), 6.94 (d, 1H), 7.43 (m, 7H), 7.70 (s, 1H), 7.78 (m, 4H) ); ES + m / z 506.1 (M- H); HRMS (C28H26FN05S): calculated; 508.15885; found; 508.15818 (M + H).

Example 12H 2- [2,5-Difluoro-4 '- (naphthalen-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid XH NMR (400 MHz, MeOH): d 0.910 (d, 3H), 0.980 (d, 3H), 2.09 (m, 1H), 3.78 (d, 1H), 4.16 (s, 2H), 6.92 (d, 1H), 7. 37 (m, 6H), 7.56 (m, 1H), 7.67 (s, 1H), 7.75 (, 4H); ES + m / z 524.1 (M-H); HRMS (C28H25F2N05S): calculated; 526.14943; found; 526.14881 (M + H).

Example 12 ES + m / z 614.1 (M-H) -HRMS: 616.16053 (M + H) +; 616.16114 Calculated H-NMR (400 MHz, DMSO): d 0.83 (d, 3H, 7 = 6.8 Hz), 0.088 (d, 3H, 7 = 6.8 Hz), 2.06 (m, 1H), 3.74 (dd, 1H, 7 = 5.6) , 10 Hz), 5.18 (s, 2H), 5.35 (d, 1H, 7 = 10 Hz), 6.92 (d, 2H, 7 = 8 Hz), 7.00 (d, 2H, 7 = 8 Hz), 7.07 ( d, 2H, 7 = 8 Hz), 7.34 (d, 2H, 7 = 8 Hz), 7.61 (d, 2H, 7 = 8 Hz), 7.69 (s, 1H), 7.79 (d, 2H, 7 = 8 Hz), 7.88 (m, 1H), 8.02 (d, 1H, 7 = 8 Hz), 8.24 (m, 1H), 12.70 (s, 1H).

Example 12J ES + m / z 598.1 (M-H) -HRMS: 600.16554 (M + H) +; 600. 16622 Calculated NMR H (400 MHz, DMSO): d 0.85 (d, 3H, 7 = 6.8 Hz), 0.08 (d, 3H, 7 = 6.8 Hz), 2.05 (m, Example 12K ES + m / z 564.1 (M-H) -HRMS: 566.13860 (M + H) +; 566.13987 Calculated NMR H (400 MHz, DMSO): d 0.84 (d, 3H, 7 = 6.8 Hz), 0.86 (d, 3H, 7 = 6.8 Hz), 2.02 (m, 1H), 3.57 (dd, 1H, 7 = 6, 9.2 Hz), 5.17 (s, 2H), 6.92 (d, 2H, 7 = 8 Hz), 6.99 (d, 2H, 7 = 8 Hz), 7.07 (m, 3H), 7.33 (m, 2H ), 7.59 (d, 2H, 7 = 8 Hz), 7.83 (m, 5H), 7.95 (d, 1H, 7 = 1.6 Hz), 8.03 (d, 1H, 7 = 8 Hz), 8.21 (m, 1H ), 12.65 (s, 1H) '.

Example 12L 1 (M-H) -HRMS: 592.16098 (M + H) +; 592. 16114 Calculated NMR aH (400 MHz, DMSO): d 0.83 (d, 3H, 7 = 6.8 Hz), 0. 88 (d, 3H, 7 = 6.8 Hz), 2.05 (m, 3H), 2.53 (t, 2H, 7 = 6 Hz), 2.91 (t, 2H, 7 = 6 Hz), 3.74 (dd, 1H, 7 = 5.6, 10 Hz), 5.28 (s, 2H), 6.98 (m, 2H), 7.60 (d, 2H, 7 = 8 Hz), 7.69 (s, 1H), 7.85 (m, 4H), 8.02 (d, 1H, 7 = 8 Hz), 8.25 (d, 1H, 7 = 8 Hz), 12.70 (s, 1H).

