MXPA06006211A

MXPA06006211A - Biaryl sulfonamides as mmp inhibitors

Info

Publication number: MXPA06006211A
Application number: MXPA/A/2006/006211A
Authority: MX
Inventors: Li Wei; Ian Levin Jeremy; Du Xuemei; Cecil Cole Derek; Shaoyun Xiang Jason; Hu Yonghan; Saltmarsh Rush Thomas Iii; Lovering Frank; Li Jianchang; Jun Wu Jun; Hotchandani Rajeev; Yikkai Tam Steve
Original assignee: Wyeth*
Priority date: 2003-12-04
Filing date: 2006-06-01
Publication date: 2006-10-17

Abstract

The present invention relates to biaryl sulfonamides and their use as, for example, metalloproteinase inhibitors:Formule (I).

Description

BIARIL ITS FONAMIDAS AS OPHTHOIDASE METHANE INHIBITORS OF MATRIX (MMP) FIELD OF THE INVENTION The present invention relates to biaryl sulfonamides and their use as, for example, metalloproteinase inhibitors.

BACKGROUND OF THE INVENTION Metalloproteinases, including matrix metalloproteinases and aggrecanases, are known to play a role in connective tissue disintegration. Matrix metalloproteinases ("MMPs") are a superfamily of proteolytic enzymes that are genetically related and capable of degrading almost all constituents of the extracellular matrix and basement membrane that restrict cell movement. The aggrecanases, members of the ADAMTS protein family (A disintegrin and metalloproteinase with thrombospondin motifs), divide aggrecan, a component of cartilage also known as the proteoglycan of large aggregant chondroitin sulfate. MMPs and aggrecanases can degrade various connective tissue components, including collagen and proteoglycan. In the absence of natural controls on this activity, a variety of pathologies and REF may occur. DO NOT. 173347 undesirable effects. In fact, it is known that MMPs and aggrecanases play a role in many disorders in which degradation / destruction of extracellular protein occurs, 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, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft-versus-host disease, diabetes, inflammatory bowel disease, shock, intervertebral disc degeneration, stroke, osteopenia, and periodontal diseases, therefore inhibitors of metalloproteinases, including MMP inhibitors and aggrecanases, are needed. directed to specific MMP and aggrecanases They are valuable to avoid potential side effects.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the present invention provides novel biaryl sulfonamide compounds. Preferred compounds of the invention are those of formula 1: wherein: R1 and R2 are, independently, H, CH (OH) R4, phenyl, heteroaryl, or C? -C6 alkyl, with the proviso that, when R1 or R2 is CH (OH) R4, then Z is substituted with NR4S02R5, S02NRR5, heterocycloalkyl, heteroaryl or C3-C6 cycloalkyl; R3 is H or C6-C6 alkyl; R4 and R5 are, independently with respect to each event, a bond with the other, H, C? -C6 alkyl, or phenyl; G and E are, independently, S, O, N (R4), C (R6) = C (R6), or N = C (R6); R6 is, independently with respect to each event, H, halogen, NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NRR5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl, heteroaryl, C? -C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; X is N (R3) C (= 0), 0C (= 0), OS (0) 2, NHS02, OCH2, CH2S (0), or CH2S (0) 2; and Z is at least one heteroaryl radical. In another aspect, the present invention provides methods for the use of biaryl sulfonamide compounds to modulate and, preferably, inhibit metalloproteinases. Preferred methods involve contacting in vitro and in vivo the metalloproteinase with a biaryl sulfonamide. Preferred methods of this type are those in which the metalloproteinase activity is determined before or after such contact and, optionally, the determination is the use to assess 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 the biaryl sulfonamide compounds of the present invention are useful in the inhibition of metalloproteinases. further, some compounds show great specificity for some metalloproteinases. Such compounds may be useful in the treatment of cancer, osteoarthritis, rheumatoid 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-versus-host disease, diabetes, inflammatory disease intestinal, shock, degeneration of the intervertebral discs, apoplexy, osteopenia and periodontal diseases. The metalloproteinase is preferably Gelatinase A (MMP-2), Macrophage metalloelastase (MMP-12), Collagenase-3 (MMP-13) or Agrecanase-1 (ADAMTS4). More preferably, the metalloproteinase is MMP-13. Preferred compounds of the invention are those of formula 1: wherein: R1 and R2 are, independently, H, CH (OH) R4, phenyl, heteroaryl, or C? -C6 alkyl, with the proviso that, when R1 or R2 is CH (OH) R4, then Z is substituted with NR4S02R5, S02NR4R5, heterocycloalkyl, heteroaryl or C3-C6 cycloalkyl; R3 is H or C6-C6 alkyl; R4 and R5 are, independently with respect to each event, a bond with the other, H, C? -C6 alkyl, or phenyl; G and E are, independently, S, O, N (R4), C (R6) = C (R6), or N = C (R6); R6 is, independently with respect to each event, H, halogen, NR R5, N [(CH2)] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NR4R5, S02R4, OR4, C (= 0) R 4, COOR 4, CONR R 5, CN, phenyl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; X is N (R3) C (= 0), 0C (= 0), 0S (0) 2, NHS02, OCH2, CH2S (o), or CH2S (0) 2; and Z is at least one heteroaryl radical. When it is other than H, R1 may be optionally substituted with halogen, C02R4, C (= 0) NR4R5, phenyl or heteroaryl. When it is other than H, R3 may be optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NRC (= 0) R5, NHC (= 0) 0R4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl. In one embodiment, each R6 is optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NRC (= 0) 0R4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl or heteroaryl. In one embodiment, Z is a 5-membered ring. In another modality, Z is bicyclic. In yet another embodiment, Z is furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, thiazole, 1, 2, 5-thiadiazole, 1, 2, 3-triazole, 1, 3, 4-thiadiazole, 1, 2, 3-thiadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1, 2,4-oxadiazole, 1,3,4-oxadiazole and furazane, or wherein: ü is selected from S, 0 and N (R4); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R5) = C (R6), C (R6) = N and N (R4); R7 is selected from a bond with R6, H, halogen, NR4R5, Nt (CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONRR5, CN, phenyl, heteroaryl, Ci-Cß alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally 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, C0NRR5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, 'NRS02R5, NR4C (= 0) R5 , NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, C0NRR5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl. Preferably, Z is: where: U is selected from S, 0 and N (R4); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N, and N (R4); R7 is selected from a bond with R6, H, halogen, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02 , S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, C0NR4R5, CN, phenyl, heteroaryl and C? -C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with NR4R5, N [ (CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R5 , CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NRR5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl. In another modality: R3 is H; G is C (H) = C (H); E is C (H) = C (H) or N = C (H); X is NHC (= 0), or OCH2; Y Z is where: U is selected from S, O and N (R); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R4); R7 is selected from a bond with R6, H, halogen, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4 , COOR4, CONRR5, CN, phenyl, heteroaryl and Ci-Cß alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally substituted with NRR5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4 , NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NRR5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl. Preferably: E is C (H) = C (H); ü is O; W is C (H), or C (CH3); M is C (R9), where R9 is H, halogen, C? -C6 alkyl, or CN; and L is C (H) = C (H). The term "alkyl", as used herein, if used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, linear and branched chains containing from 1 to 12 carbon atoms, preferably 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". Alkyl dC6 includes straight or branched chain aliphatic groups having from 1 to 6 carbons. Specifically include aliphatic hydrocarbon chains that are optionally substituted, within the definition of "alkyl". The carbon number, as used in the definitions herein, refers to the carbon skeleton and the carbon branches, but does not include carbon atoms in the substituents, such as alkoxy substitutions and the like. The term "alkenyl", as used herein, if 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 and branched chains having of 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl radical has 1 or 2 double bonds. Such alkenyl radicals can exist in E or Z conformations, and the compounds of this invention include both conformations. The C2-C6 alkenyl includes a straight or branched chain of 2 to 6 carbons having at least one carbon-carbon double bond. Specifically included are aliphatic hydrocarbon chains that are optionally substituted, within the definition of "alkenyl". Heteroatoms, such as O, S or NR4R5, attached to an alkenyl, should not be attached to a carbon atom that is bonded to a double bond. The term "alkynyl" refers to a hydrocarbon radical containing at least one carbon-carbon triple bond. C2-C6 alkynyl includes linear or branched chains of 2 to 6 carbons having at least one carbon-carbon triple bond. The term "cycloalkyl" refers to a radical saturated monovalent monocyclic, bicyclic, tricyclic, fused, bridged or spiro hydrocarbon, where the carbon atoms are located inside or outside the ring system. Any suitable ring position of the cycloalkyl radical can be covalently linked to the defined chemical structure. Examples of cycloalkyl radicals 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. C3 ~ C6 cycloalkyl includes saturated monocyclic rings of 3 to 6 carbons, optionally substituted with R6. "Heteroaryl" refers to a 5-6 membered aromatic heterocyclic ring containing from 1 to 4 heteroatoms, selected from the group consisting of oxygen, nitrogen and sulfur atoms, in the ring 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 1 to 2 heteroatoms selected from N, 0 and S. The term "phenyl", as used herein, is if used alone or as part of another group, refers to a substituted or unsubstituted phenyl group.

An optionally substituted radical may be substituted with one or more substituents. Suitable substituents for a phenyl or heteroaryl radical can be independently selected from H, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NRR5, N [(CH) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5 and CN. When such radicals are substituted, for example, they may be usually mono-, di-, tri- or per-substituted. 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 the sake of 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 so that it satisfies the valence of the atom or compound.For example, when L is C (R6) = C (R6), both carbon atoms are part of the ring to satisfy their respective valences.Also, when divalent substituents are present, understands that they are not limited to the listed order, for example, as used in this specification, "OCH2" comprises CH20 and OCH2. 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 similarly known acceptable acids when a compound of this invention contains a basic radical. The salts can also be formed from organic or inorganic bases, preferably alkali metal salts, for example, sodium, lithium or potassium, when a compound of this invention contains a carboxylate or phenolic radical, or a similar radical capable of forming salts of addition of bases. The term "patient", as used herein, refers to a mammal, preferably a human. The terms "administering" or "administration", as used herein, refer to directly administering a compound or composition to a patient, or administering a prodrug or analogue derivative of the compound to the patient, which will form an equivalent amount of the compound or active substance inside the patient's body. The term "vehicle", as used herein, It will include vehicles, excipients and diluents. The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. Although in formula I they are shown without regard to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as 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 may be provided substantially free of the corresponding enantiomer. Thus, a substantially free enantiomer of the corresponding enantiomer refers to a compound that is isolated or separated by separation techniques, or free preparation of the corresponding enantiomer. "Substantially free", as used herein, means that the compound is formed by a significantly greater proportion of a stereoisomer, preferably with less than about 50% of the other, more preferably less than about 75%, and even more preferably less of approximately 90%. Among the groups R1 and R2 observed above, C6-C6 alkyl is preferred.

Among the R3 groups observed above, H. is preferred. Among the groups R4 and R5 observed above C6-C6 alkyl is preferred. Among the groups G and E observed above, C (H) = C (H) is preferred. Among the groups U observed above, 0 and S are preferred. Among the groups noted above, C (H) and C (CH3) are preferred. Among the M groups observed above, CR6 is preferred. Among the groups L observed above, CH = CH is preferred. Among the R7 groups noted above, any other group than H is preferred. The following compounds are preferred: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1-biphenyl-4 -yl.} sulfonyl) glycine; L-2- acid. { 4 '- [(benzofuran-2-carbonyl) amino] biphenyl-4-sulfonylamino} -3-methyl-butyric; N- (. {4 '- [(1H-indol-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) glycine; (4 '- { [(5-chloro-l-benzofuran-2-yl) carbonyl] amino.} -1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(7-methoxy-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '-. {[[(5-nitro-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-amino-1-benzofuran-2-yl) carbonyl] amino] -1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- (. {4 '- [( { 5- [(methylsulfonyl) amino] -l-benzofuran-2-yl} .carbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-valine; N-. { [4 '- ( { [5- (acetylamino) -l-benzofuran-2-yl] carbonyl lamino) -1, 1' -biphenyl-4-yl] sulfonyl} -L-valine; 4 '- [(5-benzenesulfonylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine; N- [(4 '- { [(4-methoxy-l-benzofuran-2-yl) carbonyl] amino] -! -! 1' -biphenyl-4-yl) sulfonyl] -L-valine; 4 '- [(benzo [ß] thiophen-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine; 4 '- [(4-benzyloxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine; 4' -. { [4- (1-carboxy-ethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonyl-L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-asparagine; L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] biphenyl-4-sulfonylamino} -3-methyl-butyric; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' - biphenyl-4-il} sulfonyl) -L-histidine; N- ( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-leucine; L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-prop-1-ynyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- (4'- { [4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - 3-methyl-butyric; 2- acid. { 4 '- [(4-cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4'- { [4- (2-cyclopropyl-ethyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- acid butyric; L-2- (4 '- { [4- (3-methoxy-Z-propenyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3- acid methyl-butyl ico; L-2- (4 '- { [4- (3-hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - 3-methyl-butyric; L-2- (4 '- { [4- (3-hydroxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carbonyl] -amino acid} -biphenyl-4 -sulfonylamino) butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pentyl) -benzof ran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) butyric; L-2- (4 '- { [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-2- (4 '- { [4- (3-Dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - 3-methyl-butyric; L-2- (4 '- { [4- (3-dimethylamino-propyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methy1- butyrice- L-2- acid. { 4 '- [(4-ethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4'- { [4- (3,3-dimethyl-but-l-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino ) -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] -amino} -bifinyl acid -4- sulfonylamino) butyric; L-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-ethyl-butyric; L-2- (4 '- { [4- (Methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-3-hydroxy-2- (4-. {5 - [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl}. -benzenesulfonylamino) -butyric acid; L-2- (4- { 5- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl-butyric acid - L-2- (4- {5- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl-butyric acid; D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3- ethyl-butyl rich; L-2- ( {4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl.} - methyl-amino) -3-methyl- butyric; triethylamine salt of (L-3-methyl-2- {4 '- [(3-methyl-4-methylcarbamoyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric acid; triethylamine salt of 2- acid. { 4 '- [(4-dimethylcarbamoyl-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4,6-Dimethoxy-3,7-dimethyl-benzofran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; 2- acid. { 4 '- [(5-bromo-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-carbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4'- { [4- (Cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino} .beta.-biphenyl-4-sulfonylamino) -3-methyl-butyric acid; L-2- acid. { 4 '- [(4-acetylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-propionylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- acid. { 4 '- [(4-isobutyrylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(lH-benzimidazole-2-carbonyl) -amino] - biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-sec-butoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- (4'- { [4- (Acetyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-3-methyl-2- (4'- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino -butyric; L-2- (4'- { [4- (3,3-Dimethyl-butyl) -3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino acid} -3-methyl-butyric; L-2- acid. { 4 '- [(3-ethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyrice- L-2- acid. { 4 '- [(4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-methylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- acid. { 4 '- [(4-amino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-dimethylamino-3-methyl-benzofuran- 2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- ( {4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl,} -methylamino) -3-methyl-butyric acid; L-3-hydroxy-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-Methyl-2- (4'- { [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl] -amino] -biphenyl-4-sulfonylamino acid -butyric; L-3-methyl-2- (4'- { [3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran-2-carbonyl] -amino} -biphenyl-4 acid -sulfonylamino) -butyric; L-2- acid. { 4 '- [(4-ethanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (propane-2-sulfonylamino) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - butyric; L-2- (4'- { [4- (Ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-2- acid. { '- [(4-benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3- Methyl-butyric acid L-3-methyl-2- (4'- { [3-methyl-4- (thiophen-2-sulfonylamino) -benzofuran-2-carbonyl] -amino.}. -biphenyl -4-sulfonylamino) -butyric; L-2- (4 '- { [4- (1, l-dioxo-lD6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carbonyl] -amino acid} -biphenyl-4 - sulfonylamino) -3-methyl-butyric; D-3-methyl-2- acid. { 4 '- [(3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; D-2- acid. { 4 '- [(benzofuran-2-carbonyl) -methylamino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; 4-. { 5- [(benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonyl-L-valine N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} sulfonyl) -N-methyl-D- valina; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -N-methyl-L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -N-methylglycine; acid (S) -2-. { 4 '- [(1, 3-dimethyl-lH-thieno [2,3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; N- ( { 4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1'- biphenyl-4-il} sulfonyl) -N- (pyridin-3-ylmethyl) -L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} - sulfonyl) -N- (2-morpholin-4-ylethyl) - L-valine; N- [(4 '- { [(3-methyl-l-benzofuran-2-yl) carbonyl] amino] -! -! 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-Bromo-l-benzofuran-2-yl) carbonyl] amino] -! -! 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [(4-methyl-3,4,5,6-tetrahydrofuro [4, 3, 2-ef] [3] benzazepin-2-yl) carbonyl] amino.} - 1,1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-ethyl-4-methoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino] .l, 1'-biphenyl-4- il) sulfonyl] -L-valine; N- [(4 '- { [(4-ethyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L -valina; N- [(4 '- { [(5-Ethyl-4-isopropoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl} -L-valine; N-. { [4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1, 1' -biphenyl-4-yl] sulfonyl } -L-valine; N - [(4'- { [(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [4- (2,2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-valine; N-. { [4 '- ( { [4- (hydroxymethyl) -3-methyl-l-benzofuran-2- il] carbonil} amino) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-valine; N- [(4 '-. {[[(3,4-dimethyl-l-benzofuran-2-yl) carbonyl] amino]} -l, 1'-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [(4-acetyl-3-methyl-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L -valina; N- [(4 '- { [(1-hydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L -valina; N-. { (4 '- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1, 1' -biphenyl-4-yl] sulfonyl L-valine; N-methyl-N- [(4'- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.} -l, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- { [4' - ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl carbonyl.} amino) -1,1'-biphenyl-4-yl] sulfonyl.} - N-methyl-L-valine; N- { [4 '- ( { [4- (methoxymethyl ) -3-methyl-l-benzofuran-2-yl] carbonyl.} Amino) -1,1-biphenyl-4-yl] sulfonyl.} - L-valine; N- { [4'- ( { [4- (l-methoxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1,1 '-biphenyl-4-yl] sulfonyl}. -L- valine; N- { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl- 4-yl] sulfonyl] -L-valinate; N- [(4 '- { [(4-isopropoxy-l-benzofuran-2-yl) carbonyl] amino.} -! 1'-biphenyl -4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-methoxy-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; acid (S) -2-. { 4 '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(4-Ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-propoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-Methyl-2- (4'- { [3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid -butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (R) -2-. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2- (4'- { [5- (1-chloro-vinyl) -4-methoxy-3- methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid (S) -2-. { 4 '- [(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (S) -2-. { 4 '- [(5-methyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (S) -2-. { 4 '- [(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (S) -3-methyl-2-. { 4 '- [(benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(4-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyrice- (S) -3-methyl-2- acid. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-chloro-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-trifluoromethyl-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of benzofuran-2-carboxylic acid; D-2- acid. { 4 '- (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; D-2- [4 '- (benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; D-3-methyl-2- [4 '- (l-methyl-lH-benzoimidazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid; D-3-methyl-2- [4 '- (3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid; D-2- [4 '- (benzofuran-2-ylmethoxy) -3' -methoxy-biphenyl-4-sulfonylamino] -3-methyl-butyric acid; D-2- [4 '- (benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; L-2- [4 '- (5-chloro-4-methoxy-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; L-2- [4 '- (5-cyano-4-methoxy-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; N-. { [4 '- (2-furoyloxy) -1,1' -biphenyl-4-yl] sulfonyl} -D-Valine; N-. { [4 '- (3-furoyloxy) -1,1' -biphenyl-4-yl] sulfonyl J-D-valine; L-2- [4 '- (4-ethyl-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; N- [(4 '- { [4- (3-methoxypropyl) -3-methyl-1-benzofuran-2-yl] methoxy] - 1, 1' -biphenyl-4-yl) sulfonyl] - L-valine; N- ( {4 '- [(5-bromo-4-methoxy-3-methyl-1-benzof ran-2-yl) methoxy] -1,1' -biphenyl-4-yl}. Sulfonyl) -L-valine; N- ( {4 '- [(5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl) methoxy] -1, 1' -biphenyl-4-yl.} - sulfonyl) - D-valine; N- [(4'- { [(5-bromo-4-methoxy-3-methyl-l-benzofuran-2-yl) methyl] amino.} -! 1 '-biphenyl-4-yl) sulfonyl] -L-valine; L-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; D-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-3-methyl-2- acid. { 4'- [(1-methyl-naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-phenoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- (4'- { [4- (1-methoxycarbonyl-l-methyl-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - 3-methyl-butyric; L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid L-2-. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-carboxymethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - butyric; L-2- acid. { 4 '- [(4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4-. {5- [(1-ethyl-lH-benzimidazole-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl-butyric acid; N- (. {4 '- [(1,2,3-thiadiazol-4-ylcarbonyl) amino] -1,1'-biphenyl-4-yl) sulfonyl) -L-valine; D-2- [4 '- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid-D-2- [4' - (benzofuran-2-sulfinylmethyl) -biphenyl-4-acid -sulfonylamino] -3-methyl-butyric; (S) -2- (4'- { [3- (4-Chloro-phenyl) -isoxazole-5-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid; (S) -3-methyl-2- acid. { 4'- [(1-methyl-3-phenyl-1H-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-methyl-l-phenyl-lH-pyrazole-3-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(2-pyridin-4-yl-thiazole-4-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino] -butyric acid; (R) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino] -butyric acid; (R) -2- acid. { 4 '- [(furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (R) -3-methyl-2- acid. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -2- (4'- { [4- (2-tert-butoxycarbonylamino- ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid; (S) -3-Methyl-2- (4 '- { [3-methyl-4- (pyridin-2-ylmethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid -butyric; (S) -3-Methyl-2- (4'- { [3-methyl-4- (pyridin-4-ylmethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid -butyric; acid (S) -2-. { 4 '- [(4-carbamoylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -2- (4 '- { [4- (2-Amino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3- acid methyl-butyric; (S) -2- (4'- { [4- (2-dimethylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3- acid methyl-butyric; N- [(4 '-. {[[(5-chloro-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- (. {4 '- [(5-bromo-l-furoyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) -L-valine; N- [(4'-. {[[(7-nitro-lH-indol-2-yl) carbonyl] amino]} -1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [(2-pyridin-4-yl-l, 3-thiazol-5-yl) carbonyl] amino] -!, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [5- (2-nitrophenyl) -2-f-ro] amino] -l, 1'-biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [2- (2, 3-dihydro-l, 4-benzodioxin-2-yl) -1, 3-thiazol-4-yl] carbonyl} amino) -1, 1' -biphenyl-4-yl] sulfonyl} -L-valine; N- [(4 '- { [(5-methyl-3-phenylisoxazol-4-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [(4-Methyl-1,2,8-thiadiazol-5-yl) carbonyl] amino] -! -! 1'-biphenyl-4-yl) sulfonyl] -L -valina; N- [(4 '-. {[[(L-tert-Butyl-3-methyl-! H -pyrazol-5-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl ] -L-valina; N- [(4 '- { [(3-Chloro-l-benzothien-2-yl) carbonyl] amino} -1,1' -biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [3- (2-chlorophenyl) -5-methylisoxazol-4-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -D-alanine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-valine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.] Sulfonyl) -D-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-norvaline; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-norvaline; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl.} sulfonyl) -L-aspartic acid; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] 1,1'-biphenyl-4-yl.} sulfonyl) -D-aspartic acid; N-2- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -L-glutamine; N ~ 2 ~ (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -D-glutamine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-histidine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-histidine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl}. Sulfonyl) -L-isoleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl}. Sulfonyl) -D-isoleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-leucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -D-leucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl}. Sulfonyl) -L-norleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-norleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' - biphenyl-4-il} sulfonyl) -L-phenylalanine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-phenylalanine; 1- ( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -L-proline; 1- ( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl}. Sulfonyl) -D-proline; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-tryptophan; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-tryptophan; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl}. Sulfonyl) -N-methylglycine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl}. Sulfonyl) -2-methylalanine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -N-methyl-L-alanine; 1- [( { 4 '- [(1-Benzofuran-2-ylcarbonyl) amino] 1,1'-biphenyl-4-yl.] Sulfonyl) amino] cyclopentanecarboxylic acid; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl}. Sulfonyl) -N-methylvaline; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1'-biphenyl-4-yl} sulfonyl) -3-methyl-L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -2-methyleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1-biphenyl-4-yl.} sulfonyl) -D-glutamic acid; (2R) - [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1-biphenyl-4-yl} sulfonyl) amino] (phenyl) acetic acid; [(. {4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1'-biphenyl-4-yl} sulfonyl) amino] (thien-2-yl) acetic acid; (2S) -2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl}. sulfonyl) amino] -5-methoxy- 5-oxopentanoic; 3- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1-, 1-biphenyl-4-yl} sulfonyl) amino] -3-phenylpropanoic acid; 2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl} sulfonyl) amino] -4-phenylbutanoic acid; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-tyrosine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -D-tyrosine; (2S) -2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. sulfonyl) amino] -4-tert-acid. butoxy-4-oxobutanoic; (2R) -2- [( {4 '- [(1-Benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. sulfonyl) amino] -4-tert-acid. butoxy-4-oxobutanoic; (2S) - [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl}. sulfonyl) amino] (2,3-dihydro) lH- inden-2-yl) acetic; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -O-methyl-L-tyrosine; [( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino-1,1' -biphenyl-4-yl.] sulfonyl) amino] (1-methyl-1H-indol-5-yl) ) acetic; [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl} sulfonyl) amino] (l-benzothien-5-yl) acetic acid; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -4-nitro-L-phenylalanine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -3- (2-naphthyl) alanine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -beta-methylphenylalanine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) -N-methyl-L-tryptophan; N-2- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -N ~ 5 ~ -phenylglutamine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -4,4,4,4', 4 ', 4'-hexafluorovaline; 4-amino-N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-phenylalanine; (2R) -2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) amino] -5- (benzyloxy) -5-oxopentanoic; N- ( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'- biphenyl-4-il} sulfonyl) -1-benzyl-L-histidine; and N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} sulfonyl) -O-benzyl-L-tyrosine. Particularly preferred compounds are: L-2- (4'- { [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino ) -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] -amino}. -biphenyl-4 acid - sulfonylamino) -butyric; D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino -butyric; L-2- acid. { 4 '- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-Benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (thiophen-2-acid sulfonylamino) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -butyric; N-. { (4'- { [(5-Ethyl-4-methoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino]} - 1, 1 '-biphenyl-4-yl) sulfonyl] - L-valine; N- [(4'- { [(4-ethyl-3-methyl-l-benzofuran-2-yl) carbonyl] amino] -! 1! -biphenyl-4-yl) sulfonyl] -L -valina; N- [(4'- { [(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-valine; N- [(4'- { [(3,4-dimethyl-l-benzofuran-2-yl) carbonyl] amino.} -!, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L -valina; N- [(4 '- ( { [4- (1-hydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino] -1,1' -biphenyl-4-yl] sulfonyl.) -L-valine; N- [(4'- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl -4-yl) sulfonyl] -L-valine; N- { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1 '-biphenyl-4-yl] sulfonyl.}. -L-valine; N- { [4' - ( { [4- (1-methoxyethyl) -3-methyl-1-benzofuran -2-yl] carbonyl.} Amino) -1, 1'-biphenyl-4-yl] sulphoryl.}. -L-valine; N- { [4 '- ( { [4- (2 -methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl, amino) -1, 1-biphenyl-4-yl] sulfonyl) -L-valinate; acid (S) -2-. { 4 '- [(4-ethoxy-3-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (R) -2- acid. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4- [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-methyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; D-2- [4 '- (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-carboxymethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - butyric; (S) -3-methyl-2- acid. { 4 '- [(1-methyl-3-phenyl-1H-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; and (S) -3-methyl-2- (4'- { [3-methyl-4- (pyridin-4-ylmethoxy) -benzof ran-2-carbonyl] -amino acid} -biphenyl-4 -sulfonylamino) -butyric. The terms "effective amount", "therapeutically effective amount" and "effective dosage", as used herein, refer to the amount of a compound that, when administered to a patient, is effective to at least partially improve. (and, in preferred modalities, cure) a form of condition which is suspected to be suffered by 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 superficial ocular diseases, hepatitis, aortic aneurysms, tendonitis, diseases of the central nervous system, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft-versus-host disease, diabetes, inflammatory bowel disease, shock, intervertebral disc degeneration, stroke, osteopenia and / or periodontal diseases. The present invention thus provides pharmaceutical compositions comprising at least one biaryl sulfonamide compound and one or more pharmaceutically acceptable carriers, excipients or diluents. Examples of such 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, ed. Edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are compatible with the other ingredients in the formulation and biologically acceptable. The compounds of this invention can be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, emollients, compression aids, binders or tablet disintegrating agents or encapsulating materials. They are formulated in a conventional manner, for example, in a manner similar to that used for known antihypertensive, diuretic and β-blocking agents. Oral formulations containing the active compounds of this invention can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and liquids, suspensions or oral solutions. In powders, the carrier is a finely divided solid, which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a vehicle that has the necessary compression properties, in proper 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 (s) 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 celluloses. crystalline or microcrystalline, flours, jellies, gums, etc. Useful tablet formulations may be made by conventional methods of compression, wet granulation or dry granulation, and may utilize pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifying agents (including surfactants), 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, polyvinylpyrrolidone, alginic acid, gum arabic , xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting point waxes and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, keto acrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, silicate of magnesium and aluminum, and triethanolamine. Oral formulations herein may use conventional delayed or time-release formulations to alter the absorption of the active compound (s). The oral formulation may also consist of the administration of the active ingredient in water or fruit juice, containing suitable solubilizers or emulsifiers if necessary. Liquid vehicles 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 fat. 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 osmoregulators. Suitable examples of liquid carriers for oral or parenteral administration include water (particularly containing additives such as the above, for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example, glycols) and its derivatives, and oils (for example, fractionated coconut oil or peanut oil). For parenteral administration, the carrier 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, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in liquid or solid form. Preferably, the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such forms, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient; the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any of the compositions in packaged form. Such a unit dosage form may contain from about 1 mg / kg to about 250 mg / kg, and may be given in a single dose or in two or more divided doses. Such doses may be administered in any way useful for targeting the compounds active herein to the bloodstream of the recipient, including orally, by implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally and transdermally. Such 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 pathology or disorder, it is it is understood that the effective dosage may vary depending on the particular compound used, the mode of administration, the condition and severity of the condition 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 amount adequate to achieve this is defined as a "therapeutically effective amount". The dosage to be used in the treatment of a specific case must be determined subjectively by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient. In some cases, it may be desirable to administer the compounds directly to the airways in the form of an aerosol. For administration by intranasal or intrabronchial inhalation, the compounds of this invention can be formulated in 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 hydroxylpropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the improvised preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the point of being easily injected. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or 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 description, it is understood that 'transdermal administrations include all administrations across the surface of the body and the internal coatings of the body ducts, including epithelial and mucosal tissues. Such administrations can be performed using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Transdermal administration can be achieved through the use of a transdermal patch containing the active compound and a vehicle that is inert to the active compound, is not toxic to the skin, and allows the release of the agent for systemic absorption into the bloodstream to through the skin. The vehicle can take many forms, such 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. Pastes composed of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient, may also be suitable. A variety of 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 carrier, 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 suppository melting point, and glycerin. Water soluble suppository bases can also be used, such as polyethylene glycols of various molecular weights. In certain embodiments, the present invention relates to prodrugs of biaryl sulfonamide compounds. Various forms of prodrugs are known in the art as discussed in, for example, Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); idder, 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 revie, 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 by 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 being treated, and will be Subject to the judgment of the doctor involved. It is preferred that the administration of one or more of the compounds herein start at a low dose and increase until the desired effects are achieved. The compounds of the invention can be prepared using a variety of methods starting from commercially available compounds, known compounds, or compounds prepared by known methods. The general synthetic routes for many of the compounds of the invention are included in the following reaction schemes. Those skilled in the art will understand that protection and deprotection steps that are not shown in the reaction Schemes may be necessary for these syntheses, and that the order of the steps may be changed to accommodate the functionality of the target molecules.

In Reaction Scheme 1, the compounds of the invention, 1, are prepared by hydrolysis of the corresponding esters, 2, wherein R 10 is an alkyl ester such as methyl, ethyl or t-butyl, or a linker with a ang for solid phase synthesis. The methyl and ethyl esters can be divided with an aqueous base, including sodium or lithium hydroxide. The t-butyl esters and resin-bound esters can be divided using trifluoroacetic acid or hydrochloric acid. In addition, you can use lithium iodide in ethyl acetate to split methyl esters of general structure 2. Reaction Scheme 1: The routes for compounds of structure 2 are shown in Reaction Scheme 2. 4-Nitrobiphenyl, 3, is converted into sulfonyl chloride 4 in two stages, with chlorosulfonic acid followed by thionyl chloride or oxalyl chloride, with catalytic DMF . Sulfonylation of an α-amino acid derivative, 5, with the sulfonyl chloride 4, provides the sulfonamide 6. The sulfonamide 6 can optionally be alkylated with an alkyl halide, tosylate, mesylate or triflate (R11 = I, Br, Cl, Ots, Oms, OTf) to give the corresponding N-R3 alkyl sulfonamide. The side chain R3 can be further functionalized at any point in the synthesis. The NH or sulfonamide N-R3 is reduced with tin (II) chloride, or hydrogenated on palladium on carbon, or by transfer hydrogenation, to give the aniline 7. The aniline 7 is then derivatized to provide 2 by acylation with a acid chloride, or with a carboxylic acid using a peptide coupling reagent such as EDCI, or BOP in the presence of an amine tertiary in a polar aprotic solvent. The sulfonamides 2 are provided by the reaction of the aniline 7 with heteroarylsulfonyl chlorides and a tertiary amine base. The secondary anilines 2 are formed by reductive amination of 7 with a heteroaryl aldehyde in the presence of a reducing agent such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride.

Reaction Scheme 2: An alternative route for the amides 2 is shown in Reaction Scheme 3. The commercially available sulfonyl fluoride 8 is acylated with acid chlorides to give the amide derivatives 9. The sulfonyl chlorides analogues are available from the nitrobiphenyl 10 by reduction to aniline 11, acylation to give 12 and conversion of sulfonic acid to sulfonyl chloride 13. Reaction of the amino acids or aminoesters, 5, with 9 or 12 in the presence of a tertiary amine base provides compounds 2. Scheme of Reaction 3: A or B In Reaction Scheme 4, amino acid 5 is reacted with 4-bromobenzenesulfonyl chloride to give sulfonamide 14. Palladium catalyzed coupling of 14 with commercially available borate esters 15 or 16 provides the biphenylsulfonamides 17, where R12 is -OH or -NH2. The functionalization of phenol or aniline produces 2. The pyridyl analogs of the biphenyls are prepared by palladium-catalyzed conversion of bromophenylsulfonamide 14 to the corresponding borate ester, 18, followed by coupling with palladium with 2-bromo-5-nitropyridine to produce 19. The hydrogenation of 19 gives aniline 20, which can be functionalized to produce 2. Similar routes are available for additional heteroaryl analogs of the biphenylsulfonamides claimed in the invention. Reaction Scheme 4 The thioethers of the invention are prepared according to Reaction Scheme 5, starting from commercially available benzylic bromide 21. The displacement of the bromide with heteroaryl thiols in the presence of an acid scavenger provides the thioethers 22, which are coupled to bromoaryl 14 using palladium (0) and a base such as potassium carbonate or sodium carbonate, to give 23. Division of ester 23 provides thioether compounds of the invention. Reaction Scheme 5: 21 22 2. 3 The biphenylsulfonamides of the invention can also be prepared by the route shown in Reaction Scheme 6. The borate esters 15 and 16 can be functionalized to the corresponding amides, sulfonamides, amines, esters or ethers prior to palladium catalyzed coupling with the bromosulfonamide. to give the analogs 2. Hydrolysis with an ester of 2 provides the compounds of the invention. Furthermore, it is understood that the methods shown in Reaction Schemes 1-6 for the construction of biphenylsulfonamides are applicable to biphenyl heteroaryl analogs claimed in the invention. Reaction Scheme 6: ZCOCl / Et2N-i-Pf OI ZCG2B / EDG! / DtóAF / DMF 01 ZC02H / ßOP / EtgN-i-Pr / DMF or R12 «NH £OH OH RS02Cl / Et2N -Pr or 1S > 16 ZCHO aB (OAc) s ZCHgBr The new and known benzofurans of the invention are prepared as shown in Reaction Schemes 7-12. Each of the benzofuran esters of Reaction Schemes 7-12 can be converted to the corresponding acids, acid chlorides, alcohols or aldehydes and coupled as shown in Reaction Schemes 2-6. It is understood that some of the methodologies used for the construction and derivation of the benzofurans shown, is applicable to other heteroaryl ring systems of the invention. In Reaction Scheme 7, the salicylaldehydes and ketones 25, which bear a variety of substituents R7, are alkylated with a-bromoacetic acid esters to give 26, which is then cyclized in the presence of an alkoxide base in alcohol or carbonate potassium in DMF to produce the substituted benzofurans 27. The esters 27 are hydrolysed with aqueous hydroxide or TFA (for R10 = t-butyl) to give the carboxylic acids 28, which can in turn to be converted to acid chlorides 29, with oxalyl or thionyl chloride and catalytic DMF. The reduction of the esters 28 with diisobutylaluminium hydride or lithium aluminum hydride produces the alcohols 30. The alcohols can be oxidized, preferably with Dess-Martin reagent, to give the corresponding aldehydes 31. Alternatively, the alcohols can be converted into the corresponding chloride or bromide 32, with thionyl chloride, phosphorus tribromide, carbon tetrabromide-triphenylphosphine or other known method.

Reaction Scheme 7 31 The functionalization of the benzofuran nucleus is shown in Reaction Scheme 8. Although only substituents 2-, 3- and 4- are shown in benzofuran, the methodology shown in the reaction scheme can accommodate additional substituents and the group hydroxyl of 33 can be placed in other positions in benzofuran. The 4-hydroxybenzofurans 33 prepared according to Reaction Scheme 7 are converted into the respective triflates 34 with trifluoromethanesulfonic anhydride and a tertiary amine, pyridine or lutidine. The palladium-catalyzed reaction of 34 with zinc cyanide gives the nitriles 35. The nitriles can be hydrolysed in the presence of hydrogen peroxide to give the amide 36, which can be optionally alkylated with alkyl halides in the presence of sodium hydride or another strong base. Triflates 34 can also undergo Stille couplings with tributylvinyltin, or other tin alkenyl reagent, to provide styrenes 37. Similarly, triflates 34 can be coupled with alkyne derivatives to provide benzofurans 38-40 where R14 is a alkyl or aryl group. Although not shown in the reaction scheme, the alkynes can be partially hydrogenated to provide olefins, or saturated to give the corresponding alkanes. Alkynes can also be substrates in cycloadditions [3 + 2] or [4 + 2] to produce, for example, isoxazoles such as 41.

Reaction Scheme 8: Olefin 37 can be derivatized according to the methods shown in Reaction Scheme 9. Dihydroxylation with osmium tetroxide and N-methylmorpholine N-oxide provides the diols 42, which can in turn be converted to dioxolanes 43 through of the acid catalyzed reaction with acetone or other ketone or aldehyde. The oxidative cleavage of olefin 37 with osmium tetroxide and sodium periodate gives the aldehydes 44. The aldehydes can reduce with sodium borohydride in methanol or ethanol to give the alcohols 45, which in turn can be alkylated with an alkyl halide in the presence of silver oxide, sodium hydride or other base. Conversion of 45 to the corresponding bromides with carbon tetrabromide and triphenylphosphine, followed by reduction with sodium borohydride in DMSO, or other known method for the reduction of benzylic alcohols, provides the methyl substituted benzofurans 46. The hydrogenation of the olefins 37 in palladium on carbon gives the ethyl-substituted benzofurans 47. Reaction Scheme 9: Additional transformations of triflates such as 34 are shown in Reaction Scheme 10. Palladium catalyzed reactions with amines, amides, sulfonamides or carbamates provide the 48-50 derivatives, each of which can be further functionalized by alkylation of the nitrogen newly installed with an alkyl halide and a base such as sodium hydride. The carbamate 50 can be further deprotected by exposure to TEA or HCl to give the primary aniline 51. This aniline can be mono- or di-alkylated with an alkyl halide in the presence of potassium carbonate in a polar aprotic solvent to give 48, or acylated or sulfonating to give 49. The palladium-catalyzed Suzuki coupling of the triflates 34 with aryl or heteroaryl boric acids or borate esters provides 52.

Reaction Scheme 10: R1 6 = Aryl, Heteroaryl 52 49 The synthesis of acetyl-benzofurans is shown in the Reaction Scheme 11. Palladium catalyzed coupling of triflate 34 with butyl vinyl ether, followed by hydrolysis in aqueous acid yields methyl ketone 53. Reduction of the methyl ketone provides the secondary alcohols 54, which can in turn be alkylated with a lower alkyl halide. alkyl in the presence of silver oxide, sodium hydride or other base.

Reaction Scheme 11: , 2) HCJ The synthesis of 2,, 5-trisubstituted benzofurans '(R6 = H) and benzofurans 2, 3, 4, 5-tetrasubstituted is shown in Reaction Scheme 12. Hydroxybenzofurans 33 can be converted to aryl or heteroaryl ethers by reaction with aryl / heteroaryl boric acids in the presence of copper acetate. The alkyl ether derivatives 56 are synthesized by alkylation of 33 with alkyl halides in the presence of sodium hydride or potassium carbonate in a polar aprotic solvent such as DMF or THF. The compounds of structure 33 are easily halogenated with N-halogen succinimides to provide compounds 61, which can in turn be alkylated to give ethers 62. Phenols 33 and their O-alkylated derivatives undergo ortho-acylation with acetyl chloride and tetrachloride of titanium to give acetophenones 59, which can in turn be converted to vinyl chlorides 60 in the presence of oxalyl chloride and catalytic DMF. The reaction of 33 with magnesium methoxide followed by paraformaldehyde produces ortho-formylphenol 57, which can be reduced to 5-methylbenzofuran 58. Phenol 58 can be subsequently esterified by reaction with an alkyl halide in the presence of sodium hydride or potassium carbonate .

Reaction Scheme 12: R17 = Cl, Br, I eo se 62 Certain N-alkyl benzimidazoles of the invention can be achieved as shown in Reaction Scheme 13. Thus, 2-methylbenzimidazole 63 is N-alkylated with an alkyl halide and sodium hydride to give 64, followed by oxidation with selenium dioxide to provide the aldehyde 65. Oxidation of the aldehyde to the carboxylic acid 66 can be achieved with silver nitrate. The aldehyde and the carboxylate can be coupled with the compounds of Reaction Schemes 2-6.

Reaction Scheme 13: halide of AgNOs aN OH R1S - Alkyl gg ßS 64 The present invention is further described in the following examples.

EXAMPLES The following abbreviations are used throughout the experimental section: DMSO = dimethyl sulfoxide TFA = trifluoroacetic acid DMF = N, N-dimethylformamide MeOH = methanol THF = tetrahydrofuran The term "treatment" indicates dilution of the reaction mixture with ethyl acetate, washing of the combined organic layers with water and brine, drying over magnesium sulfate or sodium sulfate, filtration and concentration of the filtrate in vacuo.

Example 1: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' biphenyl-4-yl.} Sulfonyl) glycine Step 1: To a dry flammable flask was added 4-aminobiphenylsulfonyl fluoride (0.75 g, 3 mmol) and methylene chloride (20 ml). The solution was cooled in an ice bath. After the addition of N, N-disopropylethylamine (1.50 equivalents), benzofuran-2-carbonyl chloride (0.54 g, 3 mmol) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction was continued at room temperature for 5 hours. The reaction mixture was diluted with aqueous ammonium chloride solution (15 ml) and filtered and the precipitate was washed twice with ammonium chloride solution and twice with water. The resulting solid was dried under vacuum and 1.05 g of N- fluoride were obtained. { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl} sulfonyl (89% yield). Step 2: N- fluoride was added to a 10 ml round bottom flask. { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl} sulfonyl (0.118 g, 0.3 mmol) and DMSO (2 mL), followed by the addition of t-ester hydrochloride butyl glycine (5.0 equivalents), N, N-diisopropylethylamine (10 equivalents), 4- (dimethylamino) pyridine (0.3 mmol) and sodium iodide (cat.). The mixture was heated to 120 ° C for 5 hours, cooled to room temperature and diluted with aqueous solution of ammonium chloride (5 ml) and ethyl acetate (15 ml). The aqueous layer was extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate and filtered. After concentration, the crude product (110 mg) was purified by flash chromatography to give N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' t-butyl ester. -biphenyl-4-yl.}. sulfonyl) glycine (75 mg). Step 3: N- (. {4'-. {((L-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl}. Sulfonyl) glycine was dissolved. (75 mg) in a 95% solution of TFA in methylene chloride (5 ml). The solution was stirred at room temperature for 4 hours and the solvent was removed under vacuum. The crude product was triturated three times with hexane / ethyl acetate (95: 5). The product was lyophilized with benzene to give 56 mg of N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) glycine. EMCL MH + (m / z) 451. aH-NMR (300 MHz, DMSO-d6): d 10.54 ppm (s, 1H), 7.95-7.54 ppm (m, 11H), 7.34 ppm (dd, 1H, Jx = 7.5 Hz, J2 = 7.5 Hz), 7.20 ppm (dd, 1H,? V = 7.5 Hz, J2 = 7.5 Hz), 3.42 ppm (d, 2H J = 6.3 Hz).

Example 2: L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: N- fluoride was added to a 10 ml round bottom flask. { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl} sulfonyl (0.118 g, 0.3 mmol) and DMSO (2 ml), followed by the addition of L-valine t-butyl ester hydrochloride (5.0 equivalents), N, N-diisopropylethylamine (10 equivalents), 4- (dimethylamino) pyridine (0.3 mmol) and sodium iodide (cat. .). The mixture was heated to 120 ° C for 6 hours and diluted with aqueous ammonium chloride solution (5 ml) and ethyl acetate (15 ml). The aqueous layer was extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed twice with brine and dried over anhydrous sodium sulfate. After concentration, the crude product (110 mg) was purified by flash chromatography to give N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' t-butyl ester. -biphenyl-4-yl.}. sulfonyl) glycine (65 mg). Stage 2: N- (. {4'4-) t-butyl ester was dissolved. [(1-benzofuran-2-ylcarbonyl) amino] -1,1 '-bifenii-4-yl} sulfonyl) -L-valine (60 mg) in a 95% solution of TFA in methylene chloride (5 ml). The solution was stirred at room temperature for 4 hours and the solvent was removed under vacuum. The crude product was triturated three times with hexane / ethyl acetate (95: 5). The product was lyophilized with benzene to give 36 mg of N- (. {4 '-. {((L-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} - sulfonyl) glycine. EMCL MH + (m / z) 493. X H NMR (300 MHz, DMSO-d 6) d 10.53 ppm (s, 1H), 7.81-7.54 ppm (m, 11H), 7.34 ppm (dd, 1H, J? = 8- 4 Hz, J2 = 8.4 Hz), 7.20 ppm (dd, 1H, Jx = 8.4 Hz, J2 = 8.4 Hz), 3.35 ppm (d, 1H J = 6.0 Hz), 1.79 ppm (m, 1H), 0.63 ppm ( dd, 6H, Ji = 13.8 Hz, J2 = 6.6 Hz).

Example 3: N- (. {4 '- [(1H-indol-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl.} Sulfonyl) glycine N- (. {4 '- [(1H-indol-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) glycine was prepared according to the procedures of Example 1, using indole-2-carbonyl chloride and 4-aminobiphenylsulfonyl fluoride in Step 1, and L-valine t-butyl ester hydrochloride in Step 2. EMCL MH + (m / z) 492. XH NMR (300 MHz, DMSO-d6) d 11.62 ppm (s, 1H), 10.20 ppm (s, 1H), 7.95-7.22 ppm (m, 11H), 7.04 ppm (dd, 1H, Hz, J2 = 7.5 Hz), 3.43 ppm (d, 2H J = 5.8 Hz).

Example 4: (4 '- { [(5-chloro-l-benzofuran-2-yl) carbonyl) amino] -1,1' -biphenyl-4-yl) sulfonyl] -L-valine Step 1: Fmoc-L-valine-Wang resin (10 g, 0.9 mmol / g), purchased from Advanced ChemTech, was added to a 120 ml agitation vessel. The resin was rinsed with DMF (60 mi x 2). A 20% solution of piperidine in DMF was added and the mixture was stirred for 20 minutes. The solvent was filtered and the resin was washed with DMF (2X), methanol (IX) and methylene chloride (5X). Step 2: To the resin product of Step 1 were then added anhydrous methylene chloride (60 ml), N, N-diisopropylethylamine (40.5 mmol) and 4-nitrobiphenylsulfonyl chloride (27 mmol). The mixture was stirred at room temperature for 4 hours before filtration. The resin was washed with methanol, followed by methylene (3X). Step 3: The resin product of Step 2 was rinsed with DMF (2X) and then treated with a 2M tin chloride solution in DMF (60 mL). The mixture was stirred at room temperature overnight and the solvent and reagent were removed by filtration. The resin was washed with DMF (2X), methanol followed by methylene chloride (5X). Step 4: The resin product from Step 3 (0.25 g) was treated with anhydrous methylene chloride (5 ml), N, N-diisopropylethylamine (1.0 mmol) and 5-chlorobenzofuran-2-carbonyl chloride (0.67 mmol). . The mixture was stirred at room temperature for 2 hours before filtration. The resin was washed with methylene chloride (2X) and methanol, followed by methylene chloride (3X). Step 5: The resin product of Step 4 was then treated with a 95% solution of TFA in methylene chloride and stirred at room temperature for 2 hours. The solution was collected by filtration and the solvent was removed under vacuum. The crude product was then purified by flash chromatography to give 4 '-. { [(5-chloro-l-benzofuran-2-yl) carbonyl) amino] -1,1 '-biphenyl-4-yl) sulfonyl] -L-valine. EMCL MH + (m / z) 528. XH NMR (300 MHz, DMSO-d6) d 10.58 ppm (s, 1H), 7.80-7.59 ppm (m, 11H), 7.36 ppm (dd, 1H, Ja = 7.2 Hz, J2 = 1.8 Hz), 3.35 ppm (d, 1H J = 6.0 Hz), 1.75 ppm (m, 1H), 0.63 ppm (dd, 6H, J? = 10.2 Hz, J2 = 6.6 Hz).

Example 5: N- [(4 '-. {[[(7-methoxy-l-benzofuran-2-yl) carbonyl] amino]} -1,1'-biphenyl-4-yl) sulfonyl] -L- Valine According to the procedure of Example 4, using 7-methoxybenzofurancarbonyl chloride, N- [(4 '-. {[[(7-methoxy-1-benzofuran-2-yl) carbonyl] amino] was prepared. !, 1 '-biphenyl-4-yl) sulfonyl] -L-valine. EMCL MH + (m / z) 523. aH NMR (300 MHz, DMS0-d6) d 10.45 ppm (s, 1H), 7.79-7.62 ppm (m, 10H), 7.14 ppm (d, 1H, J = 21.0 Hz), 6.94 ppm (d, 1H, J = 5.0 Hz), 3.81 ppm (s, 1H), 3.36 ppm (d, 1H J = 6.0 Hz), 1.75 ppm (m, 1H), 0.63 ppm (, 6H).

Example 6: N- [(4 '-. {[[(5-nitro-l-benzofuran-2-yl) carbonyl] amino]} -1,1'-biphenyl-4-yl) sulfonyl] -L- Valine According to the procedure of Example 4, using 5-nitrobenzofurancarbonyl chloride, N- [(4 '-. {[[(5-nitro-1-benzofuran-2-yl) carbonyl] amino] was prepared. 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine. EMCL MH + (m / z) 538. 2H NMR (300 MHz, DMSO-d6) d 10.71 ppm (s, 1H), 8.69 ppm (s, 1H); 8. 21 ppm (d, 1H, J = 7.0 Hz), 7.84-7.61 ppm (m, 10H), 3.38 ppm (d, 1H J = 6.0 Hz), 1.75 ppm (m, 1H), 0.64 ppm (dd, 6H, J? = 8.7 Hz, J2 = 6.6 Hz).

Example 7: N- [(4 '-. {[[(5-amino-l-benzofuran-2-yl) carbonyl] amino]} -1,1' -bifenli-4-yl) sulfonyl] -L- Valine Stage 1: To a stirred vessel of 120 ml added Fmoc-L-Val-ang resin (10 g, 0.9 mmol / g), purchased from Advanced ChemTech. The resin was rinsed with DMF (60 ml x 2). A solution of 20% piperidine in DMF was added and the mixture was stirred for 20 minutes. The solvent was filtered and the resin was washed with DMF (2X), methanol (IX) and methylene chloride (5X). Step 2: To the resin was added anhydrous methylene chloride (60 ml), N, N-diisopropylethylamine (40.5 mmol) and 4-nitrobiphenylsulfonyl chloride (27 mmol). The mixture was stirred at room temperature for 4 hours before filtration. The resin was washed with methanol, followed by methylene chloride (3X). Step 3: The obtained resin was rinsed with DMF (2X) and then treated with a 2M tin chloride solution in DMF (60 ml). The mixture was stirred at room temperature overnight and the solvent and reagent were removed by filtration. The resin was washed with DMF (2X), methanol, followed by methylene chloride (5X).

Step 4: The resin (0.6 g) was treated with anhydrous methylene chloride (10 ml), N, N-diisopropylethylamine (2.2 mmol) and 5-nitrobenzofuran-2-carbonyl chloride (1.50 mmol). The mixture was stirred at room temperature for 2 hours before filtration. The resin was washed with methylene chloride (2X), methanol, followed by methylene chloride (3X). Tin (II) chloride solution in DMF was added to the resin (2 M, 12 mL) and stirred at room temperature overnight. The reagent was removed by filtration and the resin was washed with DMF (2X), methanol and methylene chloride (5X).

Step 5: The resin obtained above was divided into two portions of 0.3 g. A portion of the resin was treated with a 95% solution of TEA in methylene chloride (5 ml) and stirred at room temperature for 2 hours. The solution was collected by filtration and the solvent was removed under vacuum. The crude product was then purified by flash chromatography to give N- [(40 '-. {[[(5-amino-l-benzofuran-2-yl) carbonyl] amino.} -1,1'-biphenyl- 4-yl) sulfonyl] -L-valine. EMCL MH + (m / z) 508. 1 H NMR (300 MHz, DMSO-d 6) d 10.56 ppm (s, 1H), 7.80-7.30 ppm (m, 12H), 3.50 ppm (m, 1H), 1.90 ppm (m , 1H), 0.63 ppm (m, 6H).

Example 8: N- [. { 4 '- [( { 5- [(methylsulfonyl) amino] -l-benzofuran-2-yl.} Carbonyl) -amino] -1,1' -biphenyl-4-yl} sulfonyl) -L-valine N- [(4 '-. {[[(5-amino-1-benzofuran-2-yl) carbonyl] amino]} - 1, 1-biphenyl-4-yl) sulfonyl was suspended. ] -L-valine-Wang resin (0.3 g) of Example 7 in methylene chloride (6 ml). To the suspension were added N, N-diisopropylethylamine (6.0 equivalents) and methanesulfonyl chloride (3.0 equivalents). The reaction was left at room temperature for 1 hour and the reagent was removed by filtration. The resin was washed with methylene chloride (2X), methanol and methylene chloride (2X) before being treated with a solution of 95% TFA in methylene chloride (5 ml) and stirring at room temperature for 2 hours. The solution was collected by filtration and the solvent was removed by vacuum. The crude product was then purified by flash chromatography to give N- [. { 4 '- [( { 5- [(methylsulfonyl) amino] -l-benzofuran-2-yl.} Carbonyl) amino] -l, 1-biphenyl-4-yl} sulfonyl) -L-valine. EMCL MH + (m / z) 586. XH NMR (300 MHz, DMSO-d6) d 10.53 ppm (s, 1H), 9.59 ppm (s, 1H), 7.78-7.16 ppm (, 12H), 3.30 ppm (m, 1H), 1.87 ppm (m, 1H), 0.63 ppm (m, 6H).

Example 9: N-. { [4 '- ( { [5- (acetylamino) -l-benzofuran-2-l] carbonyl}. Amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine N- [(4 '-. {[[(5-amino-1-benzofuran-2-yl) carbonyl] amino]} -1, 1-biphenyl-4-yl) sulfonyl] - was suspended. L-valine-Wang resin (0.3 g) of Example 7 in methylene chloride (6 ml). To the suspension were added N, N-diisopropylethylamine (6.0 equivalents) and acetyl chloride (3.0 equivalents). The reaction was allowed to continue at room temperature for 0.5 hour and the reagent was removed by filtration. The resin was washed with methylene chloride (2X), methanol and methylene (2X) before being treated with a solution of 95% TEA in methylene chloride (5 ml) and stirring at room temperature for 2 hours. The solution was collected by filtration and the solvent was removed by vacuum. The crude product was purified, then by flash chromatography to give N-. { [4 '- ( { [5- (acetylamino) -l-benzofuran-2-yl] carbonyl}. Amino) -1,1-biphenyl-4-yl] sulfonyl} -L-valina. EMCL MH + (m / z) 550. ñ NMR (300 MHz, DMSÓ-d6) d 10.50 ppm (s, 1H), 9.92 ppm (s, 1H), 8.00-7.34 -ppm (m, 12H), 3.33ppm ( m, 1H), 1.89 ppm (s, 3H), 1.76 ppm (m, 1H), 0.63 ppm (m, 6H).

Example 10: 4 '- [(5-Benzenesulfonylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine N- [(4' -. {[[(5-amino-1)] was suspended. -benzofuran-2-yl) carbonyl] amino.}. - l, 1-biphenyl-4-yl) sulfonyl] -L-valine-Wang resin (0.3 g) of Example 7 is sulfonyl with benzenesulfonyl chloride according to the procedure of Example 8 followed by cleavage of the resin to provide 4 '- [(5-benzenesulfonylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine. EMCL MH + (m / z) 648. XH NMR (300 MHz, CD3OD) d 7.92-7.69 ppm (m, 9H), 7.58-7.43 ppm (m, 6H), 7.22-7.18 ppm (dd, 2H, Ji = 9.0 Hz, J2 = 2.5 Hz), 3.64 ppm (d, 1H, J = 5.0 Hz), 2.09-2.01 ppm (, 1H), 0.97 ppm (d, 3H, J = 7.0 Hz), 0.90 ppm (d, 3H, J = 7.0 Hz).

Example 11: N- [(4 '-. {[[(4-methoxy-l-benzofuran-2-yl) carbonyl] amino]} -1,1' -bif nyl-4-yl) sulfonyl] -L -valina According to the procedure of Example 4, N- [(4 '-. {[[(4-methoxy-1-benzofuran-2-yl) carbonyl] amino] -1, 1'-biphenyl-4 was prepared -yl) sulfonyl] -L-valine from Fmoc-L-Val-Wang resin and using 4-methoxybenzofurancarbonyl chloride. EMCL MH + (m / z) 523. XH NMR (300 MHz, DMSO-d6) d 10.62 ppm (s, 1H), 8.19-7.79 ppm (m, 9H), 7.47 ppm (dd, 1H, J? = 8.1 Hz , J2 = 8.1 Hz), 7.32 ppm (d, 1H, J = 8.4 Hz), 6.90 ppm (d, 1H, J = 8.1 Hz), 3.96 ppm (s, 3H), 1.97 ppm (m, 1H), 0.82 ppm (dd, 6H, Ja = 18.0 Hz, J2 = 6.9 Hz).

Example 12: 4 '- [(benzo [β] thiophen-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine According to the procedure of Example 4, 4 '- [(benzo [β] thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine was prepared from Fmoc-L-Val-resin of Wang and using 4-benzothiophencarbonyl chloride. EMCL MH + (m / z) 509. XH NMR (300 MHz, CD3OD) d 10.68 ppm (s, 1H), 8.41 ppm (s, 1H), 8.09-7.80 ppm (m, 12H), 7.54-7.47 ppm (m , 1H), 1.99-1.94 ppm (m, 1H), 0.86-0.80 ppm (m, 6H).

Example 13: 4 '- [(4-benzyloxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine Step 1: 4-Benzyloxy-benzofuran-2-carbonyl chloride (0.61 mmol) was added to a solution of the product of Example 2A-Step 4, L-2- (4'-amino-biphenyl-4-sulfonylamino) methyl ester. ) -3-methyl-butyric (0.55 mmol), and N, N-diisopropylethylamine (1.4 mmol) in 2 ml of CH2Cl2 maintained at 0 ° C. It was allowed to warm to room temperature and stirred for 5 hours. The mixture was diluted with ethyl acetate and washed with brine (3x). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and then concentrated to give 350 mg of 2- methyl ester. { 4'- [(4-benzyloxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} -L-valina.

Step 2: 2- methyl ester was dissolved. { 4 '- [(4-benzyloxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} -L-valine (0.24 mmol) in THF and MeOH (2: 1) (0.6 ml). A 5M solution of LiOH in water (5.0 equivalents) was then added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and acidified with 1N hydrochloric acid. The organic layer was washed with brine (2X), dried (magnesium sulfate), filtered and concentrated to give 55 mg of 2-. { 4 '- [(4-benzyloxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} -L-Valine pure. EMCL MH + (m / z) 599. XH NMR (300 MHz, DMSO-d6) d 10.55 ppm (s, 1H), 8.08 ppm (d, 1H, J = 9.2 Hz), 7.97-7.76 ppm (m, 8H) , 7.58-7.28 ppm (m, 7H), 7.02 ppm (d, 1H, J = 8.0 Hz), 5.31 ppm (s, 2H), 3.94 ppm (s, 2H), 3.58-3.52 ppm (m, 1H), 1.96-1.90 ppm (m, 1H), 0.84 ppm (d, 3H, J = 7.0 Hz), 0.81 ppm (d, 3H, J = 7.0 Hz).

Example 14: 4 '-. { [4- (1-carboxy-ethoxy) benzofuran-2-carbonyl] amino} -biphenyl-4-sulfonyl-L-valine The product of Example 13-Step 1, methyl ester of 4 '- [(4-benzyloxy-benzofuran-2-carbonyl) -amino-biphenyl-4-sulfonyl-L-valine (0.32 mmol), was dissolved in 3 ml of ethyl acetate-MeOH (2: 1) and added 10% Pd / C (20 mg). The reaction was stirred under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through celite and then concentrated to give 4 '- [(4-hydroxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine methyl ester with a yield of 80% The product (0.13 mmol) was dissolved in anhydrous DMF (1 mL) and Cs2CO3 (0.26 mmol) was added, followed by 2-bromo-propionic acid ethyl ester (0.13 mmol). After checking by TLC that the reaction was complete, the reaction was diluted with ethyl acetate and acidified with 1N hydrochloric acid. The organic layer was washed with brine (2X), dried (magnesium sulfate), filtered and concentrated to give 79 mg of 4'- methyl ester. { [4- (l- ethoxycarbonyl-ethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonyl-L-valine. The ester was taken up in THF: MeOH (2: 1.2 mL) and treated with NaOH (5 N, 5 equivalents). The reaction was stirred overnight, diluted with ethyl acetate and acidified with IN HCl. The organic layer was isolated and washed with brine (2X), dried (magnesium sulfate), filtered and concentrated to give 4 '-. { [4- (1-carboxy-ethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonyl-L-valine. EMCL MH + (m / z) 581. aH NMR (300 MHz, CD3OD) d 7.91-7.68 ppm (m, 6H), 7.40-7.09 ppm (m, 3H), 6.70 ppm (d, 1H, J = 8 Hz) , 4.99 ppm (c, 1H, J = 13 Hz), 3.69 ppm (d, 1H, J = 5.8 Hz), 2.08-2.00 ppm (m, 1H), 1.69 ppm (d, 3H, J = 6.9 Hz), 0.97 ppm (d, 3H, J = 7.0 Hz), 0.96 ppm (d, 3H, J = 7.0 Hz).

Example 15: N-2- ( {4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1' -biphenyl-4-yl.} Sulfonyl) -L-asparagine According to the procedure of Example 4, N-2- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} - sulfonyl was prepared) -L-asparagine from Fmoc-L-asparagine-Wang resin. EMCL MH + (m / z) 508. 1H NMR (300 MHz, DMSO-de) d 10.71 ppm (s, 1H), 8.16-7.50 ppm (m, 12H), 7.39 ppm (dd, 1H, J1 = 7.5 Hz, J2 = 7.5 Hz), 3.95 ppm (m, 1H) , 2.34 ppm (d, 2H, J = 6.0 Hz).

Example 16: L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino) -3-methyl-butyric Stage 1: To a stirred solution of 4-nitrobiphenyl (50.00 g, 0.25 mol) in chloroform (750 ml) was added dropwise chlorosulfonic acid (17 ml, 0.3 mol) at room temperature. The reaction mixture was stirred at 60 ° C for 6 hours. The white precipitate formed was collected by filtration and washed with cold chloroform. The product was dried in air to give 31.00 g of 4-nitrobiphenylsulfonic acid (61% yield). Step 2: The crude 4-nitrobiphenylsulfonic acid obtained above (31.00 g, 0.11 mol) was diluted with thionyl chloride (100 ml) and treated with a catalytic amount of DMF (0.1 ml). The reaction mixture was refluxed for 4 hours, cooled to room temperature, and concentrated in vacuo. To remove residual thionyl chloride, toluene was added and concentrated to give 29.00 g (84% yield) of the desired product, 4 '-nitro-biphenyl-4-sulfonyl chloride. Step 3: To a dry round bottom flask was added 4 '-nitro-biphenyl-4-sulfonyl chloride (5.09 g), anhydrous dichloromethane (50 ml), and L-valine methyl ester hydrochloride (1.10 equivalents). The reaction mixture was cooled in an ice bath before the addition of N, N-diisopropylethylamine (2.50 equivalents). The ice bath was removed and the reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was then diluted with ethyl acetate (100 ml) and saturated ammonium chloride solution (20 ml). The organic layer and the aqueous layer were separated and the aqueous layer was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate., filtered and evaporated under vacuum to provide 6.31 g of the product, L-3-methyl-2- (4'-nitro-biphenyl-4-sulfonylamino) -butyric acid methyl ester (95% yield). Step 4: The product obtained in the above Step 3 was dissolved in ethyl acetate (120 ml). SnCl 2 solution (4.0 equivalents) was added to the solution. The reaction was allowed to continue at room temperature for 6 hours. The reaction mixture was then cooled in a water bath and 2 M sodium carbonate solution was added (30 g. mi) and ethyl acetate (100 ml). The mixture was transferred to a centrifuge bottle and centrifuged for 20 minutes. The supernatant was removed and washed with water and brine and dried over anhydrous sodium sulfate. After filtration and concentration, 5.52 g of product were obtained, L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester.

Step 5: L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (5.52 g), anhydrous methylene chloride (100 ml) were added to an oven-dried flask. , and N, N-diisopropylethylamine (2.0 equivalents). The solution was cooled in an ice bath and then benzofurancarbonyl chloride (1.0 equivalent) was added. The reaction was allowed to continue at 0 ° C for 4 hours. Water was added and the precipitate was filtered and washed with cold ether. After drying in vacuo, the product was obtained, methyl ester of L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid in the form of a white solid (6.98 g, yield of 90%).

Step 6: The methyl ester product from Step 5 above was dissolved in THF (150 ml). Methanol (100 ml) and water (100 ml) were added, followed by lithium hydroxide. monohydrate (3.60 g). The reaction mixture was stirred at room temperature until no starting material remained. The reaction mixture was cooled in an ice bath and acidified with concentrated hydrochloric acid to pH 3. The resulting precipitate was filtered and washed with cold water and cold ether to provide 5.65 g of L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric.

Example 17: N- (. {4 '- [(1-benzo-uran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -L-histidine According to the procedure of Example 4, N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl.} Sulfonyl) -L was prepared -histidine from Fmoc-N-Boc-L-histidine-Wang resin. EMCL MH + (m / z) 531. 1 H NMR (300 MHz, DMSO-d 6) d 10.72 ppm (s, 1 H), 8.25 (s) , 1H), 7.98 ppm (d, 1H, J = 9.3 Hz), 7.86-7.73 ppm (m, 10H), 7.44 ppm (dd, 1H, J? = 9.6 Hz, J2 = 7.8 Hz), 7.38 ppm (dd) , 1H, J? = 7.2 Hz, J2 = 7.2 Hz), 6.68 ppm (s, 1H), 6.54 ppm (s, 1H), 2.85 ppm (d, 2H, J = 5.1 Hz).

Example 18: N- ( {4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1' biphenyl-4-yl.}. Sulfonyl) -L-leucine According to the procedure of Example 4, N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1'-biphenyl-4-yl.} - sulfonyl) - L-leucine from Fmoc-L-leucine-Wang resin. EMCL MH + (m / z) 507.? NMR (300 MHz, DMSO-d6) d 10.75 ppm (s, 1H), 8.33 (s, 1H ), 7.98 ppm (d, 1H, J = 9.3 Hz), 7.84-7.73 ppm (m, 10H), 7.52 ppm (dd, 1H, J? = 7.2 Hz, J2 = 7.2 Hz), 7.38 ppm (dd, 1H , Ji = 7.5 Hz, J2 = 7.5 Hz), 3.23 ppm (m, 1H), 1.45 (m, 2H), 0.81 (m, 7H).

Example 19: L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 0.838 g of L-valine methyl ester hydrochloride in 15 ml of dichloromethane, cooled in an ice bath, 1.34 g of 4-bromobenzenesulfonyl chloride followed by 2.79 ml of triethylamine were added. . The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane was washed with water and brine, dried over a2SO4, filtered and concentrated in vacuo to provide 1.77 g of N- [(4-bromophenyl) sulfonyl] -L-valinate methyl in the form of a colorless solid. Performance -100%. P.f. 88-90 ° C; EM 348.2 (M-H). Step 2: A mixture of 0.175 g (0.5 mmol) of methyl N - [(4-bromophenyl) sulfonyl] -L-valinate, 0.25 g (1.5 mmol) of 4-nitrophenylboronic acid, 0.087 g of tetrakis (triphenylphosphine) palladium and 8 ml of saturated sodium bicarbonate in 8 ml of ethylene glycol dimethyl ether, heated to reflux for 2 hours, and then cooled to room temperature. To the reaction was added 50 ml of ethyl acetate and 40 ml of water. The water layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried over Na 2 SO, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexane: ethyl acetate (2: 1), to give 0.159 g of N- [(4'-nitro-1,1'-biphenyl-4-yl) sulfonyl ] -L-Valinate Methyl in the form of a yellow solid. Performance 81%. P.f. 144-146 ° C: MS: 391.0 (M-H) +. Stage 3: 1.72 g of 4-bromoaniline was added to 1. 89 g of benzofuran-2-carboxylic acid chloride in 35 ml of dichloromethane cooled in an ice bath, followed by the addition of 4.9 ml of triethylamine. The reaction was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane layer was washed with water, 1N HCl, water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to provide 2.61 g of N- (4-bromophenyl) -l-benzofuran-2-carboxamide as a yellow solid. Performance 72%. P.f. 178-180 ° C; EM 314.1 (MH). "Step 4: A mixture of 0.74 g of N- (4-bromophenyl) -l-benzofuran-2-carboxamide, 0.653 g of bis (pinacolato) diboro, 0.689 g of potassium acetate and 0.096 g of complex bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane in 15 ml of DMSO, was heated at -80 ° C for 2 hours, then cooled to room temperature, then 20 ml of toluene, 40 ml were added to the reaction. of ethyl acetate and 40 ml of water The water layer was extracted with 30 ml of ethyl acetate The combined organic layers were filtered and washed 4 times with 40 ml of water, dried over Na 2 SO 4, filtered and concentrated in vacuum to obtain 0.34 g of the borate ester in the form of an oily black compound, 0.273 g of methyl N- [(4-bromophenyl) sulfonyl] -L-valinate, 0.13 g of tetrakis were added to the previous product. triphenylphosphino) palladium, 7.5 ml saturated sodium bicarbonate and 12 ml ethylene glycol dimethyl ether, and the mixture was heated to reflux. Resulting for 2 hours. The reaction mixture was then cooled to room temperature. Ethyl acetate and water were added to the reaction and the mixture was filtered. The organic layer was washed with water and brine / dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was purified by column chromatography, eluting with hexane: ethyl acetate (2: 1), to give 0.112 g of N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1 , Methyl 1 '-biphenyl-4-yl.} Sulfonyl) -L-valinate in the form of a white solid. Yield 28.4%. P.f. 195-200 ° C; MS: 507.1 (M + H) +. Step 5: According to the procedure of Example 2A, Step 6. N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl was converted. .] sulfonyl) -L-valinate in L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric.

Example 20: L-2- acid. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: In a round bottom flask with 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (6,336 g, 28.8 mmol, 1 equivalent) in methylene chloride (120 ml) was added under one atmosphere from N, N-diisopropylethylamine nitrogen (12.54 ml, 72.0 mmol, 2.5 equivalents). The mixture was cooled to 0 ° C and trifluoromethanesulfonic anhydride (7.27 ml, 43.2 mmol, 1. 5 equivalents). After stirring for one hour, the mixture was diluted with methylene chloride (350 ml) and washed twice with water. The organic layer was dried and evaporated in vacuo to give 3-methyl-4-trifluorornene-sulphonyloxy-benzofuran-2-carboxylic acid ethyl ester suitable for use without purification. 1 H NMR (400 MHz, CDC13) d ppm 1.5 (t, J = 7.1 Hz, 3H) 2.8 (s, 3H) 4.5 (c, J = 7.2 Hz, 2H) 7.2 (d, J = 9.6 Hz, 1H ) 7.5 (t, J = 8.2 Hz, 1H) 7.6 (d, J = 8.3 Hz, 1H). Step 2: To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (721 mg, 2.0 mmol, 1 equivalent) in 10 mL of DMF under a nitrogen atmosphere, 322 mg of Zn (CN) was added. ) 2 (2.74 mmol, 1.37 equivalents), and 123 mg of Pd (PPh3) 4 (0.1 mmol, 0.05 equivalents). The reaction mixture was heated to 85 ° C. It was determined by TLC that the reaction was complete in 2.5 hours. After working-up and column chromatography, eluting with 5% ethyl acetate / hexane, 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 80% yield (367 mg). XH NMR (400 MHz, CD3OD) d ppm 1. 6 (t, J = 7.1 Hz, 3H) 3.0 (s, 3H) 4.6 (c, J = 7.2 Hz, 2H) 7.8 (dd, J = 8.3, 7.6 Hz, 1H) 7.9 (m, 1H) 8.1 (dd) , J = 8.3, 1.0 Hz, 1H).