Example 12M ES "1 m / z 574.1 (M-H) -HRMS: 576.16522 (M + H) +; 576. 16622 Calculated XH NMR (400 MHz, DMSO): d 0.85 (d, 3 H, 7 = 6.8 Hz), 0.86 (d, 3 H, 7 = 6.8 Hz), 2.04 (m, 3 H), 2.53 (t, 2 H, 7 = 6 Hz), 2.91 (t, 2H, 7 = 6 Hz), 3.63 (dd, 1H, 7 = 6, 10 Hz), 5.29 (s, 2H), 6.98 (, 2H), 7.61 (d, 2H, 7 = 8 Hz), 7.85 (m, 3H), 8.20 (m, 4H), 12.70 (s, 1H). Example 12N ES + m / z 524.1 (M-H) -HRMS: 526.16859 (M + H) +; 526.16942 Calculated NMR (400 MHz, DMSO): d 0.84 (d, 3H, 7 = 6.8 Hz), 0. 87 (d, 3H, 7 = 6.8 Hz), 2.02 (m, 3H), 2.53 (t, 2H, 7 = 6 Hz), 2.91 (t, 2H, 7 = 6 Hz), 3.66 (dd, 1H, 7 = 6, 9.2 Hz), 5.27 (s, 2H), 6.98 (m, 2H), 7.58 (d, 2H, 7 = 8 Hz), 7.70 (m, 1H), 7.83 (m, 5H), 8.30 (d, 1H, 7 = 10 Hz), 12.65 ( s, 1H). Example 120 ES + m / z 629.2 (M-H) -HRMS: 631.17159 (M + H) +; 631.17204 Calculated NMR aH (400 MHz, DMSO): d 0.83 (d, 3H, 7 = 6.8 Hz), 0. 88 (d, 3H, 7 = 6.8 Hz), 2.07 (m, 1H), 2.30 (s, 3H), 3.74 (dd, 1H, 7 = 5.6, 9.6 Hz), 5.20 (s, 2H), 6.68 (d, 1H, 7 = 8 Hz), 6.95 (d, 1H, 7 = 8 Hz), 7.06 (m, 4H), 7.62 (d, 2H, 7 = 8 Hz), 7.69 (m, 2H), 7.80 (d, 2H, 7 = 8 Hz), 7.87 (dd, 1H, 7 = 1.6, 8 Hz), 8.03 (d, 1H, 7 = 8 Hz), 8.25 (d, 2H, 7 = 9.2 Hz), 12.70 (s, 1H). Example 12P ES + m / z 613.2 (M-H) -HRMS: 615.17639 (M + H) +; 615.17712 Calculated XR NMR (400 MHz, DMSO): d 0.85 (d, 3H, 7 = 6.8 Hz), 0. 87 (d, 3H, 7 = 6.8 Hz), 2.05 (m, 1H), 2.30 (s, 3-H), 3.63 (d, 1H, 7 = 6, 9.6 Hz), 5.20 (s, 2H), 6.68 (d, 1H, 7 = 8 Hz), 6.95 (d, 1H, 7 = 8 Hz), 7.06 (m, 4H), 7.63 (d, 2H, 7 = 8 Hz), 7.69 (t, 1H, 7 = 8 Hz), 7.87 (d, 2H, 7 = 8 Hz), 8.21 (m, 4H), 12.70 (s, 1H). Example 12Q ES + m / z 563.2 (M-H) -HRMS: 565.18038 (M + H) +; 565.18032 Calculated NMR H (400 MHz, DMSO): d 0.84 (d, 3H, 7 = 6.8 Hz), 0. 87 (d, 3H, 7 = 6.8 Hz), 2.04 (m, 1H), 2.30 (s, 3H), 3.66 (dd, 1H, 7 = 6, 9.6 Hz), 5.19 (s, 2H), 6.68 (d , 1H, 7 = 8 Hz), 6.95 (d, 1H, 7 = 8 Hz), 7.06 (s, 4H), 7.60 (d, 2H, 7 = 8 Hz), 7.70 (m, 2H), 7.83 (m, 4H), 8.31 (d, 1H, 7 = 9.2 Hz), 12.70 (s, 1H). Example 12R ES + m / z 579.1 (M-H) -HRMS: 581.15050 (M + H) +; 581.15077 Calculated X H NMR (400 MHz, DMSO): d 0.84 (d, 3 H, 7 = 6.8 Hz), 0.86 (d, 3 H, 7 = 6.8 Hz), 2.02 (m, 1 H), 2.30 (s, 3 H), 3.58 ( dd, 1H, 7 = 6.4, 9.6 Hz), 5.20 (s, 2H), 6.68 (d, 1H, 7 = 8 Hz), 6.95 (d, 1H, 7 = 8 Hz), 7.06 (s, 4H), 7.60 (d, 2H, 7 = 8 Hz), 7.62 (d, 2H, 7 = 8 Hz), 7.83 (m, 3H), 7.95 (d, 1H, 7 = 1.6), 8.03 (d, 1H, 7 = 8 Hz), 8.22 (d, 1H, 7 = 9.6 Hz), 12.70 (s, 1H). Class 13 Examples 13A, 13B, 13C were prepared based on Reaction Scheme 5. Example 13A (Á¡Ü) 3-Methyl-2- [4 '- (pyridin-3-ylmethoxymethyl) -biphenyl-4-sulfonylamino] -butyric acid XH NMR (400 MHz, MeOD): d; ES + m / z (M + H) 455.1; HRMS (M + H) m / z calculated 455.16352; found 455.16317; (C24H26N205S): Example 13B 3-Methyl-2- [4'- (naphthalen-2-ylmethoxymethyl) -biphenyl-4-sulfonylamino] -butyric acid XH NMR (400 MHz, CDCl3): d 0.85 (d, 3H), 0.95 (d, 3H) , 2.10 (m, 1H), 3.83 (m, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 5.25 (s broad, 1H), 7.44-7.55 (m, 7H), 7.65 (d, 2H), 7.82-7.90 (, 6H); ES + m / z (M-H) 502.1; HRMS (M + H) m / z calculated 504.18392; found 504.18503; (C29H29 05S): Example 13C (Ábs) 3-Methyl-2- [4 '- (pyridin-3-ylmethoxymethyl) -biphenyl-4-sulfonylamino] -butyric acid NMR (400 MHz, DMSO): d 0.81 (d, 3H), 0.84 (d, 3H), 1.95 (m, 1H), 3.55 (dd, 1H), 4.56 (s, 2H), 4.63 (d, 2H), 7. 44 (d, 2H), 7.50 (d, 1H), 7.70 (d, 2H), 7.74 (d, 1H), 7.84 (m, 4H), 8.08 (m, 2H); ES + m / z (M + H) 455.1; HRMS (M + H) m / z calculated 455.16352; found 455.16290; (C24H26N205S). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:
1. A compound of formula 1: characterized in that: R1 is H or alkyl of 1 to 6 carbon atoms; R2 is H, alkyl of 1 to 6 carbon atoms, (CH2) nR2 ', phenyl or benzyl; n is 0-6; R2 'is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R3 is, independently in each of the occurrences, H, halogen, OC (halogen) 3, C (halogen) 3, alkoxy or alkyl of 1 to 6 carbon atoms; X is selected from CH20, OCH2, C (R3) = C (R3), C (R3) 2- C (R3) 2, CH2NHC (= 0), 0 (C = 0) NH, O, C (= 0) CH2, S02CH2C (= 0) NH, S02NH, 0C (= 0), CH2S (0) and CH2S (0) 2; and Z is at least a portion of aryl or heteroaryl.