Step 3: To 550 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.4 mmol) in 15 mL of THF was added 5 mL of MeOH and 5 mL of IN LiOH. The reaction was completed in 2 hours. After cooling rapidly with 5 ml of IN HCl and treatment, 4-cyano-3-methyl-benzofuran-2-carboxylic acid was obtained in quantitative yield. a H NMR (400 MHz, DMSO-d 6) d ppm 2.7 (s, 3 H) 7.7 (m, 1 H) 7.9 (d, J = 7.3 Hz, 1 H) 8.1 (m, 1 H). Step 4: To a mixture of 4-cyano-3-methyl-benzofuran-2-carboxylic acid (525 mg, 2.6 mmol, 1 equivalent), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 752 mg, 3.9 mmol, 1.5 equivalents), and 4- (dimethylamino) pyridine (335 mg, 2.7 mmol, 1 equivalent) in ml of DMF under a nitrogen atmosphere, L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, the product of Example 2A, Step 4 was added. Mix at 100 ° C for 8 hours. After working-up and column chromatography (20% ethyl acetate / hexane), L-2-methyl ester was obtained. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (643 mg, 1.18 mmol) with a yield of 45%. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3 , 7.1 Hz, 1H) 7.7 (dd, J = 8.3, 7.6 Hz, 1H) 7.8 (dd, J = 8.8, 3.3 Hz, 4H) 7.9 (m, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (m, 1 H) 8.3 (d, J = 9.6 Hz, 1 H) 10.8 (s, 1H). Step 5: The methylester obtained in Step 4 (183 mg) was dissolved in THF (8 mL) and methanol (3 mL) and 1N LiOH (1 mL) was added thereto. The reaction mixture was stirred at room temperature to complete the reaction (~ l-2 days). The reaction mixture was then acidified with 1N hydrochloric acid to ~ pH 4. The resulting mixture was extracted with ethyl acetate and the combined organic layers were dried, filtered and concentrated in vacuo to give the acid 2-. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 29.7, 6. 7 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H) 3.3 (s, 1H) 7.7 (m, 1H) 7. 8 (m, 6H) 7.9 (d, J = 7.1 Hz, 1H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 8.6 Hz, 1H) 10.8 (s, 1H).

Example 21: L-3-methyl-2- acid. { 4 '- [(3-methyl-4-prop-1-ynyl-benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -butyric Stage A 3-methyl-4- ethyl ester trifluoromethanesulfonyloxybenzofuran-2-carboxylic acid (550 mg, 1.6 mmol, 1 equivalent), the product of Example 20, Step 1, in 5 ml of toluene under a nitrogen atmosphere, was added 60 mg of Pd (PPh3) 4 ( 0.05 mmol, 0.03 equivalents) and tributyl-prop-1-inyl-stannane (0.55 ml, 1.8 mmol, 1.13 equivalents). The resulting reaction mixture was heated to reflux for 18 hours. After treatment and column chromatography (3% ethyl acetate / hexane), 3-methyl-4-propyl-l-inyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 14% yield (56 mg) . 1 H NMR (400 MHz, CDC 13) d ppm 1.4 (t, J = 7.1 Hz, 3 H) 2.1 (s, 3 H) 2.8 (s, 3 H) 4.5 (c, J = 7.1 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J = 7.6, 1.8 Hz, 1H). Step 2: According to the procedure of Example 20, Step 3, the ethyl ester of 3-methyl-4-propyl-l-inyl-benzofuran-2-carboxylic acid was hydrolyzed to give the acid 3-methyl-4-propionate. l-inyl-benzofuran-2-carboxylic acid with a yield of 99%. XH NMR (400 MHz, CDC13) d ppm 2.2 (s, 3H) 2. 9 (s, 3H) 7.3 (m, 2H) 7.5 (m, 1H). Step 3: To a mixture of 3-methyl-4-prop-1-ynyl-benzofuran-2-carboxylic acid (46 mg, 0.21 mmol, 1 equivalent), L-2- (4'-amino-biphenyl) methyl ester 4-sulfonylamino) -3-methyl-butyric acid (79 mg, 0.22 mmol, 1 equivalent), the product of Example 2A, Step 4, and benzotriazole-1-hexafluorophosphate iloxitris (dimethylamino) phosphonium (BOP, 127 mg, 0.29 mmol, 1.4 equivalents) in 5 ml of DMF under a nitrogen atmosphere, was added 0.05 ml of N, N-diisopropylethylamine (0.29 mmol, 1.4 equivalents). The reaction mixture was stirred at room temperature for 18 hours. After working-up and column chromatography (25% ethyl acetate / hexane), methyl ester of L-3-methyl-2-acid was obtained. { 4 '- [(3-methyl-4-prop-1-ynyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric with a 45% yield (55 mg). XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.2 (dd, 3H) 2.8 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.4 (d, J = 7.1 Hz, 1H) 7.5 (, 1H) 7.7 (d, J = 7.6 Hz, 1H) 7.8 (t, J = 8.8 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.6 Hz, 1H) 10.6 (s, 1H). Stage 4: In accordance with the procedure of Example 20, Step 5, L-3-methyl-2- methyl ester was hydrolyzed. { 4 '- [(3-methyl-4-prop-1-ynyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric to give the acid L-3-methyl-2-. { 4 '- [(3-methyl-4-prop-1-ynyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric with quantitative performance. 2 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 1.9 (m, 1H) 2.2 (s, 3H) 2.8 (s, 3H) 3.6 (dd, J = 9.3 , 6.1 Hz, 1H) 7.4 (d, J = 6.8 Hz, 1H) 7.5 (m, 1H) 7.7 (d, J = 8.3 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H ) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.6 Hz, 1H) 10.6 (s, 1H).

Example 22: L-2- (4 '- { [4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -3-methyl-butyric Step 1: To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (860 mg, 2.4 mmol, 1 equivalent), in 7 ml of DMF under a nitrogen atmosphere, 98 mg of PdCl2 (PPh3) 2 (0.14 mmol, 0.06 equivalents), 0.42 ml of 3-methoxy-propyne (5.0 mmol, 2.1 equivalents) and 1.36 ml of triethylamine (9.7 mmol, 4.0 equivalents) were added. The reaction mixture was heated at 90 ° C for 18 hours. After workup and column chromatography (4% ethyl acetate / hexane), 4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained with a yield of 53% (343 mg). 1 H NMR (400 MHz, CDC13) d ppm 1.4 (t, J = 7.2 Hz, 3 H) 2.8 (t, 3 H) 3.5 (s, 3 H) 4.4 (s, 2 H) 4.5 (c, J = 7.2 Hz, 2 H) 7.4 (m, 2H) 7.5 (dd, J = 7.7, 1.6 Hz, 1H). Step 2: In accordance with the procedure of Example 20, Step 3, the 4-ethyl ester was hydrolysed (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid to give 4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid with a 100% performance. 1 H NMR (400 MHz, CD3OD) d ppm 2.7 (s, 3H) 3.4 (s, 3H) 4.3 (s, 2H) 7.3 (m, 2H) 7.4 (dd, J = 7.8, 1.5 Hz, 1H). Step 3: According to the procedure of Example 21, Step 3, 4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid was coupled with methyl ester of L-2- acid ( 4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric to give methyl ester of L-2- (4 '- { [4- (3-methoxy-prop-1-ynyl) -3- methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with a yield of 88%. XH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 32.5, 6.7 Hz, 6H) 2.1 (m, 1H) 2.9 (s, 3H) 3.4 (s, 3H) 3.5 (s, 3H) 3.8 (dd) , J = 10.1, 5.1 Hz, 1H) 4.4 (s, 2H) 5.1 (d, J = 10.1 Hz, 1H) 7.4 (m, 2H) 7.5 (m, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.7 (d, J = 8.6 Hz, 2H) 7.9 (dd, J = 17.8, 8.7 Hz, 4H) 8.4 (s, 1H). Step 4: According to the procedure of Example 20, Step 5, the methyl ester of L-2- (4 '- { [4- (3-methoxy-prop-1-ynyl) -3-methyl was hydrolysed -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid to give the acid L-2- (4 '- {. {4- (3-methoxy) prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric in 100% yield. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.0, 6.4 Hz, 6H) 2.0 (dd, J = 13.4, 8. 1 Hz, 1H) 2.8 (s, 3H) 3.4 (s, 3H) 3.6 (m, 1H) 4.4 (s, 2H) 7.5 (m, 2H) 7.8 (m, 7H) 8.0 (m, 3H) 10.6 (s) , 1H) 12.6 (s, 1H).

Example 23: 2- acid. { 4 '- [(4-cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl] -amino.}. -bifinyl-4-sulfonylamino) -3-methylpyrrolidone Step 1: To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (1.8 g, 5.1 mmol, 1 equivalent), in 2 ml of DMF under a nitrogen atmosphere, were added 200 mg of PdCl2 (PPh3) 2 (0.28 mmol, 0.05 equivalents), Et3N (2.85 ml, 20.4 mmol, 4 equivalents), cyclopropylethynyl trimethylsilane (1 g, 7.2 mmol, 1.4 equivalents) and tetrabutylammonium fluoride (5.1 ml, 1.0 M in THF, 5.1 mmol, 1 equivalent). The reaction mixture was sealed and heated to 80 ° C for 12 hours. After working-up and column chromatography (2% ethyl acetate / hexane), 4-cyclopropylethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 15% yield (202.6 mg). XH NMR (400 MHz, CD30D) d ppm 0.7 (m, 2H) 0.9 (m, 2H) 1.3 (t, J = 7.1 Hz, 3H) 1.5 (m, 1H) 2.7 (s, 3H) 4.3 (c, J = 7.2 Hz, 2H) 7.2 (m, 1H) 7.3 (dd, J = 8.3, 7.3 Hz, 1H) 7.4 (m, 1 H). Step 2: According to the procedure of Example 20, Step 3, the ethyl ester of 4-cyclopropylethynyl-3-methyl-benzofuran-2-carboxylic acid was hydrolyzed to give 4-cyclopropylethynyl-3-methyl-benzofuran-2-carboxylic acid with quantitative yield, - "? NMR (400 MHz, DMSO-d6) d ppm 0.8 (m, 2H) 0.9 (m, 2H) 1.6 (m, 1H) 2.7 (s, 3H) 7.3 (dd, J = 7.6, 1.0 Hz, 1H) 7.4 (m, 1H) 7.6 (dd, J = 8.3, 1.0 Hz, 1H) Step 3: According to the procedure of Example 21, Step 3, the coupling of 4-cyclopropylethynyl-3- acid methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester gave L-2- (4. -cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino] -3-methyl-butyric in 54% yield aH NMR (400 MHz, CDC13) d ppm 0.9 ( m, 10H) 1.6 (m, 1H) 2.1 (m, 1H) 2.9 (s, 3H) 3.4 (s, 3H) 3.8 (dd, J = 10.1, 5.1 Hz, 1H) 5.1 (d, J = 10.1 Hz, 1H) 7.3 (m, 2H) 7.4 (m, 1H) 7.6 (d, J = 8.8 H z, 2H) 7.7 (d, J = 8.6 Hz, 2H) 7.9 (dd, J = 18.8, 8.7 Hz, 4H) 8.4 (s, 1H). Step 4: According to the procedure of Example 20, Step 5, the methyl ester of L-2- acid was hydrolysed. { 4 '- [(4-cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl) - amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield to give L-2- acid. { 4 '- [(4-cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (m, J = 12.6, 6.6 Hz, 8H) 1.0 (m, 2H) 1.7 (m, 1H) 2.0 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.1, 5.8 Hz, 1H) 7.3 (dd, J = 7.6, 0.8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 7.3 Hz, 1H) 7.8 (d, J = 8.8 Hz , 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 24: L-2- (4 '- { [4- (2-cyclopropyl-ethyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3 acid -metil-b tirico Step 1: To a solution of the product of Example 23, Step 3, methyl ester of L-2- acid. { 4 '- [(4-cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (132 mg, 0.23 mmol), in 10 ml of THF under a nitrogen atmosphere, 5% Pd / C (32 mg) was added. A hydrogen balloon was attached to the reaction mixture. After 36 hours, the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified using preparative HPLC to give L-2- (4 '- { [4- (2-cyclopropyl-ethyl) -3-methyl-benzofuran-2-carbonyl] -amino methyl ester. .-biphenyl-4-sulfonylamino) -3-methyl-butyric with a yield of 56%. XH NMR (400 MHz, DMSO-d6) d ppm 0.1 (d, J = 4.8 Hz, 2H) 0.4 (dd, J = 8.0, 1.6 Hz, 2H) 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.6 (m, 2H) 1.9 (m, 1H) 2.8 (s, 3H) 3.1 (m, 2H) 3.4 (s, 3H) 3.6 (m, 1H) 7.1 (d, J = 7.3 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.8 (dd, J = 10.2, 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 10.1 Hz, 1H) 10.5 (s, 1H).

Step 2: According to the procedure of Example 20, Step 5, the methyl ester of L-2- (4 '- { [4- (2-cyclopropyl-ethyl) -3-methyl-benzofuran-2 was hydrolyzed. -carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid to give the acid L-2- (4 '- { [4- (2-cyclopropyl-ethyl) -3-methyl) -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.1 (d, J = 5.6 Hz, 2 H) 0.4 (d, J = 8.1 Hz, 2 H) 0.8 (m, 6 H) 1.6 (m, 2 H) 2.0 (dd, J = 13.4, 7.8 Hz, 1H) 2.8 (s, 3H) 3.1 (m, 1H) 3.6 (m, 3H) 7.1 (d, J = 7.8 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.6 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.6 Hz, 2H) 8.0 (d, J = 10.4 Hz, 1H) 10.5 (s, 1H).

Example 25: L-2- (4 '- { [4- (3-methoxy-Z-propenyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric Step 1: To a solution of the product of Example 22, methyl ester of L-2- (4 '- { [4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4- sulfonylamino) -3-methyl-butyric acid (132 mg, 0.22 mmol), in 10 ml of toluene under a nitrogen atmosphere, Pd / CaCO3 (lead poisoning, 34 mg) was added. A hydrogen balloon was attached to the reaction mixture. After 24 hours, the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC to give L-2- (4 '- { [4- (3-methoxy-Z-propenyl) -3-methyl-benzofuran-2-carbonyl] -amino methyl ester. .}. -biphenyl-4-sulfonylamino) -3-methyl-butyric with a 38% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (dd, 1H) 2.7 (s, 3H) 3.2 (s, 3H) 3.4 (s, 1H) 4.1 (m, J = 6.3, 1.5 Hz, 2H) 6.0 (m, 1H) 7.1 (d, J = 7.3 Hz, 1H) 7.2 (d, J = 12.4 Hz, 1H) 7.5 (d, 1H) 7.6 (d, J = 8.1 Hz, 1H) 7.8 (t, J = 8.8 Hz, 4H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (d, J = 9.1 Hz, 2H) 8.3 (s, 1H) 10.6 (s, 1H).

Step 2: According to the procedure of Example 20, Step 5, the methyl ester of L-2- (4 '- { [4- (3-methoxy-Z-propenyl) -3-methyl-benzofuran was hydrolyzed. -2- carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid to give the acid L-2- (4 '- { [4- (3-methoxy-Z-propenyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric in 100% yield. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.8, 6.7 Hz, 6H) 2.0 (dd, J = 13.3, 6.4 Hz, 1H) 2.7 (s, 3H) 3.2 (s, 3H) 4.1 (d, J = 7.8 Hz, 2H) 6.0 (m, 1H) 7.1 (d, J = 7.8 Hz, 1H) 7.2 (d, J = 10.4 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 7.6 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) ).

Example 26: L-2- (4 '- { [4- (3-hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -3-methyl-butyric Step 1: In accordance with the procedure of Example 22, Step 1, 4- (3-hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from propargyl alcohol and ethyl ester of 3-methyl- 4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid in 38% yield. X H NMR (400 MHz, DMSO-d 6) d ppm 1.4 (t, J = 7.1 Hz, 3 H) 2.8 (s, 3 H) 4.4 (m, 4 H) 5.4 (t, J = 6.1 Hz, 1 H) 7.4 (dd, J = 7.6.0, 8Hz, 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 0.8 Hz, 1H). Step 2: According to the procedure of Example 20, Step 3, hydrolysis of 4- (3-hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester gave 4- (3 -hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.8 (s, 3 H) 4.4 (d, J = 6.1 Hz, 2 H) 5.4 (t, J = 5.9 Hz, 1 H) 7.4 (dd, J = 7.5, 0.9 Hz , 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 1.0 Hz, 1H). Step 3: According to the procedure of Example 21, Step 3, the coupling of methyl ester of L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid with 4- (3- hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid gave methyl ester of L-2- (4 '- { [4- (3-hydroxy-prop-1-ynyl) -3- methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric in 51% yield. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 4.4 (d, J = 6.1 Hz, 2H) 5.4 (m, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.7 (d, J = 8.3, 0.8 Hz, 1H) 7.8 (t, J = 8.6 Hz , 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H).

Step 4: According to the procedure of Example 20, Step 5, the hydrolysis of the methyl ester of L-2- (4 '- { [4- (3-hydroxy-prop-1-ynyl) -3-methyl) -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric gave acid L-2- (4 '- { [4- (3-hydroxy-prop-1- inyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. "" "H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.0, 6.7 Hz, - 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.5 (m, 1H) 4.4 (d , J = 5.8 Hz, 2H) 5.4 (t, J = 6.1 Hz, 1H) 7.4 (dd, J = 7.6, 1.0 Hz, 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 1.0 Hz, 1H ) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.0 (d, J = 7.8 Hz, 1H) 10.6 (s, 1H).

Example 27: L-2- (4 '- ((4- (3-hydroxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl acid -butyric Step 1: The product of Example 26, Step 1, 4- (3-hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester, was hydrogenated to give 4- (3-ethyl ester) -hydroxy-propyl) -3-methyl-benzofuran-2-carboxylic acid according to the procedure of Example 24, Step 1, with quantitative yield. 1 H NMR (400 MHz, CDC13) d ppm 1.3 (t, J = 5.2 Hz, 1H) 1.4 (t, J = 7.1 Hz, 3H) 2.0 (m, 2H) 2.8 (s, 3H) 3.1 (m, 2H) 3.8 (m, 2H) 4.5 (c, J = 7.2 Hz, 2H) 7.1 (dd, J = 7.2 , 0.9 Hz, 1H) 7.3 (m, 1H) 7.4 (m, 1H). Step 2: The hydrolysis of the 4- (3-hydroxy-propyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was carried out according to the procedure of Example 20, Step 3, to provide the 4- (3 -hydroxy-propyl) -3-methyl-benzofuran-2-carboxylic acid with quantitative yield. 1 H NMR (400 MHz, DMSO-de) d ppm 1.8 (m, 2 H) 2.7 (s, 3 H) 3.0 (m, 2 H) 3.5 (m, 2 H) 4.6 (t, J = 5.1 Hz, 1 H) 7.1 (dd , J = 7.1, 1.0 Hz, 1H) 7.4 (m, 1H) 7.4 (m, 1H). Stage 3: The amidation of L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester with 4- (3-hydroxy-propyl) -3-methyl-benzofuran -2-carboxylic acid according to the procedure of Example 21, Step 3, gave L-2- (4 '- { [4- (3-hydroxy-propyl) -3-methyl-benzofuran-2-methyl ester -carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric with a 100% yield. aH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 32.1, 6.8 Hz, 6H) 2.0 (m, 3H) 2.9 (s, 3H) 3.1 (m, 2H) 3.4 (s, 3H) 3.8 (m , 3H) 5.1 (d, J = 10.1 Hz, 1H) 7.1 (m, 1H) 7.4 (m, 2H) 7.6 (d, J = 8.6 Hz, 2H) 7.7 (d, J = 8.8 Hz, 2H) 7.9 ( dd, J = 16.7, 8.6 Hz, 4H) 8.5 (s, 1H).

Step 4: Hydrolysis of L-2- (4 '- { [4- (3-hydroxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-methyl ester. -sulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 5, gave the acid L-2- (4 '- { [4- (3-hydroxy-propyl) -3-methyl- benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.55, 6.7 Hz, 6H) 1.8 (m, 2H) 2.0 (m, 1H) 2.8 (s, 3H) 3.1 (m, 2H) 3.5 (m, 2H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 4.6 (s, 1H) 7.1 (d, J = 7.3 Hz, 1H) 7.4 (m, 1H) 7.5 (d, J = 8.3 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 10.5 (s, 1H).

Example 28: L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carbonyl] -amino acid} - biphenyl-4-sulfonylamino) -butyric Stage 1: According to the procedure of Example 22, Step 1, 3-methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carboxylic acid ethyl ester was prepared from 4-methyl-pent-1-yl and 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester in 81% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.0 (s, 3 H) 1.0 (s, 3 H) 1.3 (t, J = 7.1 Hz, 3 H) 1.9 (m, 1 H) 2.4 (d, J = 6.6 Hz, 2H) 2.8 (s, 3H) 4.4 (c, J = 7.1 Hz, 2H) 7.4 (dd, J = 7.6, 1.0 Hz, 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 1.0 Hz, 1H ). Step 2: The hydrolysis of the ethyl ester of 3-methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carboxylic acid was carried out according to the procedure of Example 20, Step 3, to provide acid 3. -methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carboxylic acid with quantitative yield, ""? NMR (400 MHz, DMSO-d6) d ppm 1.0 (d, J = 6.6 Hz, 6H) 1.9 (, 1H) 2.4 (d, J = 6.6 Hz, 2H) 2.8 (s, 3H) 7.3 (dd, J = 7.5, 0.9 Hz, 1H) 7.4 (m, 1H) 7.6 (dd, J = 8.3, 1.0 Hz, 1H) 13.5 (s, 1H). Step 3: The amide coupling of L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester with 3-methyl-4- (4-methyl-pent-l-) acid inyl) -benzofuran-2-carboxylic acid was carried out according to the procedure of Example 21, Step 3, to provide methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- ( 4-methyl-pent-1-ynyl) -benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric in 42% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.1 (d, J = 6.6 Hz, 6H) 1.9 (m, 2H) 2.5 (d, J6.6 Hz , 2H) 2.8 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J9.0, 6.9 Hz, 1H) 7.4 (d, J = 7.3 Hz, 1H) 7. 5 (m, 1H) 7.7 (dd, J = 8.3, 1.0 Hz, 1H) 7.8 (m, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H,) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H). Step 4: Hydrolysis of the methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carbonyl] - amino.} - biphenyl-4-sulfonylamino) -butyric acid was made according to the procedure of Example 20, Step 5, to provide L-3-methyl-2- (4 '- { [3-methyl-4 - (4-methyl-pent-1-ynyl) -benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric with quantitative yield. lE NMR (400 MHz, DMSO-dg) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.1 (d, J = 6.8 Hz, 6H) 1.9 (m, 2H) 2.5 (d, J = 6.6 Hz, 2H) 2.8 (s, 3H) 3. 5 (m, 1H) 7.4 (d, J = 7.3 Hz, 1H) 7.5 (m, 1H) 7.7 (d, J = 8.1 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.0 (d, J = 9.1 Hz, 1H) 10.6 (s, 1H).

Example 29: L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pentyl) -benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -butyric Step 1: Hydrogenation of the product of Example 28, Step 1, L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pent-1-ynyl) methyl ester) -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -butyric acid, was carried out according to Example 24, Step 1, to provide methyl ester of L-3-methyl-2- (4 ') acid - { [3-Methyl-4- (4-methyl-pentyl) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -butyric with quantitative yield, - "? NMR (400 MHz , DMSO-d6) d ppm 0.8 (dd, J = 14.9, 6.8 Hz, 6H) 0.9 (m, J = 6.6 Hz, 6H) 1.3 (m, 2H) 1.6 (m, 3H) 1.9 (m, 1H) 2.8 (s, 3H) 3.0 (m, 2H) 3.3 (s, 3H) 3.6 (t, J = 6.8 Hz, 1H) 7.1 (d, J = 7.3 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H ) 7.8 (dd, J = 10.0, 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 9.1 Hz, 2H) 8.3 (d, J = 8.6 Hz, 1H) 10.5 (s, 1H).

Step 2: Hydrolysis of the methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl-pentyl) -benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino) -butyric acid according to the procedure of Example 20, Step 5, provided L-3-methyl-2- (4 '- { [3-methyl-4- (4-methyl- pentyl) -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 0.9 (d, J = 6.6 Hz, 6H) 1.3 (, 2H) 1.6 (m, 3H) 1.9 (m , 1H) 2.8 (s, 3H) 3.0 (d, 2H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.1 (d, J = 6.8 Hz, 1H) 7.4 (m, 1H) 7.5 (, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.6 Hz, 1H) 10.5 (s, 1H).

Example 30: L-2- (4 '- { [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino) -biphenyl-4-sulfonylamino) -3-methyl acid -butyric Step 1: Hydrogenation of the product of Example 22, Step 3, L-2- (4 '- { [4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-methyl ester. -carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid, in accordance with the procedure of Example 24, Step 1, gave methyl ester of L-2- (4 '-. [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield, - "? NMR (400 MHz) , DMSO-d6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 3H) 2.8 (s, 3H) 3.1 (m, 2H) 3.3 (s, 3H) 3.4 (s, 3H) 3.4 (m, J = 6.2, 6. 2 Hz, 2H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.1 (d, J = 6.6 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.8 (dd, J = 10.0, 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H). Stage 2: Hydrolysis of the methyl ester of L-2- (4'- { [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] - Not me } -biphenyl-4-sulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 5, provided L-2- (4'- { [4- (3-methoxy-propyl) -3) acid -methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. XH NMR (400 MHz, DMS0-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) d ppm 1.9 (m, 2H) 2.0 (m, 1H) 2.8 (s, 3H) 3.1 (m, 2H ) 3.3 (s, 3H) 3.4 (t, J = 6.2 Hz, 2H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.1 (d, J = 7.6 Hz, 1H) 7.4 (dd, J = 8.3, 7.3 Hz, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H).

Example 31: L-2- (4 '- { [4- (3-dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino acid} - bifenyl-4 -sullylamine) -3 -me il-butyric Step 1: To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (900 mg, 2.56 mmol, 1 equivalent), under a nitrogen atmosphere, was added 1- dimethylamino-2-propyne (425 mg, 5.11 mmol, 2 equivalents), PdCl2 (PPh3) 2 (90 mg, 0.13 mmol, 0.05 equivalents), and triethylamine (1.4 ml, 10.23 mmol, 4 equivalents), in 25 ml of toluene. The reaction mixture was heated to reflux for 15 hours until it was determined by TLC that the reaction was complete. After working-up and column chromatography (0-10% MeOH / dichloromethane), 4- (3-dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained with a yield of 65% (474 mg). aH NMR (400 MHz, DMSO-d6) d ppm 1.4 (t, J = 7.1 Hz, 3H) 2.3 (s, 6H) 2.8 (s, 3H) 3.6 (s, 2H) 4.4 (c, J = 7.1 Hz, 2H) 7. 4 (dd, J = 7.3, 1.0 Hz, 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.2, 0.9 Hz, 1H). Step 2: Hydrolysis of 4- (3-dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester according to the procedure of Example 20, Step 3, provided 4- (3 -dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid with a yield of 70%. 1H NMR (400 MHz, DMSO-d6) d ppm 2.8 (s, 3H) 2.9 (s, 6H) 4.4 (s, 2H) 7. 5 (m, 2H) 7.8 (m, 1H). Step 3: The stockpiling of 4- (3-dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) methylester) -3-methyl-butyric acid according to the procedure of Example 21, Step 3, gave methyl ester of L-2- (4 '- { [4- (3-dimethylamino-prop-1-ynyl) -3- methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3- methyl-butyric with a yield of 60%. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.9 (s, 3H) 2.9 (s, 6H) 3.4 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 4. 4 (s, 2H) 7.6 (m, 2H) 7.8 (t, J = 8.3 Hz, 5H) 7.9 (m, 2H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 1H). Step 4: Hydrolysis of the methyl ester of L-2- (4 '- { [4- (3-dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 5, provided L-2- (4 '- { [4- (3-dimethylamino-prop-1- inyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.9 (s, 3H) 2.9 (s, 6H) 3.6 (dd, J = 9.3 , 6.1 Hz, 1H) 4.4 (s, 2H) 7.6 (m, 2H) 7.8 (m, 7H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.6 Hz, 1H) 10.7 (s, 1H) 12.6 (s, 1H).

Example 32: L-2- (4 '- { [4- (3-dimethylamino-propyl) -3-methyl-benzofuran-2-carbonyl] -amino} -bifinyl-4-sulfonylamino) -3-methyl-butyric Step 1: To a solution of the product of Example 31, Step 3, methyl ester of L-2- (4 '- { [4- (3-dimethylamino-prop-1-ynyl) -3-methyl-benzofuran- 2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid (200 mg, 0.33 mmol) in 5 ml of dichloromethane, 5% Pd / C (66 mg) was added and The reaction was stirred at room temperature under 1 atmosphere of hydrogen for 72 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give methyl ester of L-2- (4'-. {4- [4- (3-dimethylamino-propyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric in 50% yield. 2 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.9, 6.8 Hz, 6H) 1.8 (dd, 2H) 1.9 (m, 1H) 2.2 (s, 6H) 2.4 (m, 2H) 2.8 (s, 3H) 3.0 (m, 2H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.1 (d, J = 7.3 Hz, 1H) 7.4 (m, 1H) 7.5 (m , 1H) 7.8 (dd, J = 9.9, 8.8 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H) . Step 2: The hydrolysis of the methyl ester of L-2- (4 '- { [4- (3-dimethylamino-propyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4 -sulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 4, provided L-2- (4 '- { [4- (3-dimethylamino-pro? il) -3-ethyl- acid benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.1 (m, 2H) 2.8 (d, J = 4.5 Hz, 6H) 2.8 (s, 3H) 3.1 (m, 2H) 3.2 (m, 2H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 7.8 ( d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 3.3 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.5 (s, H) 10.6 (s, 1H).

Example 33: L-2- acid. { 4 '- [(4-ethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: Collecting the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester with (trimethylsilyl) -acetylene according to the procedure of Example 31, Step 1, provided ethyl ester of 3-methyl-4-trimethylsilanylethynyl-benzofuran-2-carboxylic acid in 41% yield after purification using flash chromatography (1-5% ethyl acetate / hexane).

Step 2: Hydrolysis of the 3-methyl-4-trimethylsilanylethynyl-benzofuran-2-carboxylic acid ethyl ester according to the procedure of Example 20, Step 3, provided 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid in 73% yield. Step 3: The stockpiling of 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester according to the procedure of Example 21, Step 3, provided methyl ester of L-2- acid. { 4 '- [(4-ethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a yield of 96%. - "? NMR (400 MHz, DMSO-dg) d ppm 0.8 (dd, J = 14.9, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 4.6 (s, 1H) 7.5 (m, 2H) 7.8 (m, 5H) 7.9 (m, 2H) 8.0 (d, J = 9.1 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H).

Stage 4: Hydrolysis of acid methyl ester L-2-. { 4 '- [(4-ethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure of Example 20, Step 4, provided L-2- acid. { 4 '- [(4-ethynyl-3-methyl-benzofuran-2-carbonyl) -amino-biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 4.6 (s, 1H) 7.5 (m, 2H) 7.8 (m, 3H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 34: L-2- (4 '- { [4- (3, 3-dimethyl-but-l-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino acid. -4-sulfonylamino) - 3-methyl-butyric Step 1: The coupling of the product of Example , Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester with 3,3-dimethyl-1-butyne according to the procedure of Example 31, Step 1, provided 4-ethyl ester ( 3, 3-dimethyl-but-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid in 58% yield after purification by flash chromatography with 1-5% ethyl acetate / hexanes. XH NMR (400 MHz, DMS0-d6) d ppm 1.3 (s, 12H) 2.8 (s, 3H) 4.4 (c, J = 7.2 Hz, 2H) 7.3 (dd, J = 7.5, 0.9 Hz, 1H) 7.4 ( dd, J = 8.3, 7.6 Hz, 1H) 7.6 (m, 1H).

Step 2: Hydrolysis of 4- (3,3-dimethyl-but-l-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester according to the procedure of Example 20, Step 3, gave 4- (3, 3-dimethyl-but-l-inyl) -3-methyl- benzofuran-2-carboxylic acid with a yield of 80%. Step 3: The coupling of 4- (3,3-dimethyl-but-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl) 4- methyl ester sulfonylamino) -3-methyl-butyric acid according to the procedure of Example 21, Step 3, provided methyl ester of L-2- (4 '- { [4- (3, 3-dimethyl-but-1-ynyl) ) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with a yield of 52%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.4 (s, 9H) 1.9 (m, 1H) 2.8 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.3 (d, J = 7.3 Hz, 1H) 7.5 (m, 1H) 7.7 (d, J = 9.1 Hz, 1H) 7.8 (t, J = 8.8 Hz, 4H ) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H). Step 4: Hydrolysis of the methyl ester of L-2- (4'- { [4- (3,3-dimethyl-but-l-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 5, provided L-2- (4 '- { [4- (3, 3-dimethyl- but-l-inyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. "" "H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.4 (s, 9H) 2.0 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.3 (dd, J = 7.5, 0.9 Hz, 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 1.0 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 35: L-3-methyl-2- (4 '- { [3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] -amino acid} - biphenyl-4-sulfonylamino) -butyric Step 1: To the product of Example 33, Step 1, 3-methyl-4-trimethylsilanylethynyl-benzofuran-2-carboxylic acid ethyl ester (1.5 g, 4.99 mmol, 1 equivalent), in THF (10 mL) under an argon atmosphere , tetrabutylammonium fluoride (1.0 M in THF, 6 mL, 5.99 mmol, 1.2 equivalents) was added and the reaction was stirred at room temperature for 45 minutes. After treatment and flash column chromatography, 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 35% yield. ? E NMR (400 MHz, DMSO-d6) d ppm 1.4 (t, J = 7.1 Hz, 3H) 2.8 (s, 3H) 4.4 (m, J = 7.1, 7.1, 7.1 Hz, 2H) 4.6 (s, 1H ) 7.5 (m, 2H) 7.7 (dd, J = 7.7, 1.4 Hz, 1H). Step 2: To a solution of 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (228 mg, 0.99 mmol, 1 equivalent) in acetonitrile (5 mL) under an argon atmosphere was added dicarbonate. di-tert-butyl (327 mg, 1.5 mmol, 1.5 equivalents) and 4- (dimethylamino) pyridine (12 mg, 0.1 mmol, 0.1 equivalents). Nitroethane (79 μl, 1.1 mmol, 1.1 equivalents) in acetonitrile (5 ml) was added dropwise to the reaction mixture, and the reaction was stirred at room temperature for 72 hours. After treatment and flash column chromatography, 3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carboxylic acid ethyl ester was obtained in 25% yield. "" "H NMR (400 MHz, DMSO-d6) d ppm 1.4 (t, J = 7.1 Hz, 3H) 2.3 (s, 3H) 2. 4 (s, 3H) 4.4 (c, J = 7.1 Hz, 2H) 6.8 (s, 1H) 7.5 (dd, J = 7.5, 0.9 Hz, 1H) 7.6 (m, 1H) 7.9 (dd, J = 8.5, 0.9 Hz, 1H). Step 3: Hydrolysis of 3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carboxylic acid ethyl ester according to the procedure of Example 20, Step 3, provided 3-methyl- 4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carboxylic acid with quantitative yield. "" "H NMR (400 MHz, DMSO-ds) d ppm 2.3 (s, 3H) 2.4 (s, 3H) 6.8 (s, 1H) 7. 5 (d, J = 8.3 Hz, 1H) 7.6 (m, 1H) 7.9 (d, J = .1 Hz, 1H). Step 4: The coupling of 3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) methylester) -3-methyl-butyric acid according to the procedure of Example 21, Step 3, provided methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (3-methyl-isoxazole -5-yl) -benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric with a yield of 52%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.4 (s, 3H) 2.5 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 6.8 (s, 1H) 7.5 (d, J = 7.6 Hz, 1H) 7.7 (m, 1H) 7.8 (dd, J = 8.5, 6.4 Hz, 4H) 7.9 (m, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.1 Hz, 1H) 10.7 (s, 1H). Step 5: Hydrolysis of the methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] - amino.} - biphenyl-4-sulfonylamino) -butyric acid according to the procedure of Example 20, Step 5, provided L-3-methyl-2- (4 '- { [3-methyl-4- ( 3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric in 38% yield after purification by preparative HPLC. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.4 (s, 3H) 2.5 (s, 3H) 3.6 (dd, J = 9.3 , 5.8 Hz, 1H) 6.8 (s, 1H) 7.5 (dd, J = 7.6, 1.0 Hz, 1H) 7.7 (dd, J = 8.3, 7.3 Hz, 1H) 7.8 (m, 4H) 7.9 (, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H).

Example 36: L-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (800 mg, 2.27 mmol), in 25 ml of toluene, methanesulfonamide (650 mg, 6.82 mmol, 3 equivalents), Pd2 (dba) 3 (208 mg, 0.23 mmol, 0.1 equivalent), biphenyl-2-yl-di-tert-butyl-phosphine (68 mg, 0.23 mmol, 0.1 equivalent) and potassium phosphate tribasic (965 mg, 4.55 mmol, 2 equivalents) under a nitrogen atmosphere, and the resulting mixture was heated to reflux for 3 hours. After treatment and trituration, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 67% yield (450 mg). 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.1 Hz, 3 H) 2.7 (s, 3 H) 3.1 (s, 3 H) 4.4 (c, J = 7.1 Hz, 2 H) 7.3 (dd, J = 7.7, 0.9 Hz, 1H) 7.5 (dd, J = 8.3, 7.6 Hz, 1H) 7.6 (m, 1H) 9.5 (s.1H).

Step 2: According to the procedure of Example 20, Step 3, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was hydrolyzed to provide 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid with a yield of 92%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.7 (s, 3 H) 3.1 (s, 3 H) 7.2 (dd, J = 7.8, 0.8 Hz, 1 H) 7.5 (dd, J = 8.3, 7.6 Hz, 1 H) 7.6 (m, 1H) 9.5 (s, 1H).

Stage 3: According to the procedure of Example 21, Step 3, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid was coupled with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to provide Methyl ester of L-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a yield of 23%. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.1 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.3 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 9.1 Hz, 1H) 7.8 (t, J = 8.6 Hz, 4H ) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 9.5 (s, 1H) 10.6 (s, 1H).

Step 4: According to the procedure of Example 20, Step 5, methyl ester of L-2- acid was hydrolysed. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to L-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H) 3.1 (s, 3H) 3.6 (dd, J = 9.3 , 5.8 Hz, 1H) 7.3 (dd, J = 7.7, 0.9 Hz, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 ( d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 9.5 (s, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 37: L-2- (4 '- { [4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3 acid -methyl-butyric Step 1: To a mixture of the product of Example 36, Step 1, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (438 mg, 1.47 mmol, 1 equivalent) and K2C03 (430 mg, 3.11 mmol, 2.1 equivalents) in 4 ml of DMF under a nitrogen atmosphere, 0.18 ml of iodomethane (2.89 mmol, 2 equivalents) was added. The reaction mixture was sealed and heated at 80 ° C for 18 hours. After cooling to room temperature and treatment, 4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in pure form without further purification (100% yield). E NMR (400 MHz, CDC13) d ppm 1.4 (t, J = 7.1 Hz, 3H) 2.8 (s, 3H) 3.0 (s, 3H) 3.4 (s, 3H) 4.5 (c, J = 7.1 Hz, 2H) 7.2 (dd, J = 7.6, 0.8 Hz, 1H) 7.4 (m, 1H) 7.6 (m, 1H). Step 2: According to the procedure of Example 20, Step 3, the hydrolysis of 4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester gave 4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid in quantitative yield. X H NMR (400 MHz, DMS0-d 6) d ppm 2.7 (s, 3 H) 3.1 (s, 3 H) 3.3 (s, 3 H) 7.5 (m, 2 H) 7.7 (dd, J = 8.2, 1.1 Hz, 1 H). Stage 3: According to the procedure of Example 21, Step 3, the stockpiling of 4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -methyl ester - 3-methyl-butyric provided methyl ester of L-2- (4 '- { [4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4 -sulfonylamino) -3-methyl-butyric with a 100% yield. 1 H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.9, 6.8 Hz, 6H) 1.9 (m, 1H) 2.7 (d, J = 0.5 Hz, 3H) 2.8 (s, 3H) 2.9 (s, 3H) 3.1 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.6 (m, 2H) 7.7 (m , 1H) 7.8 (dd, J = 8.7, 7.2 Hz, 4H) 7.9 (m, 2H) 8.0 (m, 3H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H). Step 4: According to the procedure of Example 20, Step 5, hydrolysis of the methyl ester of L-2- (4 '- { [4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2 -carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid gave L-2- (4 '- { [4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran) -2-carbonyl-amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric with a yield of 100%. 1 H NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.9 (m, 1H) 2. 7 (s, 3H) 3.1 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.5, 6.2 Hz, 1H) 7.6 (m, 2H) 7.7 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.6 Hz, 1H) 10.6 (s, 1H).

Example 38: L-3-hydroxy-2- (4-. {5- [4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl] -benzenesulfonylamino acid -butyric Step 1: To a mixture of methyl ester hydrochloride salt of L-2-amino-3-tert-butoxy-butyric acid (4.87 g, 21.6 mmol, 1 equivalent) and 4-bromo-benzenesulfonyl chloride (5.51 g, 21.6 mmol , 1 equivalent) in 50 ml of dichloromethane at 0 ° C under a nitrogen atmosphere, was added N, N-diisopropylethylamine (7.5 ml, 43.1 mmol, 2 equivalents) dropwise. The ice bath was removed and the reaction was allowed to react at room temperature for 1 hour. After treatment and trituration with hexanes, L-2- (4-bromo-benzenesulfonylamino) -3-tert-butoxy-butyric acid methyl ester was obtained in 88% yield (7.77 g). H NMR (400 MHz, DMSO-d6) d ppm 1.0 (s, 9H) 1.0 (s, 3H) 3.4 (s, 3H) 3.8 (dd, J = 9.7, 3.4 Hz, 1H) 4.0 (dd, J = 6.2, 3.7 Hz, 1H) 7.7 (d, J = 8.8 Hz, 2H) 7.8 (m, 2H) 8.2 (d, J = 9.6 Hz, 1H). Step 2: To a mixture of L-2- (4-bromo-benzenesulfonylamino) -3-tert-butoxy-butyric acid methyl ester (811 mg, 2 mmol, 1 equivalent), bis (pinacolato) diboro (1.55 g, 6.1 mmol, 2.05 equivalents), and KOAc (622 mg, 6.34 mmol, 3.17 equivalents) under a nitrogen atmosphere in 45 ml of DMSO, was added PdCl2 (dppf) CK2C12 (110 mg, 0.13 mmol, 0.065 equivalents). The reaction mixture was heated at 80 ° C for 18 hours. After treatment and column chromatography, methyl ester of L-3-tert-butoxy-2- [4- (4,4,5,5-tetramethyl- [1,3,2]. Dioxaborolan-2- was obtained. il) benzenesulfonylamino] -butyric with a yield of 77% (696 mg). X H NMR (400 MHz, DMSO-d 5) d ppm 1.0 (s, 9 H) 1.3 (s, 12 H) 3.4 (s, 3 H) 3.8 (dd, J = 9.7, 3.7 Hz, 1 H) 3.9 (dd, J = 6.2 , 3.7 Hz, 1H) 7.8 (m, 4H) 8.1 (d, J = 9.9 Hz, 1H). Step 3: A mixture of L-3-tert-butoxy-2- [4- (4, 4, 5, 5-tetramethyl- [1, 3.2] dioxaborolan-2-yl) -benzenesulfonylamino] -butyric acid methyl ester ( 696 mg, 1.53 mmol, 1 equivalent), 2-bromo-5-nitropyridine (932 mg, 4.59 mmol, 3 equivalents), Pd (PPh3) 4 (88 mg, 0.076 mmol, 0.05 equivalents), and K2C03 (423 mg, 3.06 mmol, 2 equivalents) in 10 ml of 1,2-dimethoxyethane and 5 ml of water, was heated to 90 ° C under a nitrogen atmosphere. After 3 hours, the reaction was completed and subjected to treatment and column chromatography (20% ethyl acetate / hexane) to give L-3-tert-butoxy-2- [4- (5-nitro-pyridin-2-yl) -benzenesulfonylamino] -butyric acid methyl ester with a yield 81% (557 mg). X H NMR (400 MHz, DMSO-d 6) d ppm 1.0 (s, 12 H) 3.4 (s, 3 H) 3.9 (dd, J = 9.9, 3.5 Hz, 1 H) 4.0 (m, 1 H) 8.0 (d, J = 8.6 Hz, 2H) 8.2 (d, J = 9.9 Hz, 1H) 8.4 (m, 3H) 8.7 (dd, J = 8.8, 2.8 Hz, 1H) 9.5 (d, J = 2.5 Hz, 1H). Step 4: A 550 mg of L-3-tert-butoxy-2- [4- (5-nitro-pyridin-2-yl) -benzenesulfonylamino] -butyric acid methyl ester in 10 ml of THF under a nitrogen atmosphere was added. they added 125 mg of Pd / C to 5%. A hydrogen balloon was introduced into the reaction mixture. After 24 hours, the mixture was subjected to treatment to give L-2- [4- (5-amino-pyridin-2-yl) -benzenesulfonylamino] -3-tert-butoxy-butyric acid methyl ester in quantitative yield. 1 H NMR (400 MHz, DMSO-dg) d ppm 1.0 (s, 9 H) 1.0 (s, 3 H) 3.4 (s, 3 H) 3.8 (dd, J = 9.7, 3.7 Hz, 1 H) 3.9 (dd, J = 6.2 , 3.7 Hz, 1H) 5.7 (s, 2H) 7.8 (t, J = 9.0 Hz, 3H) 8.0 (d, J = 9.6 Hz, 1H) 8.1 (m, 3H). Step 5: The amide coupling of the product of Example 36, Step 2, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid, with L-2- [4- (5-amino-pyridin-2 -yl) -benzenesulfonylamino] -3-tert-butoxy-butyric acid, in accordance with the procedure of Example 21, Step 3, provided L-3-tert-butoxy-2- (4-. {5- [5- (4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) - amino] -pyridin-2-yl] -benzenesulfonylamino) -butyric in 42% yield. X H NMR (400 MHz, DMSO-d 6) d ppm 1.0 (s, 9 H) 1.0 (s, 3 H) 2.8 (s, 3 H) 3.1 (s, 3 H) 3.4 (s, 3 H) 3.9 (dd, J = 9.7, 3.7 Hz, 1H) 4.0 (dd, J = 6.2, 3.7 Hz, 1H) 7.3 (dd, J = 7.8, 0.8 Hz, "1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 0.8 Hz, 1H ) 7.9 (d, J = 8.6 Hz, 2H) 8.1 (m, 2H) 8.3 (d, J = 8.8 Hz, 2H) 8.4 (dd, J = 8.7, 2.7 Hz, 1H) 9.1 (d, J = 3.0 Hz , 1H) 9.6 (s, 1H) 10.8 (s, 1H) Step 6: To 100 mg of L-3-tert-butoxy-2- (4-. {5 - [(4-methanesulfonylamino- 3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl.} - benzenesulfonylamino) -butyric acid in 8 ml of dichloroethane was added 0.5 ml of trifluoroacetic acid, after 1.5 hours, the solvent was removed in vacuo To the crude residue were added THF (8 ml), MeOH (3 ml) and 1N LiOH (4.5 ml) The reaction mixture was stirred at room temperature until the starting material was consumed (-1-). 2 days), then the reaction mixture was acidified with IN hydrochloric acid to pH 4. The resulting mixture was extracted with acetate. or ethyl. The combined organic layers were concentrated in vacuo and the crude residue was recrystallized to give the 3-hydroxy-2- (4-. { 5- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -butyric with a yield of 72%. 1 H NMR (400 MHz, DMSO-d) d ppm 1.0 (s, 9 H) 1.0 (s, 3 H) 2.8 (s, 3 H) 3.1 (s, 3 H) 3.4 (s, 3 H) 3. 9 (dd, 3 = 9.1, 3. 1 Hz, 1H) 4.0 (dd, J = 6.2, 3.7 Hz, 1H) 7.3 (dd, J = 7.8, 0.8 Hz, 1H) 7.5 (m, 1H) 7.7 (dd, J = 8.3, 0.8 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.1 (m, 2H) 8.3 (d, J = 8.8 Hz, 2H) 8. 4 (dd, J = 8.7, 2.7 Hz, 1H) 9.1 (d, J = 3.0 Hz, 1H) 9.6 (s, 1H) 10.8 (s, 1H).

Example 39: L-2- (4- {5 - [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl] -benzenesulfonylamino) -3- acid methyl-butyric Step 1: L-3-methyl-2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzenesulfonylamino] -butyric acid methyl ester was prepared according to with the procedure of Example 38, Step 2, from L-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester and bis (pinacolato) diboro, in 90% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 9.0, 6.7 Hz, 6H) 1.3 (s, 12H) 1.9 (m, 1H) 3.4 (s, 3H) 3.5 (dd, J = 9.2 , 6.9 Hz, 1H) 7.8 (d, J = 8.6 Hz, 2H) 7.8 (m, 2H) 8.3 (d, J = 9.3 Hz, 1H).

Step 2: L-3-methyl-methyl ester was prepared 2- [4- (5-Nitro-pyridin-2-yl) -benzenesulfonylamino] -butyric acid according to the procedure of Example 36, Step 3, starting with methyl ester of L-3-methyl-2- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzenesulfonylamino) -butyric acid and 2-bromo-5-nitropyridine in a yield of 78%. XH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 36.1, 6.8 Hz, 6H) 2.1 (m, 1H) 3.5 (s, 3H) 3.8 (dd, J = 10.0, 4.9 Hz, 1H) 5.2 ( d, J = 9.9 Hz, 1H) 8.0 (dd, J = 8.7, 1.9 Hz, 3H) 8.2 (d, J = 8.8 Hz, 2H) 8.6 (dd, J = 8.7, 2.7 Hz, 1H) 9.5 (d, J = 3.3 Hz, 1H).

Step 3: Hydrogenation of L-3-methyl-2- [4- (5-nitro-pyridin-2-yl) -benzenesulfonylamino] butyric acid methyl ester according to the procedure of Example 36, Step 4, provided methyl ester L-2- [4- (5-Amino-pyridin-2-yl) -benzenesulfonylamino] -3-methyl-butyric acid with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.9 (m, 1H) 3.3 (s, 3H) 3.5 (dd, J = 9.3, 7.1 Hz, 1H) 5.7 (s, 2H) 7.0 (dd, J = 8.6, 2.8 Hz, 1H) 7.7 (m, 3H) 8.1 (m, 3H) 8.2 (d, J = 9.3 Hz, 1H).

Step 4: The coupling of 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid amide with L-2- [4- (5-amino-pyridin-2-yl) -benzenesulfonylamino] -3- methyl ester methyl-butyric according to the The procedure of Example 21, Step 3, gave L-2- (4- {5- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl methyl ester} -benzenesulfonylamino) -3-methyl-butyric with a yield of 22%. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.1 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.3 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.7 (d, J = 7.6 Hz, 1H) 7.8 (d, J = 8.6 Hz, 2H ) 8.1 (d, J = 8.8 Hz, 1H) 8.3 (d, 3 = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 8.4 (dd, J = 8.8, 2.5 Hz, 1H) 9.1 (dd) , J = 2.0 Hz, 1H) 9.6 (5. 1H) 10.8 (s, 1H).

Step 5: The hydrolysis of methyl ester of L-2- (4. {5 - [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl}. benzenesulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 5, provided L-2- (4-. {5- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl)] -amino] -pyridin-2-yl.}. -benzenesulfonylamino) -3-methyl-butyric with quantitative yield. H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H) 3.1 (s, 3H) 3.6 (dd, J = 9.3, 5.8 Hz, 1H) 7.3 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.7 (d, J = 7.3 Hz, 1H) 7.9 (d, J = 5.8 Hz, 2H) 8.1 (dd, J = 9.0, 3.2 Hz, 2H) 8.3 (d, J = 8.6 Hz, 2H) 8.4 (dd, J = 8.7, 2.4 Hz, 1H) 9.1 (d, J = 2.5 Hz, 1H) 9.6 (s, 1H) 10.8 (s, 1H).

Example 40: L-2- (4- {5 - [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} - benzenesulfonylamino) -3- acid methyl-butyric Step 1: The amide coupling of the product of Example 20, Step 3, 4-cyano-3-methyl-benzofuran-2-carboxylic acid, with methyl ester of L-2- [4- (5-amino-pyridine-2 -yl) -benzenesulfonylamino] -3-methyl-butyric acid, the product of Example 39, Step 3, was carried out according to the procedure of Example 21, Step 3, to give methyl ester of L-2- (4-. {5- [4-cyano-3-methyl-benzofuran-2-carbonyl] ) -amino] -pyridin-2-yl.} - benzenesulfonylamino) -3-methyl-butyric with a yield of 57%. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J = 9.3 , 7.1 Hz, 1H) 7.7 (dd, J = 8.3, 7.6 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (dd, J = 7.5, 0.9 Hz, 1H) 8.1 (m, 2H) 8.3 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 8.4 (dd, J = 8.8, 2.5 Hz, 1H) 9.1 (d, J = l.8 Hz, 1H) 11.0 (s) , 1 HOUR) . Step 2: The hydrolysis of methyl ester of L-2- (4. {5 - [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl}. benzenesulfonylamino) -3-methyl-butyric acid according to the procedure of Example 20, Step 5, provided L-2- (4- {5- [4- (4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl- butyric with quantitative yield. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.1, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 6.3 Hz, 1H) 7.7 (dd, J = 8.3, 7.6 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 7.9 (dd, J = 7.6, 0.8 Hz, 1H) 8.1 (m, 3H) 8.3 (d, J = 8.8 Hz, 2H) 8.4 (dd, J = 8.8, 2.5 Hz, 1H) 9.1 (dd, J = 2.5, 0.8 Hz, 1H) 11.0 (s, 1H).

Example 41: D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Stage 1: Suzuki's uptake of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester with 4- (4, 4, 5, 5-tetramethyl- [1.3.2] dioxaborolan-2) -yl) -phenylamine was carried out according to example 38, Step 3, to give methyl ester of D-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid with a yield of 88% . XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, 1 = 15.2, 6.8 Hz, 6H) 1.9 (m, 1H) 3.3 (s, 3H) 3.5 (dd, 1 = 9.3, 7.1 Hz, 1H) 5.4 (s, 2H) 6.7 (d, 1 = 8.6 Hz, 2H) 7.5 (d, 1 = 8.6 Hz, 2H) 7.7 (d, 1 = 4.5 Hz, 4H) 8.2 (d, J = 9.3 Hz, 1H).

Step 2: The coupling of methyl ester of D-2- (4 '-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid with 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid, performed in accordance with Example 21, Step 3, to give methyl ester of D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a yield of 58%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.1 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.3 Hz, 1H) 7.3 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.8 Hz, 1H) 7.8 (t, J = 8.3 Hz, 4H ) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 9.5 (s, 1H) 10.6 (s, 1H).

Step 3: The hydrolysis of methyl ester of D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.1 (s, 3H) 3.6 (dd, J = 9.5 , 5.9 Hz, 1H) 7.3 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 7.8 (d, J = 8.6 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 9.5 (s, 1H) 10.6 (s, 1H).

Example 42: L-2- (. {4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} -methyl-amino acid) -3 -methyl-butyric Step 1: L-3-methyl-2- (4'-nitro-biphenyl-4-sulfonylamino) -butyric acid methyl ester was prepared from 4'-nitro-biphenyl-4-sulfonyl chloride and hydrochloride acid salt of 2-amino-3-methyl-butyric acid methyl ester, according to Example 38, Step 1, XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.4, 6.8 Hz, 6H) 1.9 ( m, 1H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (dd, J = 15.8, 9.0 Hz, 4H) 8.3 (d , J = 8.8 Hz, 2H) 8.4 (d, J = 9.3 Hz, 1H). Step 2: To a mixture of L-3-methyl-2- (4'-nitro-biphenyl-4-sulfonylamino) -butyric acid methyl ester (1.05 mg, 2.7 mmol, 1 equivalent) and K2C03 (1.1 g, 8 mmol) , 3 equivalents) in 8 ml of DMF, iodomethane (0.25 ml, 4.0 mmol, 1.5 equivalents) was added under a nitrogen atmosphere. After 12 h, the mixture was subjected to treatment to give L-3-methyl-2- [methyl- (4'-nitro-biphenyl-4-sulfonyl) -amino] -butyric acid methyl ester with a 94% yield (1.023 g). 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.9 (dd, J = 8.8, 6.6 Hz, 6H) 2.1 (m, 1H) 2.8 (s, 3H) 3.3 (s, 3H) 4.0 (d, J = 10.6 Hz, 1H) '7.9 (d, J = 8.8 Hz, 2H) 8.0 (m, 4H) 8.4 (d, J = 9.1 Hz, 2H). Stage 3: Hydrogenation of acid methyl ester L-3-methyl-2- [methyl- (4'-nitro-biphenyl-4-sulfonyl) -amino] -butyric acid was made according to Example 38, Step 4, to give methyl ester of L-2- [] (4'-amino-biphenyl-4-sulfonyl) -methyl-amino) -3-methyl-butyric with quantitative yield. E NMR (400 MHz, DMSO-d6) d ppm 0.9 (dd, J = 10.4, 6.6 Hz, 6H) 2.0 (dd, 1H) 2.8 (s, 3H) 3.4 (s, 3H) 4.0 (d, J = 7.1 Hz, 1H) 5.4 (s, 2H) 6.7 (d, J = 8.6 Hz, 2H) 7.5 (d, J = 8.6 Hz, 2H) 7.7 (d, J = 8.8 Hz, 2H) 7.8 (m, 2H). Step 4: Methylester amide coupling of L-2- [(4'-amino-biphenyl-4-sulfonyl) -methyl-amino] -3-methyl-butyric acid with 4-cyano-3-methyl-benzofuran- 2-carboxylic acid (Example 20, Step 3) in 75% yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.9 (dd, J = 10.6, 6.6 Hz, 6H) 2. 1 (dd, 1H) 2.8 (s, 3H) 2.8 (s, 3H) 3.4 (s, 3H) 4.0 (d, J = 10.6 Hz, 1H) 7.7 (dd, J = 8.6, 7.6 Hz, 1H) 7.8 ( dd, J = 8.7, 3. 2 Hz, 4H) 7.9 (m, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (dd, J = 8.5, 0.9 Hz, 1H) 10.8 (s, 1H). Step 5: The hydrolysis of methyl ester of L-2- (. {4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} -methyl. -amino) -3-methyl-butyric was made from according to Example 20, Step 5, to give L-2- (. {4'- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} acid. .methyl-amino) -3-methyl-butyric with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.9 (dd, J = 21.3, 6.7 Hz, 6H) 2.0 (m, 1H) 2.8 (d, J = 10.1 Hz, 6H) 4.0 (d, J = 10.6 Hz , 1H) 7.7 (dd, J = 8.3, 7.6 Hz, 1H) 7.8 (t, J = 8.8 Hz, 4H) 7.9 (m, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (dd, J = 8.5, 0.9 Hz, 1H) 10.8 (s, 1H).

Examples 43A and B, triethylamine salt of L-3-methyl-2- acid. { 4'-t (3-methyl-4-methylcarbamoyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric acid salt and triethylamine 2-. { 4 '- [(4-dimethylcarbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 213 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 2) in 6 ml of ethanol and 6 ml of DMSO, 3 ml of Na2CO3 (3M) was added. ), followed by 3 ml of H2O2 (30% in water). After 24 hours of reaction, the mixture was subjected to treatment to give 4-carbamoyl-3-methyl-benzofuran-2-ethyl ester. carboxyl with quantitative yield, ""? NMR (400 MHz, DMSO-de) d ppm 1.4 (t, J = 7.1 Hz, 3H) 2.6 (s, 3H) 4.4 (c, J = 7.1 Hz, 2H) 7.4 (dd, J = 7.3, 1.0 Hz, 1H) 7.5 (dd, J = 8.3, 7.3 Hz, 1H) 7.7 (s, 1H) 7.8 (m, 1H) 8.0 (s, 1H). Stage 2: To 200 mg of 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.81 mmol, 1 equivalent) in 5 ml of DMF, 50 mg of NaH (60% in mineral oil, 1.25 mmol, 1.5 equivalents) under a nitrogen atmosphere. After 30 minutes of reaction, iodomethane (0.053 ml, 0.85 mmol, 1 equivalent) was added to the reaction. The mixture was then heated at 50 ° C for 12 hours. After treatment and column chromatography, a mixture of 3-methyl-4-methylcarbamoyl-benzofuran-2-carboxylic acid ethyl ester and 4-dimethylcarbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (76 mg) was obtained. . aH NMR (400 MHz, DMSO-d6) d ppm 1.-3 (t, J = 7.1 Hz, 3H) 2.8 (d, J = 4.5 Hz, 6H) 4.4 (c, J = 7.2 Hz, 2H) 7.3 ( dd, J = 7.3, 1.0 Hz, 1H) 7.5 (dd, J = 8.3, 7.3 Hz, 1H) 7.8 (dd, J = 8.5, 0.9 Hz, 1H). Step 3: Hydrolysis of the ethyl ester mixture of 3-methyl-4-methylcarbamoyl-benzofuran-2-carboxylic acid and 4-dimethylcarbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was carried out according to Example 20 Step 3. The obtained mixture of 3-methyl-4-methylcarbamoyl-benzofuran-2-carboxylic acid and 4-dimethylcarbamoyl-3-methyl-benzofuran-2-carboxylic acid was used in the next reaction without purification. XH NMR (400 MHz, DMSO-d6) d ppm 2.8 (d, J = 4.8 Hz, 6H) 7.3 (d, J = 7.3, 0.8 Hz, 1H) 7.5 (dd, J = 8.5, 7.5 Hz, 1H) 7.7 (dd, J = 8.5, 0.9 Hz, 1H). Step 4: The amide coupling using material from Step 3 and L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, was carried out according to Example 21, Step 3. After column chromatography, a mixture of two products was obtained. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.6 (s, 3H) 2.8 (d, J = 4.5 Hz, 3H) 3.4 ( s, 3H) 3.6 (m, 1H) 7.4 (dd, J = 7.3, 1.0 Hz, 1H) 7.5 (dd, J = 8.3, 7.6 Hz, 1H) 7.8 (m, 5H) 7.9 (, 2H) 8.0 (d , J = 8.8 Hz, 1H) 8.3 (d, J = 9.3 Hz, 1H) 8.5 (d, J = 4.5 Hz, 1H) 10.6 (s, 1H). Step 5: The hydrolysis of the above mixture was carried out according to the procedure of Example 20, Step 5. The final purification using preparative HPLC (with triethylamine as an additive to improve the solubility of the compounds) gave 40 mg of triethylamine salt of the acid L-3-methyl-2-. { 4 '- [(3-methyl-4-methylcarbamoyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric (43A) and 12 mg triethylamine salt of 2- acid. { 4 '- [(4-dimethylcarbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric (43B). 43A 1H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 33.9, 6.8 Hz, 6H) 2.0 (m, 1H) 2.6 (s, 3H) 2.8 (d, J = 4.8 Hz, 3H) 7.4 (d, J = 7.3 Hz, 1H) 7.5 (m, 1H) 7.8 (m, 7H) 8.0 (d, J = 8.8 Hz, 2H) 8.5 (d, J = 4.5 Hz, 1H) 10.6 (s, 1H) . 43B 1 H NMR ~ (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 28.3, 6.8 Hz, 6H) 2.0 (dd, J = 11.9, 7.1 Hz, 1H) 2.5 (s, 3H) 2.8 (s, 3H) 3.1 (s, 3H) 7.2 (d, J = 7.1 Hz, 1H) 7.6 (m, 1H) 7.8 (m, 7H) 8.0 (d, J = 8.8 Hz, 2H) 10.6 (s, 1H).

Example 44: L-2- acid. { 4 '- [(4,6-Dimethoxy-3,7-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: The coupling of 4,6-dimethoxy-3,7-dimethyl-benzofuran-2-carboxylic acid amide with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl acid methyl ester -butyric, was carried out according to Example 21, Step 3, to provide methyl ester of 2- acid. { 4 '- [(4,6-Dimethoxy-3,7-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a yield of 74%. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.3, 6.7 Hz, 6H) 1.9 (dd, J = 13.8, 6.9 Hz, 1H) 2.3 (s, 3H) 2.7 (s, 3H) 3.4 (s, 3H) 3.6 (m, 1H) 3.9 (d, J = 8.1 Hz, 6H) 6.6 (s, 1H) 7.8 (m, 4H) 7.9 (m, 2H) 7.9 (d, J = 9.1 Hz, 2H) 8.3 (d, J = 9.1 Hz, 1H) . 1 (s, 1H). Stage 2: Hydrolysis of 2- methyl ester. { 4 '- [(4,6-Dimethoxy-3,7-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid was carried out according to Example 20, Step 5 to give 2- acid. { 4'- [(4,6-Dimethoxy-3,7-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. X H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.1, 6. 8 Hz, 6H) 2.0 (dd, J = 13.3, 6.4 Hz, 1H) 2.3 (s, 3H) 2.7 (s, 3H) 3.4 (s, 1H) 3.9 (m, J = 8.1 Hz, 6H) 6.6 (s) , 1H) 7.8 (m, J = 8.8 Hz, 2H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 2H) 7.9 (d, J = 8.8 Hz, 2H) 10.1 (s, 1H).

Example 45: 2- acid. { 4 '- [(5-bromo-3-methyl-benzofuran-2-carbonyl) -amino] -bifenil-4-sulfonylamino} -3-methyl-butyric Step 1: To a mixture of 1- (5-bromo-2-hydroxy-phenyl) -ethanone (2.1 g, 9.8 mmol, 1 equivalent) and K2C03 (2.4 g, 17.4 mmol, 1.8 equivalents) in 15 ml of DMF, 1.3 ml of bromoacetic acid ethyl ester (11.7 mmol, 1.2 equivalents) was added under a nitrogen atmosphere. After 12 hours, the mixture was subjected to treatment and recrystallized the crude compound to give (2-acetyl-4-bromo-phenoxy) -acetic acid ethyl ester in a yield of 97% (2.87 g). XH NMR (400 MHz, 'CDC13) d ppm 1.3 (t, J = 7.1 Hz, 3H) 2.7 (s, 3H) 4.3 (c, J = 7.1 Hz, 2H) 4.7 (s, 2H) 6.7 (d, J = 8.8 Hz, 1H) 7.5 (dd, 1 = 8.8, 2.8 Hz, 1H) 7.9 (d, J = 2.8 Hz, 1H). Step 2: A mixture of (2-acetyl-4-bromo-phenoxy) -acetic acid ethyl ester (2.87 g, 9.5 mmol, 1 equivalent) and sodium ethoxide (0.65 g, 9.5 mmol, 1 equivalent) in 100 ml of ethanol under a nitrogen atmosphere, it was heated at 75 ° C for 3 hours. After treatment followed by column chromatography (MeOH / 20% dichloromethane), 5-bromo-3-methyl-benzofuran-2-carboxylic acid was obtained in 72% yield (1.74 g). ZH NMR (400 MHz, CD3OD) d ppm 2.5 (s, 3H) 7.5 (d, J = 8.8 Hz, 1H) 7.6 (m, 1H) 7.9 (d, J = 2.0 Hz, 1H). Step 3: The coupling of 5-bromo-3-methyl-benzofuran-2-carboxylic acid amide with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, performed in accordance with Example 21, Step 3, provided methyl ester of L-2- acid. { 4 '- [(5-bromo-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a 50% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, 1 = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.6 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3 , 7.1 Hz, 1H) 7.7 (d, J = 1. 3 Hz, 2H) 7.8 (t, J = 8.6 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (t , J = 1.4 Hz, 1H) 8.3 (d, 1 = 9.3 Hz, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(5-bromo-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to Example 20, Step 5, provided L-2- acid. { 4 '- [(5-bromo-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield, - "? NMR (400 MHz, CD3OD) d ppm 1.1 (dd, J = 24.0, 6.8 Hz, 6H) 2.2 (m, 1H) 2.8 (s, 3H) 3.9 (d) , J = 5.8 Hz, 1H) 7.8 (m, 2H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (m, 5H) 10.4 (s, 1H).

Example 46: L-2- acid. { 4 '- [(4-carbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To a solution of the product of Example 20, methyl ester of L-2- acid. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (128 mg) in a mixture of MeOH (6 ml) and DMSO (4 mL) was added 3 mL of Na2CO3 (3M) and 3 mL of hydrogen peroxide. (30% in water). The reaction was completed in 12 hours. After treatment, methyl ester of L-2- acid was obtained. { 4 '- [(4-carbamoyl-3-methyl-benzofuran-2-carbonyl) - amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.6 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J = 9.3 , 7.1 Hz, 1H) 7.4 (dd, J = 7.3, 0.8 Hz, 1H) 7.5 (dd, J = 8.3, 7.3 Hz, 1H) 7.7 (s, 1H) 7.8 (m, 5H) 7.9 (m, 2H) 8.0 (d, J = 9.1 Hz, 2H) 8.0 (s, 1H) 8.3 (m, J = 9.3 Hz, 1H) 10.6 (s, 1H). Step 2: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(-carbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid was made according to Example 20, Step 5, to provide L-2- acid. { 4 '- [(4-carbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.9 (m, 1H) 2.6 (s, 3H) 3.6 (m, 1H) 7.4 (d, J = 7.3 Hz, 1H) 7.5 (m, 1H) 7.7 (s, 1H) 7.8 (m, 5H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (m, 2H) 10.6 (s, 1H) ).

Example 47: L-2- (4 '- { [4- (cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino} -bi-4-sulfonylamino) -3- acid methyl-butyric Step 1: A 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (300 mg, 0.85 mmol, 1 eq, prepared according to Example 20, Step 1) in 8 ml of dioxane in an atmosphere of nitrogen, cyclopropyl carboxamide (87 mg, 1.02 mmol, 1.2 eq.), Fd2 (dba) 3 (16 mg, 0.017 mmol, 0.02 eq.), 4.5-bis (diphenylphosphino) -9, 9-dimethylxantene (30 mg, 0.051 mmol, 0.06 eq.), and cesium carbonate (390 mg, 1.19 mmol, 1.4 eq.). The reaction mixture was heated to reflux for 72 hours. After working-up and column chromatography (dichloromethane / hexanes), 4- (cyclopropanecarbonylamino) -3-methyl-1-benzofuran-2-carboxylic acid ethyl ester was obtained in 98% yield (238 mg). XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (m, 4H) 1.3 (t, J = 7.1 Hz, 3H) 1.8 (s, 1H) 2.6 (s, 3H) 4.4 (c, J = 7.2 Hz, 2H) 7.2 (d, J = 7, l Hz, 1H) 7.5 (m, 1H) 7. 5 (m, 1H) 10.1 (s, 1H). Step 2: Hydrolysis of the 4- (cyclopropanecarbonylamino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was done according to Example 20, Step 3, to provide 4- (cyclopropanecarbonylamino) -3 acid -methyl-benzofuran-2-carboxylic acid with a yield of 40%. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (d, J = 5.3 Hz, 4H) 1.9 (s, 1H) 2. 6 (s, 3H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 2H) 10.1 (s, 1H) 13.4 (s, 1H). Stage 3: To a mixture of acid 4- (cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-carboxylic acid (83 mg, 0.32 mmol, 1 eq.), L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl acid methyl ester -butyric (116 mg, 0.32 mmol, 1 eq.) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP, 170 mg, 0.38 mmol, 1.2 eq.) in 3 ml of DMF under a nitrogen atmosphere, they added 0.07 ml of N, -diisopropylethylamine (0.38 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 18 hours. The desired product was precipitated after the addition of ethyl acetate, and was collected by filtration, washed with IN HCl, saturated aqueous Na 2 SO and hexanes. L-2- (4'- { [4- (Cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-carbonyl] amino] -biphenyl-4-sulfonylamino) -3-methyl-butyric acid methylester was obtained. with a yield of 26% (50 mg). XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.1, 7.3 Hz, 10H) 1.9 (m, 2H) 2.7 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (t, J = 8.1 Hz, 1H) 7.5 (, 1H) 7.8 (m, 4H) 7.9 (, 2H) 8.0 (d, J = 8.6 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.1 (s, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- (4 '- { [4- (cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino ) -3-methyl-butyric acid was made according to Example 20, Step 5, to give L-2- (4 '- { [4- (cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-acid) carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric with quantitative yield. X H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (m, 10 H) 1.9 (s, 1 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.5 (dd, J = 9.5, 6.2 Hz, 1 H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H ) 8.0 (d, J = 9.6 Hz, 1H) 10.1 (s, 1H) 10.6 (s, 1H).

Example 48: L-2- acid. { 4 '- [(4-acetylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Stage 1: The coupling of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 1) with acetamide, to give 4-acetylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester, was made according to Example 47, Step 1, to provide 4-acetylamino acid ethyl ester 3-methyl-benzofuran-2-carboxylic acid with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.2 Hz, 3 H) 2.1 (s, 3 H) 2.6 (s, 3 H) 4.4 (c, J = 7.1 Hz, 2 H) 7.2 (d, J = 8.1 Hz, 1H) 7.5 (m, 2H) 9.8 (s, 1H). Stage 2: Hydrolysis of the 4- ethyl ester acetylamino-3-methyl-benzofuran-2-carboxylic acid to 4-acetylamino-3-methyl-benzofuran-2-carboxylic acid was made according to Example 20, Step 3, to provide 4-acetylamino-3-methyl-benzofuran acid -2-carboxylic with quantitative yield. aH NMR (400 MHz, DMSO-d6) d ppm 2.1 (s, 3H) 2.6 (s, 3H) 7.2 (d, J = 7.3 Hz, 1H) 7.5 (m, 2H) 9.8 (s, 1H) 13.4 (s) , 1 HOUR) . Step 3: The coupling of 4-acetylamino-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-bifeni-4-sulfonylamino) -3-methyl-butyric acid methyl ester was made from according to Example 47, Step 3, to provide methyl ester of L-2- acid. { 4 '- [(4-acetylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a 50% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.1 (s, 3H) 2.7 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.3 Hz, 1H) 7.2 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.5 (m, 1H) 7.8 (m, 4H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 9.8 (s, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-acetylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid was made according to Example 20, Step 5, to provide L-2- acid. { 4 '- [(4-acetylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with yield quantitative. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 2.0 (m, 1H) 2.1 (s, 3H) 2.7 (s, 3H) 3.6 (dd, J = 9.3 , 6.1 Hz, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 9.8 (s, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 49: L-3-methyl-2- acid. { 4 '- [(3-methyl-4-pro? Ionylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: Coupling of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 1) with propionamide, to give 3-methyl-4-propionylamino-benzofuran-2-carboxylic acid ethyl ester , was done according to Example 47, Step 1, with quantitative yield. 2 H NMR (400 MHz, DMSO-d 6) d ppm 1.1 (t, J = 7.6 Hz, 3 H) 1.3 (t, J = 7.2 Hz, 3 H) 2.4 (c, J = 7.5 Hz, 2 H) 2.6 (s, 3 H) ) 4.4 (c, J = 7.2 Hz, 2H) 7.2 (d, J = 7.3 Hz, 1H) 7.5 (m, 1H) 7.5 (, 1H) 9.8. (S, 1H). Step 2: The hydrolysis of the ethyl ester of 3-methyl-4-propionylamino-benzofuran-2-carboxylic acid was made according to Example 20, Step 3, with quantitative yield. aH NMR (400 MHz, DMSO-d6) d ppm 1.1 (t, J = 7.3 Hz, 3H) 2.4 (c, J = 8.0 Hz, 2H) 2.6 (s, 3H) 7.2 (d, J = 7.3 Hz, 1H ) 7.5 (m, 2H) 9.7 (s, 1H) 13.5 (s, 1H). Step 3: The coupling of 3-methyl-4-propionylamino-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester was done in accordance with Example 47, Step 3, to provide methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-propionylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric with a 67% yield. "" "H NMR (400 MHz, DMSO-ds) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.1 (t, J = 7.6 Hz, 3H) 1.9 (m, 1H) 2.4 (c, J = 7.5 Hz, 2H) 2.7 (s, 3H) 3. 3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.5 (m, 1H) 7.8 (m, 4H) 7.9 ( m, 2H) 8.0 (d, J = 9.1 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 9.7 (s, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-propionylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 20, Step 5, to provide L-3-methyl-2- acid. { 4 '- [(3-methyl-4-propionylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric with quantitative performance. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.1 (t, J = 7.5 Hz, 3H) 2.0 (m, 1H) 2.4 (c, J = 7.6 Hz , 2H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7. 2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H ) 8.1 (d, J = 9.3 Hz, 1H) 9.7 (s, 1H) 10.6. (s, 1H) 12.6 (s, 1H).