2. 2. The compound according to claim 1, characterized in that Z is pyridine, pyrimidine, pyrazine, pyridazine, phenyl, naphthalene, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, benzothiazole, quinoline or isoquinoline, or where: U is selected from S, 0, C (R-r) 3)? , C (RJ) = N and N (R4); W is selected from C (R3) and N; M is selected from C (R3) and N; L is selected from S, O, C Y N (R4); R4 and R5 are, independently in each of the occurrences, a bond with the other, H, alkyl of 1 to 6 carbon atoms or phenyl; R7 is selected from a bond to R3, H, halogen, C (halogen) 3, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC ( = 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl, heteroaryl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl from 2 to 6 carbon atoms; and R8 is selected from H, phenyl, heteroaryl, and alkyl of 1 to 6 carbon atoms.
3. 3. The compound according to claim 2, characterized in that R7 is substituted with NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR8, C (= 0) R4, COOR4, C0NR4R5, CN, phenyl or heteroaryl.
4. 4. The compound according to claim 2, characterized in that R8 is substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0 ) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl or heteroaryl.
5. 5. The compound according to claim 1, characterized in that R1 is H or branched alkyl.
6. 6. The compound according to claim 1, characterized in that R1 is isopropyl.
7. 7. The compound according to claim 1, characterized in that R3 is halogen, CF3, OCH3 or CH3.
8. 8. The compound according to claim 1, characterized in that X is CH20, OCH2, C (R3) = C (R3) or CH2NHC (= 0).
9. 9. The compound according to claim 1, characterized in that R7 is CH3, ethyl, isopropyl, CF3, CN or 0CH3.
10. 10. The compound according to claim 1, characterized in that R8 is CH3, phenyl and benzyl.
11. 11. The compound according to claim 1, characterized in that Z is bicyclic.
12. 12. A method for modulating the activity of a metalloproteinase, characterized in that it comprises contacting the metalloproteinases with an effective amount of the compound according to claim 1.
13. 13. The method according to claim 12, characterized in that it comprises determining the activity of metalloproteinase.
14. 14. The method according to claim 13, characterized in that the Determination is made before the contact step.
15. 15. The method according to claim 13, characterized in that the determination is made after the contact step.
16. 16. The method according to claim 12, characterized in that the metalloproteinase is aggrecanase-1.
17. 17. The method according to claim 16, characterized in that the configuration at the alpha carbon atom of the compound is _R.
18. 18. The method according to claim 12, characterized in that the metalloproteinase is collagenase-3.
19. 19. A method for treating a patient suspected of suffering from a disease associated with excessive metalloproteinase activity, characterized in that it comprises the step consisting of administering to the patient a therapeutically effective amount of the compound according to claim 1.
20. 20. The method according to claim 19, characterized in that the disease is cancer, os teoartri tis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, macular degeneration related to age, myocardial infarction, ulcer of the cornea and other diseases of the ocular surface, hepatitis, aortic aneurysms, tendonitis, diseases of the central nervous system, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft disease against host, diabetes, inflammatory bowel disease, shock, degeneration of intervertebral discs, stroke, osteopenia or periodontal diseases.