Example 50: L-2- acid. { 4 '- [(4-isobutyrylamino-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: The coupling of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 1) with isobutyramide, to give 4-isobutyrylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester , was performed according to Example 47, Step 1, with a 95% yield. XH NMR (400 MHz, DMS0-d6) d ppm 1.2 (d, J = 6.8 Hz, 6H) 1.3 (t, J = 7.1 Hz, 3H) 2.6 (s, 3H) 2.7 (m, 1H) 4.4 (c, J = 7.1 Hz, 2H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.5 (m, 1H) 9.7 (s, 1H). Step 2: Hydrolysis of the 4-isobutyrylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester to 4-isobutyrylamino-3-methyl-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, with a performance of 71%. aH NMR (400 MHz, DMSO-d6) d ppm 1.2 (d, J = 6.8 Hz, 6H) 2.6 (s, 3H) 2.7 (m, 1H) 7.2 (dd, J = 7.6, 0.5 Hz, 1H) 7.5 ( m, 2H) 9.7 (s, 1H) 13.4 (s, 1H). Step 3: The coupling of 4-isobutyrylamino-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of the L-2- acid. { 4'- [(4-isobutyrylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -4-methyl-butyric was performed according to Example 47, Step 3, with a yield of 84%. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.4 (s, 3H) 2.5 (s, 3H) 3.6 (dd, J = 9.3 , 5.8 Hz, 1H) 6.8 (s, 1H) 7.5 (dd, J = 7.6, 1.0 Hz, 1H) 7.7 (dd, J = 8.3, 7.3 Hz, 1H) 7.8 (m, 4H) 7.9 (m, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-isobutyrylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to L-2- acid. { 4 '- [(4-isobutyrylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with quantitative yield. 2 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.2 (d, J = 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 4H) 3.6 ( dd, J = 9.3, 6.1 Hz, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.5 (m, 2H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H ) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 51: L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (300 mg, 1.36 mmol, 1 eq.) Under a nitrogen atmosphere, potassium carbonate (377 mg, 2.73 mmol, 2%) was added. eq.), 5 ml of DMF and bromomethylcyclopropane (145 ul, 1.50 mmol, 1.1 eq.), and the reaction was stirred at room temperature for 16 hours. After treatment and flash column chromatography, 4-cyclopropylmethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 94% yield (350 mg). XH NMR (400 MHz, DMSO-d6) d ppm 0.4 (m, 2H) 0.6 (m, 2H) 1.3 (m, 1H) 1.3 (d, J = 14.4 Hz, 3H) 2.7 (d, 3H) 4.0 (d , J = 6.8 Hz, 2H) 4.3 (c, J = 7.1 Hz, 2H) 6.8 (dd, J = 8.1, 0.5 Hz, 1H) 7.2 (dd, J = 8.3, 0.5 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H). Stage 2: Hydrolysis of the 4-cyclopropylmethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester to 4-acid Cyclopropylmethoxy-3-methyl-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, with a yield of 96%. X NMR (400 MHz, DMSO-d6) d ppm 0.4 (m, 2H) 0.6 (m, 2H) 1.3 (m, 1H) 2.7 (s, 3H) 4.0 (d, J = 6.8 Hz, 2H) 6.8 (d , J = 8.1 Hz, 1H) 7.2 (dd, J = 8.5, 0.6 Hz, 1H) 7.4 (m, 1H) 13.3 (s, 1H). Step 3: The coupling of 4-cyclopropylmethoxy-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of the L-2- acid. { 4'- [(4-Cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid was carried out according to Example 47, Step 3, with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.4 (m, 2H) 0.6 (m, 2H) 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.3 (m, 1H) 1.9 (m, 1H) 2.8 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 4.0 (d, J = 6.6 Hz, 2H) 6.8 (d, J = 8.6 Hz, 1H) 7.2 (d, J = 7.8 Hz, 1H) 7.4 (m, 1H) 7.8 (dd, J = 12.0, 8.7 Hz, '4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to obtain L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with quantitative yield. The product was purified by recrystallization from ethyl acetate / hexanes. 1 H NMR (400 MHz, DMSO-dg) d ppm 0.4 (d, J = 4.8 Hz, 2H) 0.6 (d, J = 8.1 Hz, 2H) 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 1.3 (m, 1H) 2.0 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.5, 6.2 Hz, 1H) 4.0 (d, J = 6.8 Hz, 2H) 6.8 (d, J = 8.3 Hz, 1H) 7.2 (d, J = 8.3 Hz, 1H ) 7.4 (t, J = 8.1 Hz, 1H) 7. 8 (d, J = 8.6 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 10.5 (s, 1H) 12.6 (s, 1H) ).

Example 52: L-2- acid. { 4 '- [(1H-benzimidazole-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -3-methyl-buty rich Step 1: Coupling of commercially available 1 H-benzimidazole-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of L-acid 2 ~. { 4 '- [(IH-benzimidazole-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 47, Step 3, with a yield of 37%. 1 H NMR (400 MHz, DMS0-d 5) d ppm 0.8 (dd, J = 15.0, 6.7 Hz, 6H) 1.9 (m, 1H) 3.3 (s, 3H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 7.4 (, 2H) 7.6 (d, J = 8.1 Hz, 1H) 7.8 (m, 5H) 7.9 (m, 2H) 8.1 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 11.1 (s, 1H) 13.5 (s, 1H). Step 2: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(1H-benzimidazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to obtain L-2- acid. { 4 '~ [(lH-benzimidazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 2.0 (m, 1H) 3.6 (dd, J = 9.5, 5.9 Hz, 1H) 7.4 (d, J = 6.6 Hz, 2H) 7.8 (m, 8H) 8.1 (dd, J = ll.l, 9.1 Hz, 3H) 11.1 (s, 1H) 12.6 (s, 1H) 13.5 (s, 1H).

Example 53: L-2- acid. { 4 '- [(4-sec-butoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: The alkylation of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester with 2-bromobutane to give 4-sec-butoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was carried out in accordance with Example 51, Step 1, with a yield of 80%. aH NMR (400 MHz, DMSO-ds) d ppm 1.0 (t, J = 7.5 Hz, 3H) 1.3 (m, 6H) 1.7 (m, 2H) 2.7 (s, 3H) 4.3 (c, J = 7.1 Hz, 2H) 4.6 (m, 1H) 6.8 (d, J = 8.1 Hz, 1H) 7.2 (dd, J = 8.3, 0.5 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H ). Step 2: Hydrolysis of 4-sec-butoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester to 4-sec-butoxy-3-methyl-benzofuran-2-carboxylic acid was carried out according to Example 20, Stage 3, with quantitative performance. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.0 (t, J = 7.5 Hz, 3 H) 1.3 (d, J = 6.1 Hz, 3 H) 1.7 (m, 2 H) 2.7 (s, 3 H) 4.6 (m, 1H) 6.8 (d, J = 8.1 Hz, 1H) 7.1 (m, 1H) 7.4 (t, J = 8.2 Hz, 1H). Step 3: The coupling of 4-sec-butoxy-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain Methyl ester of L-2- acid. { 4 '- [(4-sec-butoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 47, Step 3, with quantitative performance. ^? NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.0 (t, J = 7.5 Hz, 3H) 1.3 (d, J = 6.1 Hz, 3H) 1.7 (m, 2H) 1.9 (m, 1H) 2.7 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 8.7, 7.7 Hz, 1H) 4.6 (d, 1H) 6.9 (d, J = 8.3 Hz, 1H) 7.2 (d, J = 8.1 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H) 7.8 (dd, J = 12.3, 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H ). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-sec-butoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to L-2- acid. { 4'- [(4-sec-Butoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.0 (t, J = 7.5 Hz, 3H) 1.3 (d, J = 6.1 Hz, 3H) 1.7 (m, 2H) 2.0 (m, 1H) 2. 7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 4.6 (c, J = 6.1 Hz, 1H) 6. 9 (d, J = 8.1 Hz, 1H) 7.2 (d, J = 8.1 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H) 12.6 (s, 1H).

Example 54: L-3-methyl-2- acid. { 4 '- [(3-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: The coupling of 3-phenyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of L-3 acid -methyl-2-. { 4 '- [(3-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 47, Stage 3, with a yield of 83%. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.5, 6.7 Hz, 6H) 1.9 (m, 1H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.5 (m, 4H) 7.6 (m, 1H) 7.7 (m, 3H) 7.8 (m, 5H) 7.9 (m, 4H) 8.3 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H). Stage 2: The hydrolysis of methyl ester of L-3-methyl-2- acid. { 4 '- [(3-phenyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric acid to L-3-methyl-2-. { 4 '- [(3-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 20, Step 5, with quantitative yield. NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.9 (m, 1H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.5 (m, 2H) 7.5 (m, 2H) 7.6 (m, 1H) 7.7 (m, 3H) 7.8 (d, J = 8.8 Hz, 2H) 7.8 (m, 5H) 7.9 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H) 12.6 (s, 1H).

Example 55: L-2- (4 '- { [4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino acid}. -3-methyl-butyric Step 1: A 4-Acetylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (300 mg, 1.15 mmol, 1 eq, prepared according to Example 48, Step 1) under a nitrogen atmosphere was added. 5 mi DMF, iodomethane (79 ul, 1.26 mmol, 1.1 eq.) and sadist hydride (60%, 51 mg, 1.26 mmol, 1.1 eq.). The reaction mixture was stirred at room temperature for 4 hours. After workup and flash column chromatography (5-40% ethyl acetate / hexanes), 4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in a yield of 35%. % (112 mg). X H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.2 Hz, 3 H) 1.7 (s, 3 H) 2.5 (s, 3 H) 3.2 (s, 3 H) 4.4 (m, 2 H) 7.3 (dd) , J = 7.6, 0.8 Hz, 1H) 7.6 (dd, J = 8.5, 7.7 Hz, 1H) 7.8 (dd, J = 8.5, 0.9 Hz, 1H). Step 2: Hydrolysis of 4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester to 4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid performed in accordance with Example 20, Step 3, with a yield of 55%. X H NMR (400 MHz, DMSO-d 6) d ppm 1.7 (s, 3 H) 2.5 (s, 3 H) 3.2 (s, 3 H) 7.3 (dd, J = 7.7, 0.9 Hz, 1 H) 7.6 (dd, J = 8.6 , 7.6 Hz, 1H) 7.7 (m, 1H) 13.6 (s, 1H). Step 3: The coupling of 4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl acid methyl ester -butyric to obtain methyl ester of L-2- (4 '- { [4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino .3. -3-Methyl-butyric was performed according to Example 47, Step 3, with a yield of 85% XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz , 6H) 1.7 (s, 3H) 1. 9 (m, 1H) 2.5 (s, 3H) 3.2 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.3 (m, 1H) 7.6 (m, 1H) 7.8 (m, 5H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- (4 '- { [4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4 -sulfonylamino) -3-methyl-butyric acid to obtain L-2- (4'- { [4- (acetyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino acid} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to Example 20, Step 5, in quantitative yield. The product was purified by trituration with ethyl acetate. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.7 (s, 3H) 1.9 (m, 1H) 2.5 (s, 3H) 3.2 (s, 3H) 3.6 (dd, J = 9.1, 6.1 Hz, 1H) 7.3 (dd, J = 7.6, 0.8 Hz, 1H) 7.6 (m, 1H) 7.8 (m, 3H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H) 12.6 (s, 1H).

Example 56: L-3-methyl-2- (4 '- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] -amino acid} -biphenyl- 4-sulfonylamino) -butyric Step 1: A L-2-acid methyl ester. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid (45 mg, 0.082 mmol, Example 20, Step 4) were added trimethylsilyl azide (40 ul, 0.03 mmol, 3.65 eq.), Dibutyltin oxide (10 mg, cat.) And 1 ml of toluene, then the reaction was heated at 120 ° C in a pressure tube for 72 hours. L-3-methyl-2- (4'- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] -amino} -biphenyl ester was obtained. -4-sulfonylamino) -butyric acid and was used in its crude form. XH NMR (400 MHz, DMSO-d6), d ppm 0.8 (m, J = 14.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.4 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.6 (dd, J = 7.6, 1.0 Hz, 1H) 7.7 (dd, J = 8.3, 7.3 Hz, 1H) 7.8 (dd, J = 8.6, 5.6 Hz, 4H) 7.9 ( dd, 3H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.7 (s, 1H). Step 2: The hydrolysis of methyl ester of L-3-methyl-2- (4'- { [3-methyl-4- (2H-tetrazol-5-yl) benzofuran-2-carbonyl] -amino.} .-biphenyl-4-sulfonylamino) -butyric acid to obtain L-3-methyl-2- (4 '- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] ] -amino.} - biphenyl-4-sulfonylamino) -butyric acid was carried out according to Example 20, Step 5, in quantitative yield. The product was purified by preparative HPLC. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 20.7, 6.8 Hz, 6H) 2.0 (m, 1H) 2.5 (s, 3H) 3.5 (s, 1H) 7.5 (m, 2H) 7.6 (m, J = 7.3, 2.0 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7. 8 (m, 4H) 8.0 (d, J = I Hz, 2H) 10.5 (s, 1H).

Example 57: L-2- (4 '- { [4- (3, 3-dimethyl-butyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3- ethyl-butyric Step 1: Methyl ester of L-2- (4'- { [4- (3,3-dimethyl-but-l-ynyl) -3-methyl-benzofuran-2-carbonyl} -amino was reduced. .} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid (65 mg, 0.11 mmol, prepared according to Example 34, Step 3) to methyl ester of L-2- (4 '- { 4- (3, 3-dimethyl-butyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric following the procedure of Example 32, Step 1. 1 H NMR (400 MHz, DMS0-d 6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.0 (s, 9H) 1.5 (m, 2H) 1.9 (m, 1H) 2.8 (s, 3H) 3.0 (m, 2H) 3.4 (s, 3H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 7.1 (dd, J = 7.5, 0.9 Hz, 1H) 7.4 (dd, J = 8.3, 7.3 Hz, 1H) 7.5 (m, 1H) 7.8 (dd, J = 11.2, 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.6 Hz, 1H) 10.5 (s) , 1 HOUR) . Step 2: The hydrolysis of methyl ester of L-2- (4 '- { [4- (3, 3-dimethyl-butyl) -3-methyl-benzofuran-2-carbonyl] - Not me } -biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain L-2- (4'- { [4- (3, 3-dimethyl-butyl) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to Example 20, Step 5, in quantitative yield. The product was purified by Preparative CLAR. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 13.4, 6.8 Hz, 6H) 1.0 (s, 9H) 1.5 (m, 2H) 2.0 (m, 1H) 2.8 (s, 3H) 3.0 (m, 2H) 3.5 (s, 1H) 7.1 (d, J = 7.3 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 3H) 10.5 (s, 1H).

Example 58: L-2- acid. { 4 '- [(3-ethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: (2-Propionyl-phenoxy) -acetic acid methyl ester (432 mg, 1.94 mmol, 1 eq.) Was added to a solution of sodium methoxide (105 mg, 0.94 mmol, 1 eq.) In methanol (10 mL). ) and the reaction was heated at 60 ° C for 4 hours. The reaction was acidified using IN HCl, diluted with water, extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous NaHCO3.

The aqueous layers were extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. 3-Ethyl-benzofuran-2-carboxylic acid methyl ester was obtained in 38% yield, after purification by flash column chromatography (1-5% ethyl acetate / hexanes). 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.2 (t, J = 7.6 Hz, 3 H) 3.1 (c, J = 7.6 Hz, 2 H) 3.9 (s, 3 H) 7.4 (m, 1 H) 7.5 (m, 1H) 7.7 (m, 1H) 7.9 (dd, J = 7.8, 0.8 Hz, 1H). Stage 2: Hydrolysis of acid methyl ester 3-ethyl-benzofuran-2-carboxylic acid to 3-ethyl-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, with a yield of 98%. 1 H NMR (400 MHz, CD 3 OD) d ppm 1.2 (d, J = 7.6 Hz, 3 H) 3.0 (c, J = 7.4 Hz, 2 H) 7.2 (m, 1 H) 7.4 (m, 1 H) 7.4 (m, 1 H) 7.6 (m, 1H). Step 3: The coupling of 3-ethyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of L-2 acid -. { 4 '- [(3-ethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid was carried out according to Example 47, Step 3, with a yield of 85%. ? NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.3 (t, J = 7.6 Hz, 3H) 1.9 (m, 1H) 3.2 (c, J = 7.7 Hz, 2H) 3.4 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.7 (d, J = 9.1 Hz, 1H) 7.8 (dd, J = 10.5, 8.7 Hz, 4H) 7.9 (d, J = 7.3 Hz, 1H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.6 Hz, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(3-ethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to obtain L-2- acid. { 4'- [(3-ethyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with quantitative yield. The product was purified by trituration with 25% ethyl acetate / hexane. 2 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 16.9, 6.8 Hz, 6H) 1.3 (t, J = 7.5 Hz, 3H) 2.0 (m, 1H) 3.2 (c, J = 7.7 Hz , 2H) 3.5 (s, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.7 (d, J = 8.3 Hz, 1H) 7.8 (m, 7H) 8.0 (d, J = 8.8 Hz, 2H ) 10.6 (s, 1H).

Example 59: L-2- acid. { 4 '- [(4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -3-methyl-butyric Stage 1: The 3-methyl-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester tert-butyl carbamate to give 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was carried out according to Example 47, Step 1, with a yield of 60%. X H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.1 Hz, 3 H) 1.5 (s, 9 H) 2.6 (s, 3 H) 4.4 (c, J = 7.1 Hz, 2 H) 7.1 (d, J = 7.6 Hz, 1H) 7.5 (m, 2H) 9.1 (s, 1H). Step 2: Hydrolysis of 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester to give 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid was carried out according to Example 20 , Stage 3. Yield 98%. XR NMR (400 MHz, CD3OD) d ppm 1.4 (s, 9H) 2.6 (s, 3H) 7.1 (m, 1H) 7.3 (m, 2H) 8.7 (s, 1H). Step 3: Coupling of 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to give Methyl ester of L-2- acid. { 4 '- [(4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid was carried out according to Example 47, Step 3, with a yield of 85%. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.5 (dd, 9H) 1.9 (m, 1H) 2.7 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.2 (dd, J = 7.6 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.8 (dd, J = 10.2, 8.7 Hz, 4H) 7.9 ( , 2H) 8.0 (d, J = 9.1 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 9.1 (s, 1H) 10.5 (s, 1H). Stage 4: Hydrolysis of methyl ester of L-2 acid . { 4 '- [(4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to obtain L-2- acid. { 4 '- [(4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric was carried out according to Example 20, Step 5, with quantitative yield. The product was purified by trituration with 25% ethyl acetate / hexane. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.6, 6.8 Hz, 6H) 1.5 (s, 9H) 2.0 (m, 1H) 2.7 (s, 3H) 3.5 (m, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 3H) 9.1 (s, 1H) 10.5 (s, 1H).

Example 60: L-3-methyl-2- acid. { 4 '- [(3-methyl-4-methylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (624 mg, 1.95 mmol, prepared according to Example 59, Step 1) was added 1,2-dichloroethane (12 mi) and acid trifluoroacetic acid (TFA, 6 ml). The reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo to provide 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester in quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 1.3 (t, J = 7.1 Hz, 3H) 2.7 (s, 3H) 4.3 (c, J = 7.1 Hz, 2H) 6.5 (dd, J = 7.8, 0.8 Hz , 1H) 6.8 (d, J = 8.3 Hz, 1H) 7.2 (t, J = 8.1 Hz, 1H).

Step 2: To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq.) Was added iodomethane (310 ul, 6.16 mmol, 2.7 eq.), Sodium carbonate ( 314 mg, 2.96 mmol, 1.3 eq.), And ethanol (10 mL), and the reaction was heated to reflux for 16 hours. 3-Methyl-4-methylamino-benzofuran-2-carboxylic acid ethyl ester was obtained in 17% yield after flash column chromatography, eluting with ethyl acetate / hexanes (90 mg). XH NMR (400 MHz, DMSO-d6) d ppm 1.3 (t, J = 7.1 Hz, 3H) 2.7 (s, 3H) 4.3 (c, J = 7.1 Hz, 2H) 6.5 (dd, J = 7.8, 0.8 Hz , 1H) 6.8 (d, J = 8.3 Hz, 1H) 7.2 (t, J = 8.1 Hz, 1H).

Step 3: Hydrolysis of the 3-methyl-4-methylamino-benzofuran-2-carboxylic acid ethyl ester to give 3-methyl-4-methylamino-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, with performance quantitative. X H NMR (400 MHz, DMSO-d 6) d ppm 2.7 (s, 3 H) 2.8 (d, J = 4.3 Hz, 3 H) 5.7 (d, J = 4.8 Hz, 1 H) 6.3 (d, J = 7.8 Hz , 1 HOUR) 6. 8 (dd, J = 8.3, 0.8 Hz, 1H) 7.2 (t, J = 8.1 Hz, 1H) 13.1 (s, 1H).

Stage 4: The coupling of 3-methyl-4-methylamino-benzofuran-2-carboxylic acid with acid methyl ester L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric to obtain methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-methylamino-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric was performed according to Example 47, Step 3, with a yield of 33%. XH NMR (400 MHz, DMSO-de) d ppm 1.2 (t, J = 7.6 Hz, 3H) 3.1 (c, J = 7.6 Hz, 2H) 3. 9 (s, 3H) 7.4 (m, 1H) 7.5 (m, 1H) 7.7 (m, 1H) 7.9 (dd, J = 7.8, 0.8 Hz, 1H).

Step 5: The hydrolysis of methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-methylamino-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric to provide L-3-methyl-2- acid. { 4 '- [(3-methyl-4-methylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 20, Step 5, with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 2.0 (m, 1H) 2.8 (m, 6H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 5.7 (d, J = 4.5 Hz, 1H) 6.3 (d, J = 7.8 Hz, 1H) 6.9 (d, J = 7.8 Hz, 1H) 7.3 (t, J = 8.1 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.8 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.4 (s, 1H).

Example 61: L-2- acid. { 4 '- [(4-amino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric A L-2- acid. { 4 '- [(4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (84 mg, prepared according to Example 59, Step 4) was added 1,2-dichloroethane (2 ml) and TFA (1 ml). The reaction was stirred at room temperature for 3 hours. The solvent was removed in vacuo to provide L-2- acid. { 4 '- [(4-amino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with quantitative yield. aH NMR (400 MHz, DMSO-d5) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.9 (, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 5.5 (s, 2H) 6.5 (dd, J = 8.0, 0.6 Hz, 1H) 6.8 (d, J = 8.8 Hz, 1H) 7.1 (t, J = 8.1 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H ) 7.8 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = .3 Hz, 1H) 10.3 (s, 1H).

Example 62: L-2- acid. { 4 '- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: A 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq, prepared according to Example 60, Step 1) was added with ethanol (8 ml), iodomethane (500 ul, 7.98 mmol, 3.5 eq.) and potassium carbonate (946 mg, 6.84 mmol, 3 eq.) under an argon atmosphere in a sealed tube and the mixture was heated at 80 ° C for 16 hours. After treatment and flash column chromatography, 4-dimethylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 44% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.2 Hz, 3 H) 2.7 (t, 3 H) 2.8 (s, 6 H) 4.3 (m, J = 7.1, 7.1, 7.1 Hz, 2 H) 6.9 (dd, J = 7.8, 0.8 Hz, 1H) 7.3 (dd, J = 8.3, 1.0 Hz, 1H) 7.4 (m, 1H).

Step 2: Hydrolysis of 4-dimethylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester to give 4-dimethylamino-3-methyl-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, with quantitative yield. X H NMR (400 MHz, DMSO-d 6) d ppm 2.7 (s, 3 H) 2.8 (s, 6 H) 6.9 (d, J = 7.6 Hz, 1 H) 7.2 (d, J = 7.6 Hz, 1 H) 7.4 (t, J = 8.1 Hz, 1H) 13.2 (s, 1H).

Step 3: The stockpiling of 4-dimethylamino-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of the L-2- acid. { 4 '- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid was carried out according to Example 47, Step 3, with quantitative yield.

Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to L-2- acid. { 4'- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5. Purification by preparative HPLC gave the desired product in 50% yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.8 (, 9H) 3.6 (dd, J = 9.3, 5.8 Hz, 1H) 6.9 (dd, J = 7.8, 0.8 Hz, 1H) 7.3 (dd, J = 8.3, 0.8 Hz, 1H) 7.4 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 ( d, J = 8.8 Hz, 2H) 8.0 (d, J = 9.1 Hz, 1H) 10.5 (s, 1H).

Example 63: L-3-methyl-2- acid. { 4 '- [(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -butyric Step 1: To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq, prepared according to Example 60, Step 1) was added toluene (3 mL), 1,4-dibromobutane (272 ul, 2.28 mmol, 1 eq.) And N, N-diisopropylethylamine (953 ul, 5.47 mmol, 2.4 eq.) Under an argan atmosphere in a sealed tube and the mixture was heated to 110 °. C for 16 hours. After treatment and flash column chromatography, 3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carboxylic acid ethyl ester was obtained in 48% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.1 Hz, 3 H) 1.9 (m, 4 H) 2.7 (s, 3 H) 3.1 (m, 4 H) 4.3 (c, J = 7.1 Hz, 2H) 6.8 (dd, J = 8.0, 0.6 Hz, 1H) 7.2 (dd, J = 8.3, 0.8 Hz, 1H) 7.3 (m, 1H). Step 2: The hydrolysis of 3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carboxylic acid ethyl ester to give 3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carboxylic acid was carried out in accordance with Example 20, Step 3, with a 73% yield. X H NMR (400 MHz, DMSO-d 6) d ppm 1.9 (m, 4 H) 2.7 (s, 3 H) 3.1 (m, 4 H) 6.8 (dd, J = 7.8, 0.8 Hz, 1 H) 7.2 (dd, J = 8.1 , 0.8 Hz, 1H) 7.3 (m, 1H). Stage 3: The coupling of 3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 47, Stage 3, with a yield of 27%. X H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (, 6 H) 1.9 (s, 5 H) 2.8 (d, J = 1.5 Hz, 3 H) 3.2 (s, 4 H) 3.4 (d, J = 1. 5 Hz, 3H) 3.6 (t, J = 8.0 Hz, 1H) 6.9 (d, J = 7.8 Hz, 1H) 7.2 (dd, J = 9.3, 1.3 Hz, 1H) 7.4 (m, 1H) 7.8 (m, 4H) 7.9 (m, 2H) 8.0 (dd, J = 8.6, 1.5 Hz, 2H) 8.3 (d, J = 9.6 Hz, 1H) 10.4 (s, 1H). Step 4: The hydrolysis of methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric acid to L-3-methyl-2-. { 4 '- [(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 20, Step 5, with quantitative yield. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 45.5, 6.8 Hz, 6H) 1.9 (m, 4H) 2.0 (m, 1H) 2.8 (s, 3H) 2.9 (d, J * 2.8 Hz, 1H) 3.2 (, 4H) 6.9 (dd, J = 7.8, 0.8 Hz, 1H) 7.2 (dd, J = 8.1, 0.8 Hz, 1H) 7.4 (m, 1H) 7.8 (m, 6H) 8.0 (d , J = 8.8 Hz, 2H) 8. 5 (s, 1H) 10. 4 (s, 1H).

Example 64: L-2- (. {4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -bifenyl-4-sulfonyl} -methylamino) -3 acid -me til-butírico Step 1: The stockpiling of 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid (prepared according to Example 36, Step 2) with L-2- [(4'-amino-biphenyl-4) methyl ester -sulfonyl) -methyl-amino] -3-methyl-butyric acid to obtain methyl ester of L-2- (. {4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] - biphenyl-4-sulfonyl.} - methyl-amino) -3-methyl-butyric acid was made according to Example 47, Step 3, in 43% yield. The product was purified by preparative HPLC. Step 2: Hydrolysis of L-2- (. {4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} -methyl ester. amino) -3-methyl-butyric acid to L-2- (. {4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl}. -methyl-amino) -3-methyl- butyric was performed according to Example 20, Step 5, with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.9 (dd, J = 21.0, 6.6 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H) 2.8 (s, 3H) 3.1 (s, 3H) 4.0 (d, J = 10.4 Hz, 1H) 7.3 (dd, J = 7.7, 0.9 Hz, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 7.8 (dd, J = 13.3, 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 9.5 (s, 1H) 10.6 (s, 1H).

Example 65: L-3-hydroxy-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: L-2- (4'-amino-biphenyl-4-suphonymymino) -3-tert-butoxy-butyric acid methylester was prepared according to the procedure of Example 39, Steps 1-3, using Ot methyl ester. -butyl-threonine and 4- (4, 4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenylamine. The coupling of 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid (prepared according to Example 36, Step 2) with methyl ester of L-2- (4'-amino-biphenyl-4-sulfonylamino) - 3-tert-butoxy-butyric to obtain methyl ester of L-3-tert-butoxy-2- acid. { 4 '- [(4- methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 47, Step 3, with a 38% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.0 (m, 12 H) 2.8 (s, 3 H) 3.1 (s, 3 H) 3.4 (s, 3 H) 3.8 (dd, J = 9.7, 3.7 Hz, 1 H) 4.0 (dd, J = 10.2, 6.4 Hz, 1H) 7.3 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.3 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H ) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8. 0 (d, J = 9.9 Hz, 1H) 9.5 (s, 1H) 10.6 (s, 1H). Step 2: Deprotection of the methyl ester of L-3-tert-butoxy-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric to obtain methyl ester of L-3-hydroxy-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 61, Step 1, with quantitative yield. 1H NMR (400 MHz, DMSO-de) d ppm 1.0 (d, J = 6.3 Hz, 3H) 2.8 (s, 3H) 3. 1 (s, 3H) 3.4 (s, 3H) 3.8 (dd, J = 9.3, 4.0 Hz, 1H) 4.0 (m, 1H) 7.3 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.6 ( d, J = 7.6 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.0 (d, J = 9.1 Hz, 1H) 9.5 ( s, 1H) 10.6 (s, 1H). Step 3: The hydrolysis of methyl ester of L-3-hydroxy-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric acid to L-3-hydroxy-2-. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 20, Step 5, with quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.0 (d, J = 6.3 Hz, 3H) 2.8 (s, 3H) 3.1 (s, 3H) 3.7 (dd, J = 9.3, 3.5 Hz, 1H) 4. 0 (s, 1H) 4.8 (d, J = 5.3 Hz, 1H) 7.3 (d, J = 7 8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.3 Hz, 1H) 7.7 (d, J = 9.3 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (s, 4H) 8.0 (d, J = 8.8 Hz, 2H) 9.5 (s, 1H) 10.6 (s, 1H).

Example 66: (S) -3-Methyl-2- (4 '- { [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl] -amino acid} -biphenyl- 4- sulfonylamino) -butyric Step 1: The stockpiling of 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid (commercially available) with L-2- (4'-amino-biphenyl) 4- methyl ester sulfonylamino) -3-methyl-butyric acid was carried out according to the procedure described in Example 21, Step 3. The methyl ester of (S) -3-methyl-2- (4 '- { [4-methyl- 2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric acid was obtained as a white solid in 75% yield.

Step 2: The hydrolysis of (S) -3-methyl-2- (4 '- { [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl] -amino acid methyl ester} -biphenyl-4-sulfonylamino) -butyric acid according to the procedure described in Example 20, Step 5, produced (S) -3-methyl-2- (4 '- { [4-methyl-2) acid. - (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric acid as a white solid. MS: calculated for [M + H] +: 618.67. Found: 618.17.

Example 67: L-3-methyl-2- acid. { 4 '- [(3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino.} - butyric Stage 1: The stockpiling of 3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl) 4- methyl ester sulfonylamino) -3-methyl-butyric acid to obtain methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran-2) -carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -butyric acid was carried out according to Example 47, Step 3, with a yield of 61%. XH NMR (400 MHz, DMSO-d6) d 0.8 (dd, J = 14.7, 6.6 Hz, 6H) 1. 9 (m, 1H) 2.6 (s, 3H) 3.4 (s, 3H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 7.3 (d, J = 7.8 Hz, 1H) 7.6 (m, 1H) 7.7 ( d, J = 8.3 Hz, 1H) 7.8 (m, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 11 , 5 (s, 1H). Step 2: The hydrolysis of methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran-2-carbonyl] - amino.}. -biphenyl-4-sulfonylamino) -butyric acid to L-3-methyl-2- (4 '- { [3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran] -2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -butyric acid was carried out according to Example 20, Step 5, in a yield of 25%. The product was purified by preparative HPLC. ^? NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 13.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.6 (s, 3H) 3.5 (m, 1H) 7.3 (d, J = 7.8 Hz , 1H) 7.6 (m, 1H) 7.7 (d, J = 7.6 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.0 ( d, J = 8.6 Hz, 1H) 10.6 (s, 1H).

Example 68: L-2- acid. { 4 '- [(4-ethanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (563 mg, 2.57 mmol, 1 eq, prepared according to Example 60, Step 1) was added CH2C12 (12 mL) under an argan atmosphere and the reaction cooled to < 0 ° C. Then ethanesulfonyl chloride (243 ul, 2.57 mmol, 1 eq.) And pyridine (623 ul, 7.70 mmol, 3 eq.) Were added and the reaction was stirred while warming slowly to room temperature. After treatment and flash column chromatography, 4-ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 69% yield. X H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (m, 6H) 2.8 (s, 3H) 3.2 (c, J = 7.3 Hz, 2H) 4.4 (m, J = 7.1, 7.1, 7.1 Hz, 2H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 9.6 (s, 1H).

Step 2: Hydrolysis of 4-ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester to give 4-ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, with quantitative performance. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.3 Hz, 3 H) 2.7 (s, 3 H) 3.2 (c, J = 7.3 Hz, 2 H) 7.2 (d, J = 7.6 Hz, 1 H ) 7.5 (m, 1H) 7.6 (d, J = 8.3 Hz, 1H) 9.5 (s, 1H).

Stage 3: Acid storage 4- ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to give methyl ester of L-2- acid. { 4 '- [(4-Ethanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid was carried out according to Example 47, Step 3, with quantitative yield. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (dd, J = 12.9, 7.8 Hz, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 7.2 (d, J = 7.6 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 7.8 Hz, 1H) 7.8 (t, J = 8.5 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.6 Hz, 1H) 9.6 (s, 1H) 10.6. (s, 1H).

Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-ethanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to L-2- acid. { 4 '- [(4-ethanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was performed according to Example 20, Step 5, with a yield of 71%. E NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.1, 6.8 Hz, 6H) 1.3 (t, J = 7.5 Hz, 3H) 2.0 (m, 1H) 2.8 (s, 3H) 3.2 ( c, J = 7.3 Hz, 2H) 3.6 (dd, J = 9.0, 5.9 Hz, 1H) 7.2 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 7.6 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.9 Hz, 1H) 9.6 (s, 1H) 10.6 (s, 1H) ).

Example 69: L-3-methyl-2- (4 '- { [3-methyl-4- (propane-2-sulfonylamino) -benzofran-2-carbonyl] -amino acid} -biphenyl-4 -sulfonylamino) -butyric Step 1: To a mixture of 6 ml of dichloromethane and 11 ml of ammonium hydroxide at room temperature was added 500 ul of isopropylsulfonyl chloride (4.5 mmol). After stirring overnight, the reaction was extracted with dichloromethaneThe organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give isopropylsulfonamide (121 mg) in 22% yield. 1 H NMR (400 MHz, CDC13) d ppm 1.4 (d, J = 6.8 Hz, 6H) 3.2 (m, 1H) 4.4 (s, 2H). Step 2: The coupling of isopropylsulfonamide with 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester was carried out according to Example 36. Step 1, to give 3-methyl-4- (propane) 2-sulfonylamino) -benzofuran-2-carboxylic acid with a yield of 23%. XH NMR (400 MHz, CDC13) d ppm 1.4 (t, J = 6.4 Hz, 9H) 2.9 (t, 3H) 3.5 (m, 1H) 4.5 (c, J = 7.1 Hz, 2H) 6.6 (s, 1H) 7.4 (m, 3H).

Step 3: The hydrolysis of 3-methyl-4- (propane-2-sulfonylamino) -benzofuran-2-carboxylic acid ethyl ester was carried out according to Example 20, Step 3, to give 3-methyl-4- ( propane-2-sulfonylamino) -benzofuran-2-carboxylic acid with quantitative yield. 2 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (d, J = 6.8 Hz, 6 H) 2.8 (s, 3 H) 3.4 (m, 1 H) 7.2 (d, J = 7.8 Hz, 1 H) 7.5 (m, 1H) 7.6 (d, J = 7.8 Hz, 1H) 9.5 (s, 1H). Step 4: The coupling of 3-methyl-4- (propane-2-sulfonylamino) -benzofuran-2-carboxylic acid amide with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl ester -methyl-butyric was performed according to Example 21, Step 3, to provide methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (propane-2-sulfonylamino)] -benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -butyric, with a yield of 88%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.3 (d, J = 6.6 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.3 ( s, 3H) 3.4 (m, 1H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 7.2 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.3 Hz, 1H ) 7.8 (t, J = 8.7 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (s, 1H) 8.3 (d, J = 9.6 Hz, 1H) 9.5 (s, 1 HOUR) . Step 5: The hydrolysis of methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (propane-2-sulfonylamino) -benzofuran-2-carbonyl] -amino. -biphenyl-4-sulfonylamino) -butyric acid was carried out according to Example 20, Step 5, to provide L-3-methyl-2- (4 '- { [3-methyl-4- (propane-2) acid - sulfonylamino) -benzofuran-2-carbonyl] amino} -biphenyl-4-sulfonylamino) -butyric, with quantitative yield. '' 'H NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.3 (d, J = 6.8 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H ) 3.4 (m, 1H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.2 (d, J = 7.8 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 7.8 Hz, 1H) 7.8 ( d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.6 Hz, 1H) 9.5 (s, 1H) 10.6 (s, 1H).

Example 70: L-2- (4 '- { [4- (Ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3 acid -methyl-butyric Step 1: 4-Ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (prepared according to Example 68, Step 1) was alkylated with iodomethane, according to Example 60, Step 2, to give ethyl ester of 4- (Ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid. aH NMR (400 MHz, DMSO-d5) d ppm 1.3 (m, 9H) 2.7 (s, 3H) 3.3 (s, 2H) 4.4 (c, J = 7.1 Hz, 2H) 7.5 (dd, 3 = 1.1) , 0.9 Hz, 1H) 7.6 (m, 1H) 7.7 (m, 1H). Stage 2: Hydrolysis of 4- (ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester to give 4- (ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid, was carried out according to Example 20, Step 3, in 92% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.1 Hz, 3 H) 1.5 (s, 9 H) 2.6 (s, 3 H) 4.4 (c, J = 7.1 Hz, 2 H) 7.1 (d, J = 7.6 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 9.1 (s, 1H). Step 3: The coupling of 4- (ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl acid methyl ester -butyric to give methyl ester of acid-L-2- (4'- { [4- (ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4- sulfonylamino) -3-methyl-butyric acid, was carried out according to Example 47, Step 3, with a yield of 88%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 14.9, 6.8 Hz, 6H) 1.2 (t, J = 7.1, 3H) 1.3 (t, J = 7.5 Hz, 3H) 1.9 (m, 1H) 2.0 (s, 3H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 4.0 (c, J = 7.2 Hz, 2H) 7.5 (m, 2H) 7.7 (dd, J = 8.1, 1.0 Hz, 1H) 7.8 (dd, J = 8.7, 7.5 Hz, 4H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- (4 '- { [4- (ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4 -sulfonylamino) -3-methyl-butyric acid to provide L-2- (4 '- { [4- (ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino acid} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid, was carried out in accordance with Example 20, Step 5, with a yield of 90%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.3 (t, J = 7.3 Hz, 3H) 2.0 (m, 1H) 2.8 (s, 3H) 3.3 ( s, 2H) 3.6 (dd, J = 9.5, 5.9 Hz, 1H) 5.8 (s, 3H) 7.5 (dd, J = 7.6, 1.0 Hz, 1H) 7.6 (m, 1H) 7.7 (m, 1H) 7.8 ( d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H).

Example 71: L-2- acid. { 4 '- [(4-Benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: 4-Benzenesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1) and sodium chloride. benzenesulfonyl, according to the procedure of Example 68, Step 1. Yield 83%. X H NMR (400 MHz, DMSO-d 6) d ppm 1.3 (t, J = 7.2 Hz, 3 H) 2.6 (s, 3 H) 4.4 (c, J = 7.1 Hz, 2 H) 6.6 (d, J = 7.8 Hz, 1 H 7.3 (m, 1H) 7.6 (t, J = 7.8 Hz, 3H) 7.7 (m, 3H) 10.1 (s, 1H). Stage 2: Hydrolysis of the 4- ethyl ester benzenesulfonylamino-3-methyl-benzofuran-2-carboxylic acid to give 4-benzenesulfonylamino-3-methyl-benzofuran-2-carboxylic acid, was carried out according to Example 20, Step 3. Yield 94%. X H NMR (400 MHz, DMSO-d 6) d ppm 2.6 (s, 3 H) 6.6 (d, J = 7.6 Hz, 1 H) 7.3 (m, 1 H) 7.6 (m, 3 H) 7.7 (d, J = 8.1 Hz, 3H) 10.0 (s, 1H) 13.5 (s, 1H). Step 3: The stockpiling of 4-benzenesulfonylamino-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester to obtain methyl ester of the L-2- acid. { 4'- [(4-Benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid, was carried out according to Example 21, Step 3. Yield 70%. 1 HOUR NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 6.6 (d, J = 7.6 Hz, 1H) 7.3 (m, 1H) 7.6 (m, 3H) 7.7 (m, 3H) 7.8 (t, J = 9.0 Hz, 4H) 7.9 (m, 2H ) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.1 (s, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-2- acid. { 4 '- [(4-Benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid to obtain L-2- acid. { 4 '- [(4-Benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid, was carried out according to Example 20, Step 5, and the product was purified by trituration with ethyl acetate.

Performance 50%. 2 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 6.6 (d, J = 8.1 Hz, 1H) 7.3 (m, 1H) 7.6 (m, 3H) 7.7 (m, 3H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.1 (s, 1H) 10.6 (s, 1H).

Example 72: L-3-methyl-2- (4 '- { [3-methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -butyric Step 1: 3-Methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1) and 2-thiophenesulfonyl chloride, according to the procedure of Example 68, Step 1. Yield 68%. XH NMR (400 MHz, DMSO-d6) d ppm 1.3 (t, J = 7.1 Hz, 3H) 2.6 (s, 3H) 4.4 (c, J = 7.1 Hz, 2H) 6.7 (dd, J = 7.8, 0.8 Hz, 1H) 7.2 (dd, J = 4.9, 3.7 Hz, 1H) 7.4 (m, 2H) 7.6 (dd, J = 8.3, 0.8 Hz, 1H) 8.0 (dd, J = 4.9, 1.4 Hz, 1H) 10.2 (s, 1H). Stage 2: Hydrolysis of 3-methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carboxylic acid ethyl ester to give 3-methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carboxylic acid, was made according to Example 20, Step 3. Yield 92%. 2H NMR (400 MHz, DMSO-d6) d ppm 2.6 (s, 3H) 6.7 (dd, 3 = 1.1, 0.9 Hz, 1H) 7.2 (dd, J = 5.1, 3.8 Hz, 1H) 7.4 (m, 1H) 7.5 (dd, J = 3.7, 1.4 Hz, 1H) 7.6 (dd, J = 8.3, 0.8 Hz, 1H) 8.0 (dd, J = 5.1, 1.3 Hz, 1H) 10.2 (s, 1H) 13.5 (s) , 1 HOUR) . Step 3: The coupling of 3-methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3- methyl ester Methyl-butyric acid to obtain methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (thiophen-2-sulfonylamino) -benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric, was done according to Example 47, Stage 3. Quantitative performance. 1 H NMR (400 MHz, DMSO-d 5) d ppm 0.8 (dd, J = 14.8, 6.7 Hz, 6H) 1.9 (dd, J = 13.6, 6.8 Hz, 1H) 2.7 (s, 3H) 3.3 (s, 3H) 3.6 (dd, J = 9.3, 7.1 Hz, 1H) 6.8 (dd, J = 7.8, 0.8 Hz, 1H) 7.2 (dd, J = 4.8, 3.8 Hz, 1H) 7.4 (m, 1H) 7.5 (dd, J = 3.8, 1.3 Hz, 1H) 7.6 (d, J = 7.8 Hz, 1H) 7.8 (t, J = 9.0 Hz, 4H) 7.9 (m, 2H) 8.0 (m, 3H) 8.3 (d, 3 = .3 Hz, 1H) 10.2 (s, 1H) 10.6 (s, 1H). Step 4: The hydrolysis of methyl ester of L-3-methyl-2- (4 '- { [3-methyl-4- (thiophen-2-sulfonylamino) -benzofuran-2-carbonyl] -amino. -biphenyl-4-sulfonylamino) -butyric acid to obtain L-3-methyl-2- (4 '- { [3-methyl-4- (thiophen-2-sulfonylamino) -benzofuran-2-carbonyl] amino acid} biphenyl-4- sulfonylamino) -butyric acid, was carried out according to Example 20, Step 5, and the product was purified by trituration with ethyl acetate. Performance 78%. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.8, 6.7 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 6.8 (d, J = 7.8 Hz, 1H) 7.2 (dd, J = 5.1, 3.8 Hz, 1H) 7.4 (m, 1H) 7.5 (dd, J = 3.8, 1.3 Hz, 1H) 7.6 (dd, J = 8.1 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (m, 3H) 8.1 (d, J = 9.1 Hz, 1H) 10.2 (s, 1H) 10.6 (s, 1H) .

Example 73: L-2- (4 '-. {[4- (1, 1-dioxo-l6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carbonyl] -amino acid} .-biphenyl-4-sulfonylamino) -3-methyl-butyric Step 1: 4- (3-Chloro-propane-1-sulfonylamino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1) and 3-chloropropanesulfonyl chloride according to the procedure of Example 68, Step 1. Yield 70%. XR NMR (400 MHz, DMSO-d6) d ppm 1.4 (m, 3H) 2.2 (m, 2H) 2.8 (s, 3H) 3.3 (m, 2H) 3.8 (t, J = 6.4 Hz, 2H) 4.4 (c, J = 7.2 Hz, 2H) 7.2 (d, J = 7.3 Hz, 1H) 7.5 (m, 1H) 7.7 (m, 1H) 9.7 (s, 1H) . Step 2: 4- (3-Chloro-propane-1-sulfonylamino) -3-methyl-benzofuran-2-carboxylic acid ethyl ester (246 mg, 0.68 mmol, 1 eq.) In THF (10 mL) cooled to < 0 ° C, sodium hydride (60%, 30 mg, 0.75 mmol, 1.1 eq.) Was added. The reaction was allowed to slowly warm to room temperature, then transferred to a pressure tube and heated at 74 ° C for 16 hours. After work-up and flash column chromatography, 4- (1, l-dioxo-l6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained. Performance 64%. ^? NMR (400 MHz, DMSO-de) d ppm 1.3 (t, 3 = 1. 1 Hz, 3H) 2.5 (m, 2H) 2.7 (s, 3H) 3.5 (m, 2H) 3.7 (dd, J = 6.8 Hz , 2H) 4.4 (c, J = 7.1 Hz, 2H) 7.4 (dd, J = 7.8, 0.8 Hz, 1H) 7.6 (m, 1H) 7.7 (dd, J = 8.3, 0.8 Hz, 1H). Step 3: The hydrolysis of 4- (1,1-dioxo-l6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester to give 4- (1, 1-dioxo- l6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carboxylic acid was made according to Example 20, Step 3, to give 4- (1,1-dioxo-l6-isothiazolidin-) acid. 2-yl) -3-methyl-benzofuran-2-carboxylic acid. Yield 94%. aH NMR (400 MHz, DMSO-d6) d ppm 2.5 (dd, J = 14.7, 7.6 Hz, 2H) 2.7 (s, 3H) 3.5 (m, 2H) 3.7 (t, J = 6.8 Hz, 2H) 7.4 ( m, 1H) 7.6 (m, 1H) 7.7 (d, J = 8.6 Hz, 1H).

Step 4: The coupling of 4- (1,1-dioxo-l6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino) -methyl ester biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain methyl ester of L-2- (4'- { [4- (1, l-dioxo-ll? s-isothiazolidin-2-yl) -3 -methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid, was carried out according to Example 47, Step 3. Yield 89%. XR NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 14.7, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.3 (s, 3H) 3.5 (m, 2H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 3.8 (t, J = 6.8 Hz, 2H) 7.5 (dd, J = 7.8, 0.8 Hz, 1H) 7.6 (m, 1H) 7.8 (m, 5H) 7.9 ( m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.3 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H).

Step 5: The hydrolysis of methyl ester of L-2- (4'-. {[[4- (l, l-dioxo-l? 6-isothiazolidin-2-yl) ~ 3-methyl-benzofuran-2-carbonyl] ] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid to obtain L-2- (4 '- { [4- (1,1-dioxo-l? -isothiazolidin-2-) il) -3-methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid, was carried out according to Example 20, Step 5, and the product was purified by trituration with ethyl acetate. Performance 67%. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.9 (m, 1H) 2.8 (s, 3H) 3.5 (m, 2H) 3.6 (dd, J = 9.3 , 5.8 Hz, 1H) 3.8 (t, J = 6.8 Hz, 2H) 7.5 (dd, J = 7.7, 0.9 Hz, 1H) 7.6 (m, 1H) 7.7 (dd, J = 8.2, 0.9 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, 3 = 9, 3 Hz, 1H) 10.6 (s, 1H). Example 74: D-3-methyl-2- acid. { 4 '- [(3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: The coupling of 3-methyl-benzofuran-2-carboxylic acid amide with 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenylamine was carried out according to Example 20, Step 4, to give [4- (4, 4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl] -amide of the acid 3-methyl-benzofuran-2-carboxylic acid with a 55% yield. 1 H NMR (400 MHz, DMS0-d 6) d ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 7.4 (m, 1H) 7.5 (m, 1H) 7.7 (m, 3H) 7.8 (d, J = 7.3 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 10.5 (s, 1H).

Step 2: A HD-Val-OtBu-HCl (22.5 g, 0.107 mol, 1 eq.) In 400 ml of dichloromethane under an argon atmosphere, cooled using an ethanol / ice bath, was added 4-bromobenzenesulfonyl chloride (27.4 g, 0.107 mol, 1 eq.). Then N, N-diisopropylethylamine (43 ml, 0.247 mol, 2.3 eq.) Was added via an addition funnel and the reaction was stirred for 3 hours under slow heating at room temperature. ambient. After treatment, D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tere-butyl ester was obtained in 94% yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 11.4, 6.8 Hz, 6H) 1.2 (s, 9H) 1.9 (m, 1H) 3.5 (dd, J = 9.5, 6.2 Hz, 1H) 7.7 (d, J = 8.8 Hz, 2H) 7.8 (m, 2H) 8.2 (d, J = 9.6 Hz, 1H).

Stage 3: The Suzuki coupling of [4- (4, 4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl] -amide of 3-methyl-benzofuran-2-acid carboxylic acid with D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester was carried out according to Example 38, Step 3, to give tert-butyl ester of D-3-methyl acid -2-. { 4 '- [(3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric with a yield of 66%. XH NMR (400 MHz, CDC13) d ppm 0.9 (d, J = 6.8 Hz, 3H) 1.0 (d, J = 6.8 Hz, 3H) 1.2 (s, 9H) 2.1 (m, 1H) 2.7 (s, 3H) 3.7 (dd, J = 10.0, 4.4 Hz, 1H) 5.1 (d, J = 9.9 Hz, 1H) 7.4 (m, 1H) 7.5 (m, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.6 Hz , 2H) 7.7 (d, J = 8.6 Hz, 3H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (d, J = 8.6 Hz, 2H) 8.5 (s, 1H).

Step 4: The removal of the t-butyl ester of D-3-methyl-2- acid. { 4 '- [(3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was performed according to Example 1, Step 3, with yield quantitative. aH NMR (400 MHz, CD3OD) d ppm 0.8 (dd, J = 24.1, 6. 7 Hz, 6H) 1.9 (m, 1H) 2.6 (s, 3H) 3.6 (d, J = 5.8 Hz, 1H) 7.3 (t, J = 7.6 Hz, 1H) 7.4 (m, 1H) 7.5 (d, J = 8.3 Hz, 1H) 7.6 (m, 3H) 7.7 (d, J = 8.3 Hz, 2H) 7.8 (m, 4H) 10.1 (s, 1H).

Example 75: D-2- acid. { 4 '- [(benzofuran-2-carbonyl) -methylamino] -bifenil-4-sulfonylamino} -3-me til-butírico Step 1: Coupling of benzofuran-2-carboxylic acid amide with 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2.] Dioxaborolan-2-yl) -phenylamine was carried out in accordance with Example 20, Step 4, to give [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl} -amide of benzofuran-2-carboxylic acid with a yield of 83%. 1 H NMR (400 MHz, DMS0-de) d ppm 1.3 (s, 12H) 7.4 (m, 1H) 7.5 (m, 1H) 7.7 (d, J = 8.3 Hz, 2H) 7.7 (dd, J = 8.5, 0.9 Hz, 1H) 7.8 (m, 4H) 10.6 (s, 1H). Step 2: To a solution of benzofuran-2-carboxylic acid [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) phenyl] amide (195 mg, 0.54 mmol , 1 eq.) In 3.5 ml of DMF under a nitrogen atmosphere was added NaH (60% in mineral oil, 23 mg, 0.58 mmol, 1.1 eq.). After 30 min of reaction, iodomethane (0.05 ml, 0.8 mmol, 1.5 eq.) Was added and the reaction was allowed to proceed for 12 hours. After treatment and column chromatography, methyl- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide of benzofuran-2 acid was obtained. carboxylic acid (83 mg) with a yield of 41%. ? E NMR (400 MHz, Benzene-de) d ppm 1.3 (s, 12H) 3.4 (s, 3H) 6.9 (d, J = 0.8 Hz, 1H) 7.0 (m, 4H) 7.2 (m, 2H) 8.1 ( d, J = 8.3 Hz, 2H). Step 3: The Suzuki coupling of methyl- [4- (4,4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl] -amide of benzofuran-2-carboxylic acid with D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid tert-butyl ester was made according to Example 38, Step 3, to give tert-butyl ester of D-2- acid. { 4 '- [(benzofuran-2-carbonyl) -methyl-amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric with a yield of 77%. XR NMR (400 MHz, CD3OD) d ppm 0.8 (m, 6H) 1.1 (s, 9H) 1.9 (m, 1H) 3.4 (s, 3H) 3.5 (d, J = 5.8 Hz, 1H) 6.6 (s, 1H ) 7.1 (m, 1H) 7.2 (m, 2H) 7.3 (d, J = 8.8 Hz, 2H) 7.4 (d, J = 7.8 Hz, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (d, J = 8.6 Hz, 2H) 7.8 (m, 2H). Step 4: The removal of the t-butylester was carried out according to Example 1, Step 3, in quantitative yield. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6H) 1.9 (m, 1H) 3.5 (dd, J = 9.3, 6.1 Hz, 1H) 5.1 (s, 2H) 7.1 (d, J = 8.8 Hz, 2H) 7.5 (m, 1H) 7.6 (d, J = 7.6 Hz, 1H) 7.7 (d, J = 8.8 Hz, 2H) 7.8 (s, 4H) 7.9 (dd, J = 7.8, 1.3 Hz, 1H) 8. 0 (d, J = 9.3 Hz, 1H). Example 76: 4-. { 5- [(benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonyl-L-valine Step 1: 4-Bromo-benzenesulfonyl-L-valine-t-butyl ester, prepared from L-valine-t-butyl ester and 4-bromobenzenesulfonyl chloride was dissolved according to the procedure of Example 38, Step 1 (10.2 mmol), in DMSO (40 mL). PdCl2 (dppf) (0.51 mmol), KOAc (30.6 mmol), bis (pinacolato) diboro (13.3 mmol), and dppf (0.51 mmol) were added to the solution. The reaction mixture was degassed and stirred overnight at 75 ° C. The mixture was diluted with EtOAc and washed with brine (3x). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to yield 1.57 g of [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) benzenesulfonyl] -L-valine- ester. t-butyl. Step 2: The ester from Step 1 (0.45 mmol) was dissolved in 1,4-dioxane (2 mL). They were added to the solution Pd (PPh3) 4 (0.022 mmol), K3P04 (0.90 mmol), and 2-bromo-5-nitro-pyridine (0.48 mmol). After degassing, the mixture was stirred at 80 ° C for 16 hours. The mixture was diluted with ethyl acetate and washed with brine (3x). The organic layer was separated and dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by flash chromatography to yield 4- (5-nitro-pyridin-2-yl) -benzenesulfonyl] -L-valine-t-butyl ester in 56% yield. Steps 3-6: The nitro group of the product was reduced to the amino group using the procedure of Example 2, Step 4. The resulting product was acylated with benzofuran-2-carbonyl chloride using the same procedure as for N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1-biphenyl-4-yl.} Sulfonyl to give 4- {5- [(benzofuran-2-carbonyl) ester ) -amino] -pyridin-2-yl.} - benzenesulfonyl-L-valine-t-butyl The tere-butyl group was removed using the procedure of Example 1, Step 3, to give 4-. [(benzofuran-2-carbonyl) -amino] -pyridin-2-yl.} - benzenesulfonyl-L-valine EMCL MH + (m / z) 494. a H NMR (300 MHz, CDCl 3 / CD 3 OD) d 9.0 ppm ( d, 1H, J = 2.5 Hz), 8.45 ppm (dd, 1H,., = 8.6 Hz, J2 = 2.6 Hz), 8.08-7.93 ppm (dm, 4H), 7.85 ppm (d, 1H, J = 9.0 Hz ), 7.77-7.62 ppm (m, 3H), 7.54-7.48 ppm (, 1H), 7.39-7.33 ppm (m, 1H), 4.43 ppm (s, 1H), 3.75 ppm (d, 1H, J = 5.2 Hz ), 2.17 ppm (m, 1H), 1.01 ppm (d, 3H, J = 6.0 Hz), 0.92 ppm (d, 3H, J = 6.0 Hz).

Example 77: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' bifenyl-4-yl.} Sulfonyl) -N-methyl-D-valine Stage 1: At 0.117 g of D-valine in 2.5 ml of dioxane and 2.5 ml of water, cooled in an ice bath, 0.31 g of 4'-nitro-1, 1'-biphenyl-4- chloride was added. sulfonyl, followed by 0.4 ml of triethylamine. The reaction was then stirred at room temperature overnight. After concentrating the reaction mixture in vacuo, the residue was extracted with ethyl acetate and IN HCl. The organic layer was washed with water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give 0.35 g of N- [(4'-nitro-1,1'-biphenyl-4-yl) sulfonyl] -D -valina in the form of a solid. Performance 74.5%. p.f. 165-167 ° C; EM 377.0 (M-H) " Step 2: A 0.25 g of N- [(4'-nitro-1,1 '-biphenyl-4-yl) sulfonyl} -D-valine and 0.40 g of potassium carbonate were added 0.16 ml of iodomethane and the reaction was stirred overnight. After concentrating the reaction mixture in vacuo, the residue was extracted with dichloromethane and washed with water. The organic layer was washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo to give provide 0.27 g of methyl N-methyl-N- [(4 '-nitro-1, 1' -biphenyl-4-yl) sulfonyl] -D-valinate. Performance -100%. p.f. 117-118 ° C; MS 406 (M ~). Step 3: To 0.22 g of N-methyl-N- [(4'-nitro-1, 1'-biphenyl-4-yl) sulfonyl] -D-valinate methyl in 8 ml of ethyl acetate, was added 1.21 g of tin (II) chloride dihydrate and the reaction was stirred at room temperature overnight. About 8 ml of 2N sodium carbonate was added to the reaction to adjust the pH to ~8-9. The reaction was then filtered through celite. The filtrate was washed with water and brine, dried over Na 2 SO 4, filtered and concentrated to provide 0.19 g of methyl N-methyl-N- [(4'-amino-1, 1'-biphenyl-4-yl) sulfonyl] -D-valinate in the form of an oil. 95% yield. MS: 377.2 (M + H) +. Step 4: A 0.11 g of N- [(4'-amino-1, 1'-biphenyl-4-yl) sulfonyl] -N-methyl-D-valinate methyl in 4 ml of dichloromethane cooled in an ice bath , 0.058 g of 2-benzofurancarbonyl chloride was added thereto, and N, N-diisopropylethylamine (0.15 ml) was added dropwise. The reaction was stirred at room temperature overnight and then diluted with dichloromethane. The organic layer was washed with water, 5% HCl and brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography, eluting with hexane: ethyl acetate (2: 1) to give 0.13 g of N - ( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1- biphenyl-4-il} sulfonyl) -N-methyl-D-valinate methyl. Yield 86.6%, p.f. 67-69 ° C; MS 521.3 (M + H) +. Step 5: A 0.13 g of N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) -N-methyl-D methylvalue in 12 ml of ethyl acetate was added 0.67 g of lithium iodide and the mixture was heated to reflux overnight. The reaction was diluted with ethyl acetate and IN HCl. The organic layer was washed with water, sodium thiosulfate solution, water and brine, dried over Na 2 SO, filtered and concentrated to provide 0.099 g of N- (. {4 '- [(1-benzofuran-2-ylcarbonyl)). amino] -1,1 '-biphenyl-4-yl.}. sulfonyl) -N-methyl-D-valine. Yield 77.9%. p.f. 239-241 ° C. EM 505.1 (M-H) ".

Example 78: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -N-methyl-L-valine According to the same general method as Example 77, 0.2 g of L-valine methyl ester hydrochloride gave 0.13 g of N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1 '-biphenyl-4-yl.}. Sulfonyl) -N-methyl-L- Valina Yield 77.6%. p.f. 237-239 ° C. MS 505.0 (M-H). "Example 79: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' biphenyl-4-yl.} Sulfonyl) -N-methylglycine According to the same general method of Example 77, 0.14 g of sarcosine methyl ester hydrochloride provided 0.1 g of N- (. {4 '"- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl.} sulfonyl) -N-methylglycine. p.f. 226-228 ° C; EM 463.1 (M-H) ".

Example 80: (S) -2- acid. { 4 '- [(1,3-dimethyl-lH-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: The coupling of 1,3-dimethyl-lH-thieno [2,3-c] pyrazole-5-carboxylic acid (commercially available) with L-2- (4'-amino-biphenyl) 4- methyl ester sulfonylamino) -3-methyl-butyric acid was carried out according to Example 21, Step 3. Methyl ester of (S) -2- acid was obtained . { 4 '- [(1,3-dimethyl-lH-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid with a yield of 75%.

Step 2: The hydrolysis of methyl ester of (S) -2- acid. { 4 '- [(1,3-dimethyl-lH-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure of Example 20, Step 5, produced (S) -2- acid. { 4 '- [(1,3-dimethyl-1 H -thieno [2, 3-c. Pyrazole-5-carbonyl] -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. MS: calculated for (M + H) +: 527.64; found 527.21.

Example 81: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl}. Sulfonyl) -N- (pyridin-3-yl- methyl) -L-valine In accordance with the general procedure of Example 77, starting with L-valine and alkylating with 3-picolyl chloride hydrochloride in Step 2. N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) was obtained. ) amino] -1, 1 '-biphenyl-4-yl.}. sulfonyl) -N- (pyridin-3-yl-methyl) -L-valine. p.f. 261-262 ° C; EM 584.2 (M + H) +.

Example 82: N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -N- (2-morpholin-4) il-ethyl) -L-valine In accordance with the general procedure of Example 77, starting with L-valine and alkylating with 4- (2-chloroethyl) -morpholine hydrochloride in Step 2. N- (. {4 '- [(1-benzofuran -2-ylcarbonyl) amino] -1, V -biphenyl-4-yl.}. Sulfonyl) -N- (2-morpholin-4-yl-ethyl) -L-valine. p.f. 181-185 ° C; MS 606.3 (M + H) +.

Example 83: N- [(4 '-. {[[(3-methyl-l-benzofuran-2-yl) carbonyl] amino]} -1,1'-biphenyl-4-yl) sulfonyl] -L- valina In accordance with the general procedure of the Example 2A, from L-valine methyl ester and acylating L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester with 3-methyl-benzofuran-2-carbonyl chloride in Step 5, N- [(4 '-. {[[(3-methyl-1-benzofuran-2-yl) carbonyl] amino]} -! 1' -biphenyl-4-yl) sulfonyl] was obtained. -L-valina. p.f. 264-266 ° C; EM 505.2 (M-H) ".

Example 84: N- [(4 '-. {[[(5-bromo-l-benzofuran-2-yl) carbonyl] amino) -1,1' -biphenyl-4-yl) sulfonyl] -L-valine In accordance with the general procedure of Example 2A, starting with L-valine methyl ester and acylating L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester with 5-bromobenzofuran chloride -2-carbonyl in Step 5, N- [(4 '-. {[[(5-bromo-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4 was obtained -yl) sulfonyl] -L-valine. p.f. 263-265 ° C; EM 569.0 (M-H) ~.

Example 85: N- [(4 '- { [(4-methyl-3,4,5,6-tetrahydrofuro (4,3,2-ef] [3] benzazepin-2-yl) carbonyl] amino} -l, 1 '-biphenyl-4-yl) sulfonyl] -L-valine In accordance with the general procedure of Example 2A, starting with L-valine methyl ester and acylating methyl ester of L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid with 3,4,5,6,6-tetrahydro-4-methylfuro [4, 3, 2-ef] [] chloride 3] benzazepine-2-carbonyl in Step 5, N- [(4'- { [(4-methyl-3,4,5,6-tetrahydrofuro [4,3,2-ef]] [3] was obtained. ] benzazepin-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl} -L-valina. p.f. > 300 ° C; EM 562.3 (M + H) +.

Example 86: N- [(4 '-. {[[(5-ethyl-4-methoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino] -1,1'-biphenyl -4-yl) sulfonyl] -L-valine Step 1: To a solution of 2.0 g (11.1 mmol) of 2,6-dihydroxy-3-ethyl-acetophenone in 21 ml of acetone was added 2.45 g (17.8 mmol) of potassium carbonate and 1.35 ml. (12.2 mmol) of ethyl bromoacetate. The resulting mixture was heated to reflux for 3.5 hours and then cooled to room temperature and filtered. The filtrate was diluted with water, acidified with IN HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:10), to provide 2.1 g of (2-acetyl-4- ethyl-3-hydroxyphenoxy) -acetic acid ethyl acetate. Step 2: To a solution of 1.92 g (7.22 mmol) of ethyl (2-acetyl-4-ethyl-3-hydroxyphenoxy) -acetate in 35 ml of absolute ethanol was added 0.54 g (7.94 mmol) of sodium ethoxide. The reaction was refluxed for 3 hours and then cooled to room temperature, acidified with 1N HCl, and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1: 9), to give 0.9 g of ethyl 3-methyl-4-hydroxy-5-ethylbenzofuran-2-carboxylate. Step 3: To a solution of 0.25 g (1.01 mmol) of ethyl 3-methyl-4-hydroxy-5-ethylbenzofuran-2-carboxylate in 3.0 ml of DMF was added 0.417 g (3 eq.) Of potassium carbonate and 0.63 ml (10 eq.) Of iodomethane and the reaction was stirred at room temperature for 14 hours. The reaction was then diluted with ether and water. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:10), to give 0.24 g of ethyl 3-methyl-4-methoxy-5-ethylbenzofuran-2-carboxylate.

Step 4: To a solution of 0.22 g (0.82 mmol) of ethyl 2-methyl-3-methoxy-4-ethylbenzofuran-2-carboxylate in 4.1 ml of methanol and 4.1 ml of THF was added 4.1 ml of hydroxide solution. sodium The reaction was stirred for 12 hours at room temperature and then acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 0.201 g of 3-methyl-4-methoxy-5-ethylbenzofuran-2-carboxylic acid. Step 5: To 0.094 g of 3-methyl-4-methoxy-5-ethylbenzofuran-2-carboxylic acid, 0.27 g of benzotriazole-1-yloxytri (pyrrolidinphosphonium) hexafluorophosphate and 0.145 g of L-2- methyl ester (4 '-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric (Example 2A, Step 4), in 1.5 ml of DMF, cooled in an ice bath, N, N-diisopropylethylamine was added and the resulting mixture was stirred at 0 ° C for 5 minutes. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was extracted with dichloromethane and water. The organic layer was washed with water and brine, dried over Na 2 SO 4, filtered, concentrated in vacuo and purified by column chromatography, eluting with hexane: ethyl acetate (3: 2), to give 0.17 g of N- [(4 '- { [(5-ethyl-4-methoxy-3-methyl-l-benzofuran-2- il) carbonyl] amino} methyl-1, 1 '-biphenyl-4-yl) sulfonyl] -L-valinate. Performance 73.9%. p.f. 170-172 ° C; MS 579.3 (M + H) +. Step 6: According to the procedure of Example 2A, Step 6. 0.16 g of N- [(4 '- { [(5-ethyl-4-methoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino! -! -! 1'-biphenyl-4-yl) sulfonyl] -L-valinate gave 0.11 g of N- [(4'-. {[[(5-ethyl-4-methoxy)] 3-methyl-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine. Performance 70.5%. p.f .: 225-228 ° C; EM 565.3 (M + H) +.

Example 87: N- [(4 '- { [(4-ethyl-3-methyl-l-benzofuran-2-yl) carbonyl] amino) -1,1' -biphenyl-4-yl) sulfonyl] - L-Valine Step 1: To a solution of 2.48 g (7.05 mmol) of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (Example 20. Step 2) in 30 ml of DMF was added 2.16 ml (7.40 mmol). ) of tributyltin vinyl, 0.898 g (21.1 mmol) of lithium chloride and 0.247 g, (0.352 mmol) of tetrakis (triphenylphosphine) palladium (0). The reaction was heated at 90 ° C for 3 hours and then cooled to room temperature. The reaction was diluted with water and extracted with ether. The combined organic layers they were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:25) to provide 1.22 g of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester. Step 2: To a solution of 0.40 g (1.74 mmol) of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester in 25 ml of ethyl acetate under a nitrogen atmosphere was added 0.050 g of 10% palladium. on carbon. The reaction was stirred in a Parr hydrogenator at 40 psi (275.71 kPa) of hydrogen for 4 hours. The reaction was then filtered through a pad of celite. The celite was washed with an additional 150 ml of ethyl acetate and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:30) to provide 0.395 g of 3-methyl-4-ethylbenzofuran-2-carboxylic acid ethyl ester. Stage 3: To a solution of 0.380 g (1.64 mmol) of 3-methyl-4-ethylbenzofuran-2-carboxylic acid ethyl ester in 8 ml of methanol and 8 ml of THF was added 8.2 ml of IN sodium hydroxide solution and the reaction mixture was stirred for 14 hours at room temperature and then acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 0.321 g of 3-methyl-4-methylbenzofuran-2-carboxylic acid. Step 4: According to the procedure of Example 86, Step 5, 0.082 g of 3-methyl-4-ethylbenzofuran-2-carboxylic acid and 0.15 g of acid methyl ester L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric gave 0.19 g of N- [(4'- { [(4-ethyl-3-methyl-1-benzofuran- 2-yl) carbonyl.] Amino.} - l, 1'-biphenyl-4-yl) sulfonyl] -L-valinate. Yield 86.3%. p.f. 183-185 ° C; EM 549.2 (M + H) +. Step 5: According to the procedure of Example 2A, Step 6, 0.16 g of N- [(4'-. {[[(4-ethyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino] -1, 1'-biphenyl -4-yl) sulfonyl] -L-valinate afforded 0.075 g of N- [(4'-. {[[(4-ethyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]. -! 1'-bifenyl-4-yl) sulfonyl] -L-valine. Performance 48.1%. mp: 239-241 ° C; MS 535.3 (M + H) +.

Example 88: N- [(4 '- { [(5-ethyl-4-isopropoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} -1, 1'-biphenyl-4 -il) sulfonyl] -L-valine Stage 1: According to the procedure of Example 86, Step 3, 0.200 g (0.81 mmol) of 3-methyl-4-hydroxy-5-ethylbenzofuran-2-carboxylic acid ethyl ester (Example 86, Step 2) and 0.379 ml (4.03 mmol) of 2-bromopropane gave 0.211 g of 5-ethyl-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester after chromatography on silica gel, eluting with ethyl acetate / hexanes (1:20). Step 2: According to the procedure of Example 86, Step 4, 0.170 g (0.586 mmol) of 5-ethyl-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester gave 0.142 g of 5-ethyl acid -4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid, purified by washing with hexanes. Step 3: According to the procedure of Example 86, Step 5, 0.052 g (0.2 mmol) of 5-ethyl-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid and 0.073 g of methyl ester of L-2 acid - (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric yielded 0.11 g of N- [(4 '- { [(5-ethyl-4-isopropoxy-3-methyl-1-benzofuran -2-yl) carbonyl] amino.} - l, 1'-biphenyl-4-yl) sulfonyl] -L-valinate. Performance 89.3%. p.f. 182-184 ° C; MS 607.3 (M + H) +. Step 4: According to the procedure of Example 2A, Step 6, 0.055 g of N- [(4 '-. {[[(5-ethyl-4-isopropoxy-3-methyl-1-benzofuran-2-yl)] carbonyl] amino.} -!, methyl 1 '-biphenyl-4-yl) sulfonyl] -L-valinate gave 0.053 g of N- [(4' -. {[[(5-ethyl-4-isopropoxy) 3-methyl-1-benzofuran-2-yl) carbonyl] amino.} -!, 1 '-biphenyl-4-yl) sulfonyl] -L-valine. Performance -100%. p.f. 159-162 ° C; EM 591.3 (M-H) ".

Example 89: N-. { [4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-1-benzofuran-2-yl] carbonyl) amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valina Step 1: According to the procedure of Example 86, Step 3, 0.250 g (1.01 mmol) of 3-methyl-4-hydroxy-5-ethylbenzofuran-2-carboxylic acid ethyl ester (Example 86, Step 2) and 0.599 ml (5.04 mmol) of benzyl bromide gave 0.341 g of 5-ethyl-4-benzyloxy-3-methylbenzofuran-2-carboxylic acid ethyl ester after chromatography on silica gel, eluting with ethyl acetate / hexanes (1:20). Step 2: According to the procedure of Example 86, Step 4, 0.307 g (0.908 mmol) of 5-ethyl-4-benzyloxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester gave 0.219 g of 5-ethyl acid -4-benzyloxy-3-methyl-benzofuran-2-carboxylic acid, purified by washing with hexanes. Step 3: According to the procedure of Example 86, Step 5, 0.155 g (0.5 mmol) of 5-ethyl-4-benzyloxy-3-methyl-benzofuran-2-carboxylic acid and 0.18 g of methyl ester of L-2 acid - (4 '-amino-biphenyl-4-sulfonylamino) - 3-methyl-butyric provided 0.21 g of N-. { [4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1, 1-biphenyl-4-yl] sulfonyl } -L-Valinate Methyl. Performance 63.6%. p.f. 191-193 ° C; EM 655.2 (M + H) +. Stage 4: In accordance with the procedure of Example 2A, Step 6, 0.06 g of N-. { [4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl} sulfonyl} -L-Valinate methyl provided 0.054 g of N- [. { 4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valina. Yield 86%. p.f. 224-226 ° C; MS 639.2 (M-H).

Example 90: N- [(4 '-. {[[(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino] -1, 1'-biphenyl -4-yl) sulfonyl] -L-valine Stage 1: At 0.1 g (0.15 mmol) of N-. { [4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1, 1' -biphenyl-4-yl] sulfonyl } -L-Valinate Methyl from Example 89, dissolved in 20 ml of methanol and 10 ml of THF, was added 0.2 g of 10% palladium on active carbon and the mixture was hydrogenated in a Parr hydrogenator at 40 psi (275.71 kPa ) During 4 hours. The reaction mixture was filtered then through celite and the celite was washed with methanol. The filtrate was concentrated in vacuo to provide 0.11 g of N- [(4'-. {[[(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino]. 1, 1 '-biphenyl-4-yl) sulfonyl} -L-Valinate Methyl. Performance -100%. p.f. 75-80 ° C; EM 565.2 (M + H) +. Step 2: According to the procedure of Example 2A, Step 6, 0.098 g of N-. { (4 '- { [(5-Ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl}. Amino.} -!, 1' -biphenyl-4-yl) sulfonyl ] -L-Valinate Methyl afforded 0.054 g of N- [(4 '-. {[[(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl} amino]. .--, 1 '-biphenyl-4-i1) sulfonyl} -L-valina. Yield 56.8%. p.f. 122-125 ° C; EM 549.2 (M-H) ".

Example 91: N-. { [4 '- ( { [4- (2,2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-valina Step 1: To a solution of 0.146 g (1.25 mmol) of N-methylmorpholine N-oxide in 1 ml of THF and 3 ml of water were added 0.272 ml of osmium tetroxide (2.5% by weight in t-butanol, 0.022 mmol) followed by 0.250 g (0.087 mmol) of ethyl ester of the 3-vinylbenzofuran-2-carboxylic acid (Example 87, Step 1) dissolved in 1 ml of THF. The reaction was stirred for 2 hours at room temperature and then rapidly cooled with an excess of aqueous sodium hydrosulfite solution. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1: 1), to provide 0.202 g of 4- (1, 2-dihydroxyethyl) -3-methyl-benzofuran-2-ethyl ester. -carboxylic Step 2: To a solution of 0.150 g (0.568 mmol) of 4- (1-ethyl ester, 2-dihydroxyethyl) -3-methylbenzofuran-2-carboxylic acid dissolved in 5 ml of acetone was added 0.010 g of p-toluenesulfonic acid and the reaction was stirred at room temperature overnight. Saturated sodium bicarbonate was added and the acetone was removed in vacuo. The residue was extracted with ether, the organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1: 5) to give 0.172 g of 4- (2, 2-d-J-methyl-l, 3-dioxolan-4-yl) ethyl ester) 3-methyl-benzofuran-2-carboxylic acid. Step 3: According to the procedure of Example 86, Step 4, 0.172 g (0.566 mmol) of 4- (2,2-dimethyl-1,3-dioxolan-4-yl) -3-methylbenzofuran-2-ethyl ester -carboxylic acid provided 0.147 g of 4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-benzofuran-2- acid carboxylic acid in the form of a white solid after purification by washing with ether / hexanes (1: 1). Step 4: According to the procedure of Example 86, Step 5, 0.116 g (0.41 mmol) of 4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-benzofuran-2 acid. -carboxylic acid and 0.18 g of acid methyl ester L-2- (4'-amino-bifenyl-4-sulfonylamino) -3-methyl-butyric gave 0.18 g of N-. { [4'- ( { [4- (2,2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-Valinate Methyl. Performance 89.4%. p.f. 192-194 ° C; EM 619.3 (M-H). "Stage 5: In accordance with the procedure of Example 2A, Step 6, 0.157 g of N-. { [4 '- ( { [4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-bif enyl-4-yl] sulf onyl} -L-Valinate methyl provided 0.084 g of N-. { . { 4 '- ( { [4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-bif enyl-4-yl] sulf onyl} -L-valina. Yield 54.9%. p.f. 240 ° C (d); MS: 605.2 (MH). "Example 92: N- { [4 '- ( { [4- (hydroxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) - 1,1 '-biphenyl-4-yl] sulf onyl.}. -L-valine Step 1: To a solution of 0.250 g (1.087 mmol) of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester (Example 87, Step 1) in 7.5 ml of dioxane and 2.5 ml of water were added 0.272 ml of 2.5% by weight osmium tetroxide in t-butanol (0.022 mmol) and the reaction was stirred for 10 minutes at room temperature , turning yellowish brown. Sodium periodate (0.488 g, 2282 mmol) was added in several portions over 30 minutes and a white precipitate formed. The reaction was stirred at room temperature for 2 hours and then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:10) to provide 0.225 g of 4-carbonyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester.

Step 2: To a solution of 0.123 g (0.530 mmol) of 4-carbonyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester in 10 ml of ethanol was added 0.019 g (0.505 mmol) of sodium borohydride. The reaction was stirred at room temperature for 2 hours and then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1: 3) to give 0.113 g of 4-hydroxymethyl-3-methyl-benzofran-2-carboxylic acid ethyl ester.

Step 3: To a solution of 0.220 g (0.940 mmol) of 4-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester in 5 ml of DMF was added 0.156 g (1034 mmol) of t-butyldimethylsilyl chloride. and 0.160 g (2350 mmol) of imidazole, and the reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ether. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:10) to provide 0.315 g of 4-tert-butyl (dimethyl) silyloxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester. Step 4: According to the procedure of Example 86, Step 4, 0.277 g (0.796 mmol) of 4-tert-butyl (dimethyl) silyloxymethyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester afforded 0.054 g of acid 4 -tert-butyl (dimethyl) silyloxymethyl-3-methyl-benzofuran-2-carboxylic acid after chromatography on silica gel, eluting with ethyl acetate / hexanes (1: 3). Stage 5: According to the procedure of Example 86, Step 5, 0.115 g of 4- (. {[[Tert-Butyl (dimethyl) silyl] oxy} methyl] -3-methyl-1-benzofuran-2-carboxylic acid and 0.13 g of acid methyl ester L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric gave 0.20 g of N-. { [4 '- ( { [4- ( { [Tert-Butyl (dimethyl) silyl] oxy} methyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) - 1,1 '-biphenyl-4-yl] sulfonyl} -L-Valinate Methyl. Performance 84.5%. p.f. 204-206 ° C; EM 663.4 (M-H) ".

Stage 6: In accordance with the procedure of Example 2A, Step 6, 0.18 g of N-. { [4 '- ( { [4- ( { [Tert -Butyl (dimethyl) silyl] oxy} methyl] -3-methyl-1-benzofuran-2-yl} carbonyl} amino ) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-Valinate methyl provided 0.13 g of N-. { [4 '- ( { [4- (hydroxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valina. Performance 73.3%. p.f. 272 ° C (d); MS: 535.12 (MH). "Example 93: N- [(4 '- { [(3,4-dimethyl-l-benzofuran-2-yl) carbonyl] amino.} -1, 1'-biphenyl -4-yl) sulfonyl] -L-valine Step 1: To a solution of 0.200 g (0.855 mmol) of 4-hydroxymethyl-3-methyl-benzofuran-2-ethyl ester carboxylic acid (Example 92, Step 2) in 5 ml of THF was added 0.336 g (1.28 mmol) of trifluorophosphine and 0.355 g (1.07 mmol) of carbon tetrabromide. The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was diluted with 20 ml of ether and filtered. The filtrate was concentrated in vacuo and chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:10) to give 0.196 g of 4-bromomethyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester.

Step 2: To a solution of 0.291 g (0.98 mmol) of 4-bromomethyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester in 5 ml of DMSO was added 0.074 g (1.96 mmol) of sodium borohydride and stirred the reaction at room temperature for 2 hours. The reaction was diluted with water and extracted with ether. The organic layers were washed with water and brine, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexanes (1:10), to provide 0.209 g of 4-methyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.

Step 3: According to the procedure of Example 86, Step 4, 0.206 g (0.95 mmol) of 4-methyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester gave 0.175 g of 4-methyl-3-methyl acid -benzofuran-2-carboxylic acid.

Step 4: According to the procedure of Example 86, Step 5, 0.067 g of 4-methyl-3-methyl-benzofuran-2-carboxylic acid and 0.13 g of L-2- (4'-amino-biphenyl) methyl ester 4-sulfonylamino) -3-methyl-butyric gave 0.14 g of N- [(4 '-. {[[(3,4-dimethyl-1-benzofuran-2-yl) carbonyl] amino]. 1 '-biphenyl-4-yl) sulfonyl} -L-Valinate Methyl. Yield 53.8%. p.f. 199-200 ° C; MS 535.1 (M + H) +.

Step 5: According to the procedure of Example 2A, Step 6, 0.12 g of N- [(4 '-. {[[(3,4-dimethyl-l-benzofuran-2-yl) carbonyl] amino]. -! 1 '-biphenyl-4-yl) sulfonyl} Methyl-L-valinate gave 0.12 g of N- [(4 '-. {[[(3,4-dimethyl-l-benzofuran-2-yl) carbonyl] amino] -! 1'-biphenyl- 4-yl) sulfonyl] -L-valine. Performance -100%. p.f. 250-252 ° C; MS 519.2 (MH). "Example 94: N- [(4 '- { [(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} -1 -1' - biphenyl- -il) sulfonyl] -L-valine Step 1: To a solution of 2.061 g (5.86 mmol) of 3-methyl-4-trifluoromethanesulfonyloxy- ethyl ester benzofuran-2-carboxylic acid (Example 20, Step 2) in 26 ml of DMF was added 3. 0 ml butyl vinyl ether, 1.6 ml triethylamine, 0. 077 g of palladium acetate and 0. 139 g of 1. 3-bis (difenilf osf ino) propane. The resulting mixture was heated at 60 ° C for 24 hours and then cooled to room temperature. The mixture was diluted with water and extracted with ether. The organic layers were washed with water and brine, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel, eluting with ethyl acetate / hexanes (1: 10), to give a mixture of 4-acetyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester and - ethyl (1-butoxy vinyl) -3-methyl-l-benzofuran-2-carboxylate. The mixture was dissolved in 12.9 ml of acetic acid and 8.6 ml of 3N HCl and stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with ether. The organic layers were washed with water and brine, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel, eluting with ethyl acetate / hexanes (1: 20) to provide 1. 16 g of 4-acetyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester.

Step 2: According to the procedure of Example 86, Step 4, 0.200 g of 4-acetyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester gave 0.165 g of 4-acetyl-3-methyl-benzofuran-2 acid. -carboxylic Step 3: According to the procedure of Example 86, Step 5, 0.165 g of 4-acetyl-3-methyl-1-benzofuran-2-carboxylic acid and 0.27 g of methyl ester of L-2- (4'-amino) acid -biphenyl-4-sulfonylamino) -3-methyl-butyric gave 0.20 g of N- [(4 '-. {[[(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]. methyl-1, 1 '-biphenyl-4-yl) sulfonyl] -L-valinate. Performance 47.6%. p.f. 197-199 ° C; MS 535.1 (M + H) +. Step 4: According to the procedure of Example 2A, Step 6, 0.23 g of N- [(4 '- { [(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino. .! -!, Methyl 1 '-biphenyl-4-yl) sulfonyl] -L-valinate gave 0.11 g of N - [(4'-. {[[(4-acetyl-3-methyl-1-benzofuran- 2-yl) carbonyl] amino.} - l, 1 '-biphenyl-4-yl) sulfonyl} -L-valina. Yield 50.1%. p.f. 228-235 ° C; EM 547.2 (M-H). Example 95: N-. { [4 '- ( { [4- (1-hydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valina Step 1: To a solution of 0.05 g of N - [(4'-. {[[(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino] -! '-biphenyl-4-yl) sulfonyl] -L-valine, the product of Example 94, Step 3, in 18 ml of ethanol was added 0.01 g of sodium borohydride and the reaction was stirred at room temperature. environment for 2 hours. The reaction was quenched with IN HCl, adjusting to -pH 3. The reaction mixture was concentrated in vacuo and then the residue was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to provide 0.037 g of N-. { [4 '- ( { [4- (1-hydroxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-11] sulfonyl} -L-valina. Performance 74%. p.f. 148 ° C (d); EM 549.1 (M-H) ".

Example 96: N- [(4 '-. {[[(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino]} -1,1' -biphenyl-4-yl) sulfonyl ] -L-valina Step 1: According to the procedure of Example 86, Step 4, 0.300 g (1304 mmol) of 3-methyl-4-vinyl-benzofuran-2-carboxylic acid ethyl ester (Example 87, Step 1) gave 0.256 g of acid 3-Methyl-4-vinyl-benzofuran-2-carboxylic acid after chromatography on silica gel, eluting with ethyl acetate / hexanes (1: 3).

Stage 2: According to the procedure of Example 86, Step 5, 0.081 g of 3-methyl-4-vinyl-benzofuran-2-carboxylic acid and 0.15 g of methyl ester of acid L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric gave 0.18 g of N- [(4 '- { [(3-methyl-4-vinyl-1-benzofuran- 2-yl) carbonyl] amino.} - l, 1 '-biphenyl-4-yl) sulfonyl] -L-valinate. Performance 82%. p.f. 185 ° C (d); MS 547.3 (M + H) +.

Step 3: According to the procedure of Example 2A, Step 6. 0.16 g of N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl]. methyl amino.} -1,1 '-biphenyl-4-yl) sulfonyl] -L-valinate afforded 0.065 g of N - [(4'- { [(3-methyl-4-vinyl-l- benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine. Yield 42%. p.f. 285 ° C (d); EM 531.2 (MH). "Example 97: N- { [4 '- ( { [4- (1,2-Dihydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl. amino) -1,1 '-biphenyl-4-yl] sulfonyl.}. -L-valine Step 1: To a solution of N-methyl-morpholine N-oxide (50 wt% solution in water, 0.103 g, 0.44 mmol) in THF and water (1 ml / 0.3 ml) was added 0.096 ml. (0.38 mmol) of osmium tetroxide (2.5% by weight in t-butanol). To the solution, 0.21 g was quickly added (0.38 mmol) of N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1'-bifenyl-4- il) sulfonyl] -L-valinate (Example 96, Step 2). The reaction was stirred at room temperature for 2 hours and then rapidly quenched with an excess of sodium hydrosulfite in water. The reaction mixture was extracted with ethyl acetate and water.

The organic layer was washed with water and brine, dried over Na 2 SO 4, filtered and concentrated to give 0.19 g of N- [. { 4 '- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl}. Amino) -l, 1-biphenyl-4-yl] sulfonyl } -L-Valinate Methyl.

Yield 85.2%. p.f. 90-95 ° C; EM 581.2 (M + H) +. Step 2: According to the procedure of Example 2A, Step 6, 0.18 g of N-. { [4 '- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl) sulfonyl ] -L-Valinate from methyl provided 0.11 g of N-. { [4'- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1,1 '-biphenyl-4-yl] sulfonyl } -L-valina. Performance 61.9%. p.f. 165 ° C (d); EM 565.3 (M-H) ".

Example 98: N-methyl-N- [(4 '-. {[[(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino]} -1, 1'-bifenyl- 4-yl) sulfonyl] -L-valine Step 1: To a solution of 0.077 g (0.14 mmol) of the product of Example 96, Step 2, N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1'-biphenyl -4-yl) sulfonyl] -L-valinate, in 1 ml of DMF, 0 was added. 05 g of potassium carbonate, followed by 0. 018 ml of iodomethane. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to provide 0.1 g of N-methyl-N- [(4 '-. {[[(3-methyl-4-vinyl-l- benzofuran-2-yl) carbonyl] amino.} - l, l '-biphenyl-4-yl) sulfonyl] -L-valinate.

Performance 63.4%. EM 561 (M + H) +. Step 2: According to the procedure of Example 2A, Step 6, 0.05 g of N-methyl-N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.}. -1. 1'-bifenyl-4-yl) sulfonyl] -L-valinate afforded 0.033 g of N-methyl-N- [(4 '-. {[[(3-methyl)] -4-vinyl-l-benzofuran-2-yl) carbonyl] amino.} -1, 1 '-bifinyl-4-yl) sulfonyl] -L-valine. EM 547.2 (M + H) +.

Example 99: N-. { [4 '- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1? -bif enyl-4-yl] sulfonyl} -N-methyl-L-valine Step 1: According to the procedure of Example 97, Step 1, 0.14 g (0.25 mmol) of N-methyl-N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.} -! , 1 '-biphenyl-4-yl) sulfonyl] -L-valinate were oxidized to give 0.09 g of N-. { [4 '- ( { [4- (1,2-dihydroxyethyl) -3-methyl-l-benzofuran- ^ 2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl} -N-methyl-L-valinate methyl. Yield 60.8%. p.f. 182-185 ° C; MS 595.3 (M + H) +. Step 2: According to the procedure of Example 2A, Step 6, 0.07 g of N-. { [4 '- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl } Methyl-N-methyl-L-valinate gave 0.049 g of N-. { [4 '- ( { [4- (1,2-Dihydroxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl } -N-methyl-L-valine. Performance 71.9%. p.f. 222-225 ° C; EM 579.1 (M-H). " Example 100: N-. { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valina Step 1: To a solution of 0.19 g (0.81 mmol) of ethyl 4- (hydroxymethyl) -3-methyl-1-benzofuran-2-carboxylate (Example 92, Step 2) in 2 ml of chloroform was added sodium oxide. silver (II) (0.34 g, 1. 46 mmol, 1.8 eq.) and 2 ml of iodomethane and the Mix in sealed tube at -55 ° C for 4.5 days. The reaction was filtered and concentrated in vacuo to provide 0.20 g of ethyl 4- (methoxymethyl) -3-methyl-l-benzofuran-2-carboxylate. Yield -93.8% p.f. 45-47 ° C; MS 249.1 (M + H) +. Step 2: According to the procedure of Example 86, Step 4, 0.21 g (0.85 mmol) of ethyl 4- (methoxymethyl) -3-methyl-1-benzofuran-2-carboxylate afforded 0.18 g of 4- (methoxymethyl) acid ) -3-methyl-l-benzofuran-2-carboxylic acid. 100% performance p.f. 164-166 ° C; EM 219.0 (M-H) ".

Stage 3: According to the procedure of Example 86, Step 5, 0.066 g (0.3 mmol) of 4- (methoxymethyl) -3-methyl-1-benzofuran-2-carboxylic acid and 0.109 g (0.3 mmol) of N-. { (Methyl 4 '-amino-1, 1' -bifenil-4-yl) sulfonyl] -L-valinate, after purification by column chromatography, eluting with hexane / ethyl acetate (1: 1), gave 0.12. g of N-. { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -bif enii-4-yl] sulfonyl} - L-Valinate Methyl. Yield 71.0% p.f. 144-146 ° C; EM 565.3 (M + H) +.

Step 4: According to the procedure of Example 2A, Step 6, 0.09 g of N-. { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-Valinate methyl provided 0.076 g of N-. { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl} sulfonyl} -L-valina. Yield 86.3% p.f. 227-230 ° C; MS 551.2 (MH). "Example 101: N- { [4 '- ( { [4- (1-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1 '-biphenyl-4-yl] sulfonyl.}. -L-valine Stage 1: According to the procedure of Example 92, Step 2, 1065 g (4.33 mmol) of 4-acetyl-3-methylbenzofuran-2-carboxylic acid ethyl ester (Example 94. Step 1) afforded 0.75 g of 4- (1-hydroxyethyl) -3-methyl- ethyl l-benzofuran-2-carboxylate. Stage 2: According to the procedure of Example 100, Step 1, 0.21 g of 4- (1-hydroxyethyl) -3-methyl-1-benzofuran-2-carboxylic acid ethyl ester, after heating with iodomethane for 8 days, gave 0.22 g of 4- (1-methoxyethyl) Ethyl) -3-methyl-l-benzofuran-2-carboxylate. Yield -100% p.f. 67-69 ° C; EM 263.2 (M + H) +. Step 3: According to the procedure of Example 86. Step 4, 0.17 g of ethyl 4- (1-methoxyethyl) -3-methyl-l-benzofuran-2-carboxylate afforded 0.15 g of 4- (1-methoxyethyl) ) -3-methyl-l-benzofuran-2-carboxylic acid. 100% yield p.f. 113-115 ° C; EM 233.1 (M-H) ".

Step 4: According to the procedure of Example 86, Step 5, 0.09 g (0.4 mmol) of 4- (l-methoxyethyl) -3-methyl-1-benzofuran-2-carboxylic acid and 0.15 g (0.4 mmol) of N- [(4'-amino-1, 1'-biphenyl-4-yl) sulfonyl] -L-valinate, after purification by column chromatography, eluting with hexane / ethyl acetate (1: 1), gave 0.19. g of N-. { [4 '- ( { [4- (1-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-Valinate Methyl. Yield 82.6% p.f. 186-188 ° C; MS 579.3 (M + H) +. Stage 5: According to the procedure of Example 2A, Step 6, 0.16 g of N-. { [4 '- ( { [4- (1-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl) sulfonyl} -L-Valinate methyl provided 0.12 g of N-. { [4 '- ( { [4- (1-methoxyethyl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1,1' -bifenii-4-yl] sulfonyl} -L-valina. Yield 76.9% p.f. 97 ° C (d); MS: 563.3 (M-H). " Example 102: N-. { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valinato Step 1: To a solution of 0.35 g (1.5 mmol) of 3-methyl-4-vinyl-benzofuran-2-carboxylate (Example 87, Step 1) in 3 ml of THF, cooled in an ice bath, was added 1 ml (1 mmol) of borane-THF complex (1.0 M solution in THF). . The reaction was stirred at room temperature for 2 hours. The reaction was cooled in an ice bath and 1.5 ml of water was added. Then 0.61 g of sodium percarbonate was added in one portion. The reaction was heated at -50 ° C for 1 hour and then cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane / ethyl acetate (2: 1), to provide 0.20 g of ethyl 4- (2-hydroxyethyl) -3-methyl-l-benzofuran-2-carboxylate . Yield 54% p.f. 88-90 ° C; MS 249.1 (M + H) +. Step 2: According to the procedure of Example 100, Step 1, 0.16 g (0.65 mmol) of ethyl 4- (2-hydroxyethyl) -3-methyl-1-benzofuran-2-carboxylate were heated to -55 ° C. for 7 days to provide 0.17 g of ethyl 4- (2-methoxyethyl) -3-methyl-l-benzofuran-2-carboxylate. Yield -100%; MS: 263.1 (M + H) +. Step 3: According to the procedure of Example 86, Step 4, 0.16 g of ethyl 4- (2-methoxyethyl) -3-methyl-l-benzofuran-2-carboxylate afforded 0.14 g of 4- (2-methoxyethyl) ) -3-methyl-l-benzofuran-2-carboxylic acid. 100% performance; p.f. 138-140 ° C; MS: 233.1 (M-H). Step 4: According to the procedure of Example 86, Step 5, 0.13 g (0.56 mmol) of 4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-carboxylic acid and 0.20 g (0.56 mmol) of N- [(4'-amino-1, 1'-biphenyl-4-yl) sulfonyl] -L-valinate, after purification by column chromatography, eluting with hexane / ethyl acetate (1: 1), gave 0.21. g of N-. { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-Valinate Methyl. Yield 66% p.f. 67-70 ° C; MS: 579.1 (M + H) +. Step 5: According to the procedure of Example 2A, Step 6, 0.16 g of N-. { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino] -1,1' -biphenyl-4-yl] sulfonyl} -L-Valinate methyl, provided 0.144 g of N-. { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino] -1,1' -biphenyl-4-yl] sulfonyl} -L-valina. Yield 93%; p.f. 100-110 ° C; MS: 563.2 (M-H). " Example 103: N- [(4 '-. {[[(4-isopropoxy-l-benzofuran-2-yl) carbonyl] amino]} -1,1'-biphenyl-4-yl) sulfonyl] -L- valina Step 1: To a solution of 0.41 g (2.13 mmol) of methyl ester of 4-hydroxy-2-benzofurancarboxylic acid in 7 ml of DMF was added 0.80 ml (8.54 mmol) of 2-bromopropane and 1.18 g (8.54 mmol) of potassium carbonate. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.49 g of methyl 4-isopropoxy-l-benzofuran-2-carboxylate. Yield -100%; p.f. 43-45 ° C; MS: 235.1 (M + H) +. Step 2: At 0.15 g (0.62 mmol) of 4-isopropoxy-1-benzofuran-2-carboxylate in 2.5 ml of methanol and 2.5 ml of THF was added 3 ml of 1 N sodium hydroxide solution. The solution was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo, the residue diluted with water and neutralized with 1 N HCl to pH -3-4, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.13 g of 4-isopropoxy-1-benzofuran-2-carboxylic acid. Yield 94%; p.f. 148-150 ° C; MS: 219.1 (MH). "Step 3: According to the procedure of Example 86, Step 5, 0.11 g (0.5 mmol) of 4-isopropoxy-1-benzofuran-2-carboxylic acid and 0.18 g (0.5 mmol) of N - [(4'-amino-1,1'-biphenyl-4-yl) sulfonyl] -L-valinate, after purification by column chromatography, eluting with hexane / ethyl acetate (1: 1), afforded 0.14 g of N- [(4 '-. {[[(4-isopropoxy-1-benzofuran-2-yl) carbonyl] amino] .) - methyl 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valinate. Yield 52%; p.f. 226-229 ° C; MS: 563.3 (MH). "Step 4: According to the procedure of Example 2A, Step 6, 0.14 g of N- [(4 '- { [(4-isopropoxy-1-benzofuran-2-yl)] carbonyl] amino.}., 1'-biphenyl-4-yl) sulfonyl] -L-valinate afforded 0.07 g of N - [(4'-. {[[(4-isopropoxy-1-benzofuran- 2-yl) carbonyl] amino.} -!, 1 '-biphenyl-4-yl) sulfonyl] -L-valine Yield 50%, mp 132 ° C (d); MS: 549.2 (MH) ".

Example 104: N- [(4 '-. {[[(5-methoxy-l-benzofuran-2-yl) carbonyl] amino]} -1,1'-biphenyl-4-yl) sulfonyl] -L- valina Step 1: According to the procedure of Example 86, Step 5, 0.24 g (0.6 mmol) of 5-methoxy-2-benzofurancarboxylic acid and 0.44 g (0.6 mmol) of N- [(4'-amino-1, 1 '-biphenyl-4-yl) sulfonyl] -L-valinate, after purification by column chromatography, eluting with hexane / ethyl acetate (1: 1), afforded 0.33 g of N- [(4 '-. {[[(5-methoxy-1-benzofuran-2-yl) carbonyl] amino.} -1-1' methyl-biphenyl-4-yl) sulfonyl] -L-valinate. Yield 53%; p.f. 234-235 ° C; MS: 537.3 (M + H) +.

Step 2: According to the procedure of Example 2A, Step 6, 0.31 g of N- [(4 '-. {[[' (5-methoxy-1-benzofuran-2-yl) carbonyl] amino]. methyl l, 1'-biphenyl-4-yl) sulfonyl] -L-valinate afforded 0.17 g of N - [(4'-. {[[(5-methoxy-1-benzofuran-2-yl) carbonyl] amino] ., .l, 1'-biphenyl-4-yl) sulfonyl] -L-valine. Yield 53%; p.f. 257-259 ° C; MS: 521.2 (M-H). " Example 105: (S) -2- acid. { 4 '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -bif nil-4-sulfonylamino} -3-methyl-butyric Step 1: 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with iodomethane (0.5 ml), K2CO3 (200 mg) and 2 ml DMF. The mixture was stirred Room temperature during the night. The mixture was mixed with brine and extracted with ethyl acetate and the combined ethyl acetate layers were washed with brine. Upon removal of the solvent gave the crude product which was purified by column chromatography to give 162 mg (76% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester in the form of a color oil amber Step 2: To 150 mg of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester dissolved in 1 ml of THF was added 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20) . The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried in vacuo to give 120 mg (91% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.

Step 3: To 110 mg (0.53 mmol) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 ml of oxalyl chloride, the resulting mixture was heated at reflux for 4 hours in the presence of a catalytic amount. of DMF, and then the excess oxalyl chloride was removed in vacuo.

The residue was dissolved in 2 ml of dichloromethane and added to a mixture of 232 mg (0.64 mmol) of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester. and 2 ml of pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. All solvents were removed under vacuum. Column chromatography on silica gel gave 95 mg (33% yield) of methyl ester of (S) -2- acid. { 4 '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid.

Step 4: To a solution of 80 mg of methyl ester of (S) -2- acid. { 4 '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric dissolved in 1 ml of THF was added 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo and triturated with acetonitrile to give 63 mg (81% yield) of (S) -2- acid. { 4 '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric, obtained as a white solid. 1 H NMR (400 MHz, DMS0-d 6) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 5.8 Hz, 1H) 3.9 (s, 3H) 6. 9 (d, J = 8.1 Hz, 1H) 7.2 (d, 3 = 1.8 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H) 12.6 (s, 1H). Example 106: (S) -2- acid. { 4 '- [(4-Ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with ethyl iodide (0.5 ml), K2C03 (200 mg) and 2 ml of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removing the solvent in vacuo gave the crude product, which was purified by column chromatography to give 175 mg (77% yield) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester in the form of a Solid white. Step 2: To a solution of 160 mg of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester dissolved in 1 ml of THF was added 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 130 mg (92% yield) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid. Step 3: A solution of 115 mg (0.46 mmol) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid in 2 ml of oxalyl chloride was refluxed for 4 hours in the presence of a catalytic amount of DMF, then excess oxalyl chloride was removed in vacuo. The residue was dissolved in 2 ml of dichloromethane and added to a mixture of 201 mg (0.56 mmol) of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester. and 2 ml of pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. Then all the solvents were removed under vacuum. Column chromatography on silica gel gave 237 mg (93% yield) of (S) -2- methyl ester. { 4 '- [(4-Ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. Step 4: To 100 mg of methyl ester of (S) -2- acid. { 4 '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric dissolved in 1 ml of THF are they added 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo and triturated with acetonitrile to give 89 mg (91% yield) of (S) -2- acid. { 4 '- [(4-Ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. "" "H NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.6 Hz, 6H) 1.4 (t, J = 6.9 Hz, 3H) 2.0 (m, 1H) 2.7 (s, 3H ) 3.6 (m, 1H) 4.2 (c, J = 6.9 Hz, 2H) 6.8 (d, J = 8.3 Hz, 1H) 7.2 (d, J = 8.3 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H ) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 10.5 (s, 1H) 12.6 (s, 1 HOUR) .

Example 107: (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-propoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with iodopropane (0.5 ml), K2CO3 (200 mg) and 2 ml DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. On removal of the solvent gave the crude product, which was purified by column chromatography to give 176 mg of 3-methyl-4-propoxy-benzofuran-2-carboxylic acid ethyl ester as a white solid. Step 2: To a solution of 160 mg of 4-propoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester dissolved in 1 ml of THF was added 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 mi H20). The atmosphere was stirred at night. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 124 mg (87% yield) of 4-propoxy-3-methyl-benzofuran-2-carboxylic acid obtained as a white solid. Step 3: A solution of 110 mg (0.47 mmol) of 4-propoxy-3-methyl-benzofuran-2-carboxylic acid in 4 ml of oxalyl chloride was refluxed for 4 hours in the presence of a catalytic amount of DMF. Then the excess oxalyl chloride was removed in vacuo. It dissolved The residue in 2 ml of dichloromethane was added to a mixture of 204 mg (0.56 mmol) of (S) -2- (4 '-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester and my pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. All solvents were removed under vacuum. Column chromatography on silica gel yielded 152 mg (57% yield) of methyl ester of (S) -2- acid. { 4'-. { (3-methyl-4-propoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. Step 4: To 100 mg of methyl ester of (S) -2- acid. { '- [(4-ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric dissolved in 1 ml of THF was added 3 ml of LiOH solution (3.6 g LiOH / 50 ml 15 MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried to give 84 mg (86% yield) of 20. (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-propoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric, obtained in the form of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 1.1 (t, 3 = 1.3 Hz, 3H) 1.8 (m, 2H) 2.0 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.1, 6.1 Hz, 1H) 4.1 5 (t, J = 6.2 Hz, 2H) 6.8 (d, J = 8.1 Hz, 1H) 7.2 (d, J = 8.1 Hz , 1 HOUR) 7. 4 (t, J = 8.2 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J9.3 Hz, 1H) 10.5 (s, 1H) 12.6 (s, 1H). Example 108: (S) -2- acid. { 4 '- [(4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3- ethyl-butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (200 mg, 0.8 mmol) in 4 ml of DMF were added 2-bromopropane (0.5 ml) and K2CO3 (200 mg) . The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Upon removal of the solvent gave 176 mg of 3-methyl-4-isopropoxy-benzofuran-2-carboxylic acid tert-butyl ester in the form of colorless crystals. Step 2: To 220 mg of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 3 ml of TFA / dichloromethane (1: 1). The solution was stirred at room temperature for 3 hours. The vacuum solvents and triturated the residue with acetonitrile. Filtration of the precipitate gave 210 mg of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid. Step 3: To 200 mg (0.91 mmol) of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid in 4 ml of DMF were added 329 mg (1 eq.) Of methyl ester of (S) -2- ( 4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid, 482 mg (1.2 eq.) Of BOP and 0.19 ml of N, N-diisopropylethylamine. The mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 395 mg (69% yield) of methyl ester of (S) -2- acid. { 4 '- [(4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid in the form of a colorless oil. Step 4: To 370 mg of methyl ester of (S) -2- acid. { 4 '- [(4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric dissolved in 2 ml of THF was added 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 6 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The acidity solution and filtered the resulting suspension. The solid product was dried in vacuo to give 286 mg of (S) -2- acid. { 4'- [(4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric, obtained as a white solid. 1 H NMR (400 MHz, DMS0-d 6) d ppm 0.8 (dd, J = 13.5, 6.7 Hz, 6H) 1.4 (d, J = 6.1 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.5 ( t, J = 7.2 Hz, 1H) 4.8 (m, 1H) 6.9 (d, J = 8.6 Hz, 1H) 7.2 (d, J = 8.6 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H) 7.8 ( d, J = 8.8 Hz, 2H) 7.8 (m, 4H) 8.0 (m, 3H) 10.5 (s, 1H).

Example 109: (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (100 mg, 0.4 mmol) were added N, N-diisopropylethylamine (130 mg, 1 mmol) and 2 mL of dichloromethane. The solution was cooled to < -10 ° C. Trifluoromethanesulfonic anhydride (0.1 ml, 0.6 mmol) was added dropwise. The reaction mixture was stirred at -10 ° C for 2 hours and then poured into water. The mixture was extracted with dichloromethane and the combined organic layers were washed with water and dried over sodium sulfate. On removal of the solvent gave 145 mg (95% yield) of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester. Step 2: 3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester (85 mg, 0.25 mmol) was mixed with K2CO (68 mg, 0.5 mmol), phenylboronic acid (31 mg, 0.25 mmol), Pd (Ph3) 4 (14 mg, 0.01 mmol), 1 ml of 1,2-dimethoxyethane and 2 drops of water. The solution was heated and stirred in an oil bath at 85 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Filtration followed by removing the solvent in va cuo gave the crude product (71 mg), which was purified by column chromatography to give 53 mg (77% yield) of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butylester as a white solid. Step 3: 3-Methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butylester was dissolved in 2 ml of TFA / dichloromethane (1: 1). The solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo and the residue was triturated with ether. Filtration gave 66 mg of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid as a white solid. Step 4: To 60 mg (0.24 mmol) of 3-methyl-4- acid phenyl-benzofuran-2-carboxylic acid was added 1 ml of oxalyl chloride and the mixture was refluxed for 1 hour in the presence of a catalytic amount of DMF, then the excess of oxalyl chloride was removed in vacuo. The residue was dissolved in 1 ml of dichloromethane and added to a mixture of 129 mg (0.36 mmol) of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester. , 87 mg (0.714 mmol) of 4- (dimethylamino) pyridine and 2 ml of in an ice / water bath. The mixture was stirred at room temperature overnight. All solvents were removed under vacuum.

Column chromatography on silica gel gave 41 mg (29% yield) of (S) -3-methyl-2-methyl ester. { 4 '- [(3-methyl-4-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. Step 5: To 38 mg of methyl ester of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric dissolved in 0.5 ml of THF were added 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 12 mg of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-phenyl-benzofuran-2-carbonyl) -amino] - biphenyl-4-sulfonylamino} -butyric, obtained in the form of a light brown solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 13.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.2 (s, 3H) 3.5 (m, 1H) 7.2 (dd, J = 7.3 , 1.0 Hz, 1H) 7.5 (m, 5H) 7.6 (dd, J = 8.3, 7.3 Hz, 1H) 7.7 (dd, J = 8.3, 1.0 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.8 (, 4 H) 8.0 (m, 3H) 10.6 (s, 1H).

Example 110: (S) -3-Methyl-2- (4 '- { [3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carbonyl] -amino} -bif nil -4-sulfonylamino) -butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (100 mg, 0.4 mmol) were added N, N-diisopropylethylamine (130 mg, 1 mmol) and 2 mL of dichloromethane. The solution was cooled to < -10 ° C. Trifluoromethanesulfonic anhydride (0.1 ml, 0.6 mmol) was added dropwise. The reaction mixture was stirred at -10 ° C for 2 hours and then poured into water. The mixture was extracted with dichloromethane and the combined organic layers were washed with water and dried over sodium sulfate. Upon removal of the solvent gave 145 mg (95% yield) of tert-butylester of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid. Step 2: 3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester (380 mg, 1 mmol) was mixed with K2CO3 (280 mg, 2 mmol), 3-nitro-phenylboronic acid (334 mg, 2 mmol), Pd (Ph3) 4 (115 mg, 0.1 mmol), 4 ml of 1,2-dimethoxyethane and 5 drops of water. The mixture was heated and stirred in an oil bath at 85 ° C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. On removal of the solvent gave the crude product, which was purified by column chromatography to give 310 mg (88% yield) of 3-methyl-4- (3-nitro-phenyl) -benzofuran-2-tert-butylester -carboxylic, obtained in the form of a white solid. Step 3: To 300 mg of 3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFA / dichloromethane (1: 1). The solution was stirred at room temperature for 5 hours. The solvents were removed in vacuo and the residue triturated with ether. Filtration gave 232 mg (92% yield) of 3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carboxylic acid as a white solid. Step 4: To 100 mg (0.34 mmol) of 3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carboxylic acid was added 2 ml of oxalyl chloride and the resulting mixture was refluxed for 2 hours in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed in vacuo. The residue was dissolved in 1 ml of dichloromethane and added to a mixture of 183 mg (0.5 mmol) of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester. and 2 ml of pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. All solvents were removed under vacuum. Column chromatography on silica gel gave 41 mg of (S) -3-methyl-2- (4 '- { [3-methyl-4- (3-nitro-phenyl) -benzofuran-2-methyl ester) carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric in the form of a white solid. Step 5: A 41 mg of (S) -3-methyl-2- (4 '- { [3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carbonyl] -amino methyl ester. .}. - biphenyl-4-sulfonylamino) -butyric dissolved in 0.5 ml of THF were added 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 29 mg of (S) -3-methyl-2- (4 '- { [3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carbonyl) acid. .}. -amino.}. -biphenyl-4-sulfonylamino.} - butyric, obtained in the of a light brown solid. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 1.9 (m, 1H) 2.2 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.3 (dd, J = 7.3, 0.8 Hz, 1H) 7.6 (dd, J = 8.3, 7.3 Hz, 1H) 7.8 (m, 8H) 8.0 (d, J = 8.8 Hz, 3H) 8.1 (d, J = 9.3 Hz, 1H) 8.3 (t, J = 1.9 Hz, 1H) 8.3 (m, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 111: (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (100 mg, 0.4 mmol) were added N, N-diisopropylethylamine (130 mg, 1 mmol) and 2 mL of dichloromethane. The solution was cooled to < -10 ° C. Trifluoromethanesulfonic anhydride (0.1 ml, 0.6 mmol) was added dropwise. The reaction mixture was stirred at -10 ° C for 2 hours and then poured into water. The mixture was extracted with dichloromethane and the combined organic layers were washed with water and dried over sodium sulfate. When removing the solvent gave 145 mg (95% yield) of tert-butylester of acid 3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid. Step 2: 3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester (285 mg, 0.75 mmol) in 3 ml of 1,2-dimethoxyethane was added K2C03 (363 mg, 3.5 eq.), Pyridine-3-boronic acid (138 mg, 1.13 mmol), Pd (Ph3) (43 mg, 0.05 eq.) And 0.5 ml of water. The mixture was heated and stirred in an oil bath at 85 ° C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography to give 202 mg of 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid tert-butylester in the form of a Solid white. Step 3: To 185 mg of 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFN / dichloromethane (1: 1). The solution was stirred at room temperature for 5 hours. The solvents were removed in vacuo and the residue was triturated with ether. Filtration gave 136 mg of desired 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid as a white solid. Step 4: A 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid (123 mg, 0.49 mmol) in 4 mL of DMF was added (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (352 mg, 0.97 mmol), BOP (429 mg, 0.97 mmol) and N, N-diisopropylethylamine ( 0.17 ml, 0.97 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 115 mg of (S) -3-methyl-2-methyl ester. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran ~ 2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric, obtained in the form of a white solid. Step 5: To 100 mg of methyl ester of (S) -3-methyl-2- acid. { 4' -. { (3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric were dissolved in 1 ml of THF, 3 ml of LiOH solution (3.6 g L1OH / 50 ml MeOH / 50 ml H20) was added. The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The pH of the solution was adjusted to 7 and filtered the resulting suspension. The solid product was dried in vacuo to give 75 mg of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric, obtained in the form of a white solid. 1 H NMR (400 MHz, DMS0-d 6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.2 (s, 3H) 3.6 (dd, J = 9.3 Hz, 1H) 7.3 (dd, J = 7.3, 1.0 Hz, 1H) 7.5 (m, 1H) 7.6 (dd, J = 8.3, 7.6 Hz, 1H) 7.8 (m, 3H) 7.9 (m, 4H ) 7.9 (m, 1H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 8.7 (m, 2H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 112: (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (100 mg, 0.4 mmol) were added N, N-diisopropylethylamine (130 mg, 1 mmol) and 2 mL of dichloromethane. The solution was cooled to < -10 ° C. Trifluoromethanesulfonic anhydride (0.1 ml, 0.6 mmol) was added dropwise. The reaction mixture was stirred at -10 ° C for 2 hours and then poured into water. The mixture was extracted with dichloromethane and the combined organic solution was washed with water and dried over sodium sulfate. On removal of the solvent gave 145 mg (95% yield) of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester.

Step 2: 3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester (258 mg, 0.68 mmol) was mixed with K2CO3 (207 mg, 2.2 eq.), Pyridine-4-boronic acid (110 mg , 1.3 eq.), Pd (Ph3) 4 (43 mg, 0.05 eq.), 3 ml of 1,2-dimethoxyethane and 0.5 ml of water. The mixture was heated and stirred in an oil bath at 85 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. On removal of the solvent gave the crude product, which was purified by column chromatography to give 156 mg of 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid tert-butylester, obtained in the form of a Solid white. Step 3: To 141 mg of 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFA / dichloromethane (1: 1). The solution was stirred at room temperature for 5 hours. The solvents were removed in vacuo and the residue triturated with ether. Filtration gave 98 mg of 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid as a white solid.

Step 4: To 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid (88 mg, 0.35 mmol) in 4 ml of DMF were added methyl ester of (S) -2- (4'-amino) -bifenil-4- sulfonylamino) -3-methyl-butyric acid (252 mg, 0.7 mmol) ,. BOP (307 mg, 0.7 mmol) and N, N-diisopropylethylamine (0.12 mL, 0.7 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 172 mg of (S) -3-methyl-2-methyl ester. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric, obtained in the form of a white solid.

Step 5: To 160 mg of methyl ester of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The pH of the solution was adjusted to 7 and filtered the resulting suspension. The solid product was dried in vacuo to give 132 mg of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric obtained in the form of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 21.5, 6.8 Hz, 6H) 2.0 (m, 1H) 2.2 (s, 3H) 3.4 (s, 1H) 7. 3 (dd, J = 7.3, 1.0 Hz, 1H) 7.5 (m, 2H) 7.6 (dd, J = 8.3, 7.3 Hz, 1H) 7.8 (m, 5H) 7.9 (m, 2H) 8.0 (d, J = 8.8 Hz, 2H) 8.7 (m, 2H) 10.6 (s, 1H). Example 113: (S) -2- acid. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (100 mg, 0.4 mmol) were added N, N-diisopropylethylamine (130 mg, 1 mmol) and 2 mL of dichloromethane. The solution was cooled to < -10 ° C. Trifluoromethanesulfonic anhydride (0.1 ml, 0.6 mmol) was added dropwise. The reaction mixture was stirred at -10 ° C for 2 hours and then poured into water. The mixture was extracted with dichloromethane and the combined organic layers were washed with water and dried over sodium sulfate. On removal of the solvent gave 145 mg (95% yield) of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester.

Step 2: 3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester was mixed (285 mg, 0.75 mmol) with K2C03 (207 mg, 2.2 eq.), Furan-3-boronic acid (101 mg, 1.2 eq.), Pd (Ph3) 4 (43 mg, 0.05 eq.), 3 ml. 1, 2-dimethoxyethane and 0.5 ml of water. The mixture was heated and stirred in an oil bath at 85 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removing the solvent in vacuo gave the crude product, which was purified by column chromatography to give 153 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid tert-butylester, obtained as of a white solid.

Step 3: To 174 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFA / dichloromethane (1: 1). The solution was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was triturated with ether. Filtration gave 124 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid as a white solid.

Step 4: 4-Furan-3-yl-3-methyl-benzofuran-2-carboxylic acid (114 mg, 0.47 mmol) was added with (S) -2- (4 '-amino-biphenyl-4-methyl ester. sulfonylamino) -3-methyl-butyric acid (170 mg, 0.47 mmol), BOP (249 mg, 1.2 eq.), N, N-diisopropylethylamine (0.1 ml, 1.2 eq.) And 4 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Upon removal of the solvent gave the crude product, which was purified by column chromatography on silica gel to give 258 mg of methyl ester of (S) -2- acid. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -bifenil-4-sulfonylamino} -3-methyl-butyric, obtained as a white solid.

Step 5: A 240 mg of methyl ester of (S) -2- acid. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 2 ml of THF and 4 ml of LiOH solution (3.6 g LiOH / 50 ml MeO H / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified to pH 2 and filtered the resulting suspension. The solid product was dried in vacuo to give 171 mg of (S) -2- acid. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric, obtained as a white solid. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 13.1, 6.8 Hz, 6H) 2.4 (s, 3H) 3.5 (m, 1H) 6.8 (dd, J = 1.9, 0.9 Hz, 1H) 7.2 (dd, J = 7.3, 1.0 Hz, 1H) 7.5 (dd, 3 = 1.6 Hz, 1H) 7.7 (dd, J = 8.5, 0.9 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.8 ( m, 4H) 7.9 (m, 2H) 7.9 (dd, J = 1.5, 0.8 Hz, 1H) 8.0 (m, 3H) 10.6 (s, 1H) 12.6 (s, 1H). Example 114: (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (100 mg, 0.4 mmol) were added N, N-diisopropylethylamine (130 mg, 1 mmol) and 2 mL of dichloromethane. The solution was cooled to < -10 ° C. Trifluoromethanesulfonic anhydride (0.1 ml, 0. 6 mmol). The reaction mixture was stirred at -10 ° C for 2 hours and then poured into water. The mixture was extracted with dichloromethane and the combined organic layers were washed with water and dried over sodium sulfate. Upon removal of the solvent gave 145 mg (95% yield) of tert-butylester of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid.

Step 2: To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butylester (190 mg, 0.5 mmol) were added K3P04 (159 mg, 0.75 mmol), morpholine (52 mg, 0.6 mmol), Pd (OAc) 2 (10 mg) and 4 ml of dioxane. The mixture was heated and stirred in an oil bath at 86 ° C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removing the solvent in vacuo gave the crude product, which was purified by column chromatography to give 96 mg of 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid tert-butylester, obtained as of a white solid.

Step 3: To 140 mg of 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFA / dichloromethane (1: 1). The solution was stirred at room temperature for 5 hours. The solvents were removed in vacuo and the residue was triturated with ether. Filtration gave 107 mg of 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid as a white solid.

Step 4: 3-Methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid (97 mg, 0.37 mmol) was added with (S) -2- (4'-amino-bifenyl-4-methyl ester. -sulfonylamino) -3-methyl-butyric acid (268 mg, 0.74 mmol), BOP (327 mg, 0.74 mmol), N, N-diisopropylethylamine (0.13 ml, 0. 74 mmol) and 4 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The solution combined organic was washed with brine and water. Removing the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 184 mg of (S) -3-methyl-2-methyl ester. { 4 '- [(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric, obtained in the form of a whitish solid.

Step 5: To 160 mg of methyl ester of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric were added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried in vacuo to give 150 mg of (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric, obtained in the form of a whitish solid. aH NMR (400 MHz, DMSO-d5) d ppm 0.8 (dd, J = 14.1, 6.8 Hz, 6H) 2.0 (dd, J = 12.1, 6.8 Hz, 1H) 2.8 (s, 3H) 3.0 (m, 4H) 3.5 (m, 1H) 3.8 (m, 4H) 7.0 (d, 3 = 1. 8 Hz, 1H) 7.4 (d, J = 8.3 Hz, 1H) 7.4 (m, 1H) 7.8 (d, J = 8.6 Hz , 2H) 7.8 (m, 4H) 8.0 (d, J = 9.1 Hz, 3H) 10.5 (s, 1H).

Example 115: acid (S) -2-. { 4 '- [(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: A 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.5 g, 2.27 mmol) was added with 5 ml of carbon tetrachloride and the mixture was cooled in an ethanol / ice bath, while added 1 equivalent of N-chlorosuccinimide in small portions. After stirring at -10 ° C for 3 hours, the reaction mixture was filtered, charged the filtrate onto a silica column and subjected to chromatography to give 259 mg (48% yield) of 5-chloro-5-ethyl ester 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid in the form of an off-white solid. Step 2: To 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (110 mg) were added 2 ml of isopropyl bromide, 150 mg of K2C03 and 4 ml of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined layers of ethyl acetate were washed with brine.

Upon removal of the solvent in vacuo, he gave 134 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a colorless, dense oil (100% yield). Step 3: To 110 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 my H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried under vacuum to give 94 mg (94% yield) of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid. Step 4: To 80 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid was added 121 mg of (S) -2- (4'-amino-biphenyl-4-tert-butylester. -sulfonylamino) -3-methyl-butyric, 159 mg of BOP, 46 mg of N, N-diisopropylethylamine and 4 ml of DMF. The mixture was stirred at room temperature for 48 hours. Brine was added to the mixture and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent and purification of the residue by column chromatography on silica gel yielded 178 mg (yield 98%) of tert-butylester of (S) -2- acid. { 4 '- [(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a colorless semi-solid.

Step 5: To 160 mg of tert-butylester of (S) -2- acid. { 4 '- [(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid 3 ml of TFA / dichloromethane (1: 1) were added and the solution was stirred at room temperature for 9 hours. When the reaction was completed, the solvents were removed in vacuo and the residue was triturated with acetonitrile. The mixture was lyophilized to yield 120 mg (77% yield) of (S) -2- acid. { 4 '- [(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 1.3 (d, J = 6.1 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.6 ( dd, J = 9.3, 6.1 Hz, 1H) 4.7 (m, 1H) 7.5 (d, J = 8.8 Hz, 1H) 7.6 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H ) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 116: (S) -2- acid. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Stage 1: A 4-hydroxy-3-methyl-ethyl ester benzofuran-2-carboxylic acid (0.5 g, 2.27 mmol) was added 5 ml of carbon tetrachloride and the mixture was cooled with an ethanol / ice bath, while 1 equivalent of N-chlorosuccinimide was added in small portions. After stirring at -10 ° C for 3 hours, the reaction mixture was filtered and the filtrate was loaded onto a silica column. Chromatography gave 259 mg (48% yield) of 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as an off-white solid. Step 2: To 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (120 mg, 0.47 mmol) was added 0.3 ml (4.7 mmol) of iodomethane, 130 mg (2 eq.) Of K2CÜ3 and 4 ml of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Upon removal of the solvent in vacuo, it gave 119 mg (94% yield) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid. Step 3: To 105 mg of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 my H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was triturated with dichloromethane and dried in vacuo to give 82 mg (87% yield) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid. Step 4: To 80 mg (0.33 mmol) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 ml of oxalyl chloride and the mixture was refluxed for 2 hours, then stirred at room temperature overnight. Excess oxalyl chloride was removed in vacuo. The residue was dissolved in 2 ml of dichloromethane and added to a mixture of 181 mg (0.5 mmol) of acid methyl ester.

(S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid and 1 ml of pyridine in an ice / water bath. The mixture was stirred at 0 ° C overnight. The reaction mixture was diluted with dichloromethane and washed with 2 N HCl and with water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography to give 168 mg (86% yield) of (S) -2- methyl ester. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. Step 5: To 100 mg of methyl ester of (S) -2- acid. { 4 '- [(5-chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 2 ml of THF and 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 3 hours. days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried in vacuo to give 60 mg (62% yield) of (5) -2- acid. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. 1 H NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (dd, J = 13.1, 6.6 Hz, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 3.9 (s, 3H) 7.5 (d, J = 8.6 Hz, 1H) 7.6 (m, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz , 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 117: (S) -2- acid. { 4 '- [(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: A 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.5 g, 2.27 mmol) was added with 5 ml of carbon tetrachloride and the mixture was cooled with an ethanol / ice bath, while added 1 equivalent of N-chlorosuccinimide in small portions. After shaking at -10 ° C for 3 hours, the reaction mixture was filtered and the filtrate was loaded onto a column of silica gel. Chromatography gave 190 mg (30% yield) of 5,7-dichloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as an off-white solid. Step 2: To 120 mg of ethyl ester of 5,7-dichloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid was added 1 ml of iodomethane, 200 mg of K2CO3 and 4 ml of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removing the solvent in vacuo gave 125 mg (99% yield) of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as an off-white solid. Step 3: To 110 mg of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH) / 50 mi H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried under vacuum to give 96 mg (96% yield) of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid, obtained as a white solid.

Step 4: To 80 mg of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 120 mg of (S) -2- (4'-amino-biphenyl) tert-butylester. 4-sulfonylamino) -3-methyl-butyric acid, 154 mg of BOP, 50 mg of N, N-diisopropylethylamine and 4 ml of DMF. The mixture was stirred at room temperature for 48 hours. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Upon removal of the solvent in vacuo and purification of the residue by column chromatography on silica gel, it gave 110 mg (yield 60%) of tert-butylester of (S) -2- acid. { 4 '~ [(5, 7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. Step 5: A 102 mg tert-butylester of (S) -2- acid. { 4 '- [(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid 3 ml of TFA / dichloromethane (1: 1) were added and the solution was stirred at room temperature for 3 hours. When the reaction was complete, the solvents were removed in vacuo and the residue was triturated with ether / chloroform. Filtration of the suspension gave 67 mg (72% yield) of acid (S) -2-. { 4 '- [(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric, obtained as a white solid. aH NMR (400 MHz, DMSO-d6) d ppm 0. 8 (dd, J = 12.4, 6.8 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 3.9 (s, 3H) 7.8 (m, 5H) 7.9 (m, 2H) 7.9 (d, J = 8.6 Hz, 2H) 8.1 (d, J = 9.6 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 118: (S) -2- acid. { 4 '- [(5-bromo-4-me oxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 200 mg (0.81 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 2 ml of carbon tetrachloride. The mixture was cooled with a water / ice bath, while 1 equivalent of N-bromosuccinimide was added in small portions.

After stirring at 0 ° C for 6 hours, the reaction mixture was filtered and the filtrate was loaded onto a column and purified by column chromatography to give 225 mg ( 85%) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a white solid. Step 2: A 220 mg (0.67 mmol) of tert-butylester of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid were added 0.42 ml (6.7 mmol) of iodomethane, 185 mg (1.34 mmol) of K2CO3 and 2 ml of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined layers of ethyl acetate were washed with brine. Upon removal of the solvent gave 230 mg (100% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a colorless oil. Stage 3: A 220 mg of tert-butyl ester of acid -bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 3 ml of TFA / dichloromethane (1: 1) and the solution was stirred at room temperature for 10 hours. When the reaction was complete, the solvents were removed in vacuo and the residue was triturated with hexane / dichloromethane. Filtration of the suspension gave 141 mg (77% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid. Step 4: To 40 mg (0.14 mmol) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 0.5 ml of oxalyl chloride and the mixture was refluxed for 2 hours, then the excess oxalyl chloride was removed in vacuo. The residue was dissolved in 0.5 ml of dichloromethane and added to a mixture of 92 mg (0.25 mmol) of (S) -2- (4'-amino-biphenyl-4) methyl ester. sulfonylamino) -3-methyl-butyric acid, 34 mg (0.28 mmol) of 4- (dimethylamino) pyridine and 1 ml of dichloromethane in an ice / water bath. The mixture was stirred at 0 ° C overnight. The mixture was diluted with dichloromethane and washed with 2 N HCl and water. Upon removal of the solvent from the organic solution it gave 20 mg (23% yield) of (S) -2- methyl ester. { 4'- [(5-Bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. Step 5: To 18 mg of methyl ester of (S) -2- acid. { 4 '~ [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 0.5 ml of THF and 0.5 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 6 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried in vacuo to give 8 mg (39% yield) of (S) -2- acid. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. XE NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.0, 5.9 Hz, 1H) 3.9 (s, 3H) 7.5 (d, J = 8.8 Hz, 1H) 7.7 (d, J = 8.8 Hz, 1H) 7.8 (d, J = 8.6 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 119: acid (R) -2-. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-me il-butyric Step 1: To 2 g (8.1 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 20 ml of carbon tetrachloride, and the mixture was cooled with a water / ice bath, while 1 equivalent of N-bromosuccinimide was added in small portions. After stirring at 0 ° C for 3 hours, the reaction mixture was filtered and the filtrate was loaded on a column and purified by column chromatography to give 1.6 g (59% yield) of 5-bromo-4-ethyl ester hydroxy-3-methyl-benzofuran-2-carboxylic acid in the form of a white solid.

Step 2: To 200 mg (0.67 mmol) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester were added 0.5 ml of iodomethane, 200 mg of K2C03 and 2 ml of DMF.

The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. ethyl. The combined layers of ethyl acetate were washed with brine. When the solvent was removed in vacuo, it gave 185 mg (88% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.

Step 3: To 170 mg of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 my H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried in vacuo to give 156 mg (100% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid, obtained as a white solid.

Step 4: To 75 mg (0.263 mmol) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 ml of oxalyl chloride and the mixture was refluxed for 2 hours in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed in vacuo. The residue was dissolved in 0.5 ml of dichloromethane and added to a mixture of 143 mg (0.39 mmol) of (R) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, 2 mi of pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. Column chromatography on silica gel gave 89 mg (54% yield) of (R) -2- methyl ester. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid.

Step 5: To 89 mg of methyl ester of (R) -2- acid. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried in vacuo and triturated with 0.5 ml of chloroform to give 49 mg (56% yield) of (R) -2- acid. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 3.9 (s, 3H) 7.7 (d, J = 8.8 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 8.3 (s, 1H) 10.6 (s, 1H) 12.6 (s, 1H).

Example 120: (S) -2- acid. { 4 '- [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 4.4 g (17.7 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 40 ml of carbon tetrachloride, the mixture was cooled with a water / ice bath, while 1 equivalent of N-iodosuccinimide was added in small portions. After stirring at 0 ° C for 3 hours, the reaction mixture was loaded onto a column and purified by column chromatography to give 2.55 g (38% yield) of 5-iodo-4-hydroxy-tert-butylester. 3-methyl-benzofuran-2-carboxylic acid in the form of a white solid. Step 2: To 748 mg (2 mmol) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 1.42 g (10 mmol) of iodomethane, 553 mg (4 mmol) of K2C03 and 10 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. To the Removal of the in vacuo solvent gave 790 mg (100% yield) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a light brown oil. Step 3: To 140 mg (0.36 mmol) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 3 mL of TFA / dichloromethane (1: 1) and the mixture was stirred. solution at room temperature for 2.5 hours. When the reaction was complete, the solvents were removed in vacuo and the residue was triturated with hexane / dichloromethane. Filtration of the suspension gave 120 mg (100% yield) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid. Step 4: To 132 mg (0.33 mmol) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 132 mg (1.1 eq.) Of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, BOP (34 mg, 1.2 eq.), N, N-diisopropylethylamine (52 mg, 1.2 eq.) And 4 ml of DMF. The mixture was stirred at room temperature for 48 hours. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2 N HCl and water. Concentration of the organic extracts in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 106 mg (47% yield) of (S) -2- methyl ester. { 4 '- [(5-iodo-4-methoxy-3- methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} - 3-methyl-butyric, obtained as an off-white solid. Step 5: To 96 mg of methyl ester of (S) -2- acid. { 4 '~ [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 0.5 ml of THF and 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H2O). The mixture was stirred at room temperature for 3 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried under vacuum to give 60 mg (63% yield) of (S) -2- acid. { 4 '- [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. 1 H NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 13.9, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.5 (m, 1H) 3.9 (s, 3H) 7.3 (d, J = 8.6 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 5H) 8.0 (d, J = 9.1 Hz, 3H) 10.6 (s, 1H).

Example 121: (S) -2- acid. { 4 '- [(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (300 mg, 1.21 mmol) were added iodomethane (0.75 ml, 10 eq.), K2CO3 (332 mg, 2.4 mmol) and 2 mi of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Upon removal of the solvent gave 312 mg (98% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of an amber oil. Step 2: To 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (310 mg, 1.18 mmol) dissolved in 9 ml of chlorobenzene was added acetyl chloride (0.3 ml, 3.6 eq.). The solution was cooled to < 0 ° C while titanium tetrachloride (0.61 ml, 4.8 eq.) Was added dropwise. The reaction mixture was stirred at 0 ° C, below for 6 hours and then heated in an oil bath at 85 ° C for 3.5 hours. The reaction mixture was poured into ice / water, and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2 N HCl and water. On removal of the solvents in vacuo gave 167 mg (57% yield) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid. Step 3: To 75 mg (0.3 mmol) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 1 ml of oxalyl chloride and the mixture was refluxed for 2.5 hours in the presence of a catalytic amount of DMF, then the excess of oxalyl chloride was removed in vacuo. The residue was dissolved in 1 ml of dichloromethane and added to a mixture of 163 mg (0.46 mmol) of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, and 2 ml of pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. All solvents were removed under vacuum. Column chromatography on silica gel gave 54 mg (31% yield) of (S) -2- methyl ester. { 4 '- [(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. Step 4: A (S) -2- acid methyl ester. { 4 '- [(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid (89 mg) was added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 2 days. The solvents were removed in vacuo and the residue was triturated with 4 mL of 2N HCl and filtered. The solid product was dried in vacuo to give 54 mg of acid (S) -2-. { '- [(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 2.9 (s, 3H) 3. 6 (dd, J = 9.3, 6.1 Hz, 1H) 4.0 (s, 3H) 7.0 (d, J = 8.8 Hz, 1H) 7.8 (m, 4H) 7.9 (m, 4H) 8.0 (d, J = 8.6 Hz , 1H) 8.1 (d, J = 9.3 Hz, 1H) 10.3 (s, 1H) 12.6 (s, 1H).

Example 122: (S) -2- (4 '- { [5- (1-Chloro-vinyl) -4-methoxy-3-methyl-benzofuran-2-carbonyl] -amino acid} -bifile -4-sulfonylamino) - 3 -methyl-butyric Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (300 mg, 1.21 mmol) were added iodomethane (0.75 ml, 10 eq.), K2CO3 (332 mg, 2.4 mmol) and 2 mi of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Upon removal of the solvent gave 312 mg (98% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of an amber oil. Step 2: To 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (310 mg, 1.18 mmol) dissolved in 9 ml of chlorobenzene was added acetyl chloride (0.3 ml, 3. 6 eq. ). The solution was cooled to < 0 ° C while titanium tetrachloride (0.61 ml, 4.8 eq.) Was added dropwise. The reaction mixture was stirred at 0 ° C, for below 6 hours and then heated in an oil bath at 85 ° C for 3.5 hours. The reaction mixture was poured into ice / water, and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2 N HCl and water. Upon removal of the solvents gave 167 mg (57% yield) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid. Step 3: To 75 mg (0.3 mmol) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 1 ml of oxalyl chloride and the mixture was refluxed for 2.6 hours-in the presence of a catalytic amount of DMF, then excess oxalyl chloride was removed in vacuo. The residue was dissolved in 1 ml of dichloromethane and added to a mixture of 163 mg (0.46 mmol) of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester, and 2 ml of pyridine in an ice / water bath. The mixture was stirred at room temperature overnight. All solvents were removed under vacuum. Column chromatography on silica gel yielded 36 mg (20% yield) of (S) -2- (4'- { [5- (1-chloro-vinyl) -4-methoxy-3-methyl ester. methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid as an off-white solid. Step 4: A (S) -2- (4 '-. {[5- (1- chloro-vinyl) -4-methoxy-3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid (29 mg) were added 0.5 ml of THF and 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 3 days. The solvents were removed in vacuo and the residue triturated with 2 mL of 2N HCl and filtered. The solid product was dried in vacuo to give 23 mg of (S) -2- (4 '- { [5- (1-chloro-vinyl) -4-methoxy-3-methyl-benzofuran-2-carbonyl acid. ] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric, obtained in the form of an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 4.0 (s, 3H) 5.9 (d, J = 2.3 Hz, 1H) 6.7 (d, J = 2.3 Hz, 1H) 7.0 (d, J-8.6 Hz, 1H) 7.7 (d, J = 8.6 Hz, 1H) 7.8 (m, 8H) 8.1 (d, 1H) 10.3 (s, 1H) 12.6 (s, 1H).

Example 123: acid (S) -2-. { 4 '- [(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-me til-bu tí rico Step 1: To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.5 g, 2.27 mmol) were added 15 ml of chlorobenzene, 0.27 g (3.4 mmol) of acetyl chloride and 0.63 ml (5.7 mmol). ) of titanium tetrachloride. The mixture was sealed in a pressure tube and the tube was placed in an oil bath at 95 ° C for 5 hourswith agitation. The reaction mixture was washed with 0.5 N HCl and extracted with ethyl acetate. Upon removal of the solvents gave the crude product, which was purified by column chromatography to give 0.33 g (59% yield) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester in the form of a white solid. Step 2: To 100 mg of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 ml of THF and 3 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 my H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 82 mg (92% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid. Step 3: To 70 mg (0.3 mmol) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 115 mg (2 eq.) Of EDCI, 109 mg (1 eq.) of (S) -2- (4 '-amino-biphenyl-4) methyl ester sulfonylamino) -3-methyl-butyric acid and 2 ml of DMF. The mixture was stirred at 65 ° C overnight. The reaction mixture was poured into brine and extracted with dichloromethane. The organic solution was washed with 2 N HCl and water. On removal of the solvents in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 20 mg (10% yield) of methyl ester of (S) -2- acid. { 4 '- [(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. Step 4: A (S) -2- acid methyl ester. { 4 '- [(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid (15 mg) was added 0.5 ml of THF and 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 4 days. The solvents were removed in vacuo and 2 ml of water was added. The aqueous solution was acidified and the resulting solid was collected by filtration to give 7 mg of (S) -2- acid. { 4 '- [(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 2.8 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.3 (d, J = 9.1 Hz, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (dd, J = 9.1, 3.8 Hz, 2H) 10.5 (s, 1H) 13.7 (s, 1 HOUR) .

Example 124: (S) -2- acid. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 4.4 g (17.7 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 40 ml of carbon tetrachloride and the mixture was cooled with a water / ice bath, while 1 equivalent of N-iodosuccinimide was added in small portions. After stirring at 0 ° C for 3 hours, the reaction mixture was loaded onto a column and purified by column chromatography to give 2.55 g (38% yield) of 5-iodo-4-hydroxy tert-butylester 3-methyl-benzofuran-2-carboxylic acid in the form of a white solid. Step 2: To 748 mg (2 mmol) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 1.42 g (10 mmol) of iodomethane, 553 mg (4 mmol) of K2C03 and 10 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. To the removing the solvent gave 790 mg (100% yield) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a light brown oil. Step 3: A 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (490 mg, 1.26 mmol) added 356 mg (3 mmol) of Zn (CN) 2, 140 mg of Pd (PPh3) 4 and 4 ml of DMF. The mixture was stirred at 90 ° C for 3 hours. After cooling to room temperature, the reaction mixture was loaded onto a column of silica gel and purified by column chromatography to give 260 mg (72% yield) of 5-cyano-4-methoxy-tert-butylester. 3-methyl-benzofuran-2-carboxylic acid, obtained in the form of a white solid. Step 4: To 150 mg of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFA / dichloromethane (1: 1) and the solution was stirred at room temperature during 3 hours. When the reaction was complete, the solvents were removed in vacuo and the residue was triturated with hexane / dichloromethane. Filtration of the suspension gave 121 mg (100% yield) of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid. Step 5: To 110 mg (0.48 mmol) of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 207 mg (1.2 eq.) Of methyl ester of (S) -2- (4 '-amino-biphenyl-4- sulfonylamino) -3-methyl-butyric, BOP (252 mg1.2 eq. ), N, N-diisopropylethylamine (74 mg, 1.2 eq.) And 4 ml of DMF. The mixture was stirred at room temperature for 48 hours. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2 N HCl and with water. Concentration of the organic extracts in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 89 mg (32% yield) of (S) -2- methyl ester. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. Step 6: To 70 mg of methyl ester of (S) -2- acid. { 4'- [(5-Cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 1.5 ml of THF and 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature for 3 days. The solvents were removed in vacuo and the residue was dissolved in 5 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 42 mg (61% yield) of (S) -2- acid. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. aH NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.5, 5.9 Hz, 1H) 4.2 (s, 3H) 7.6 (d, J = 8.6 Hz, 1H) 7.8 (m, 7H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 10.7 (s, 1H).

Example 125: (S) -2- acid. { 4 '- [(5-methyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To 1.24 g (5 mmol) of 4-hydroxy-benzofuran-2-carboxylic acid tert-butylester was added 9.5 g of magnesium methoxide / methanol solution (6-10% by weight) and 25 ml of toluene . The mixture was heated to reflux for 45 minutes. The methanol was distilled off. Then an additional 10 ml of toluene was added for further distillation, to ensure that the methanol was completely removed. 2.4 g of paraformaldehyde was added in small portions over 35 minutes. The reaction mixture was stirred at 130 ° C for another 30 minutes. The mixture was washed with 2N HCl and extracted with ethyl acetate. On removal of the solvents gave the crude product, which was purified by column chromatography to give 440 mg of 5-formyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester.

Step 2: To 5-formyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (430 mg, 1.56 mmol) was added 8 mL of THF and sodium cyanoborohydride (117 mg, 1.87 mmol) was added. ) in one portion. The solution was stirred at room temperature for 1 hour and then placed in an oil bath at 65 ° C overnight. The solvent was removed under vacuum and water was added. The mixture was extracted with ethyl acetate. On removal of the solvent gave the crude product, which was purified by column chromatography to give 70 mg of 4-hydroxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butylester in the form of a white solid . Step 3: To 80 mg of 4-hydroxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butylester was added 1 ml of iodomethane, 80 mg of K2C03 and 1 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Upon removal of the solvent gave 82 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butylester as a light yellow solid. Step 4: To 80 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butylester was added 2 ml of TFA / dichloromethane (1: 1) and the solution was stirred at room temperature for 3 hours. hours. When the After the reaction, the solvents were removed in vacuo and the residue was triturated with hexane / dichloromethane. Filtration of the suspension gave 55 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid as a light brown solid. Step 5: To 45 mg (0.2 mmol) of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid were added 124 mg (1.5 eq.) Of tert-butylester of (S) -2- (4 '-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid, BOP (106 mg, 1.2 eq.), N, N-diisopropylethylamine (31 mg, 1.2 eq.) and 2 ml of DMF. The mixture was stirred at room temperature for 24 hours. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2 N HCl and water. Removing the solvent from the organic solution gave the crude product, which was purified by column chromatography on silica gel to give 89 mg of tert-butylester of (S) -2- acid. { 4 '- [(4-methoxy-3,5-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. Stage 6: To 80 mg of tert-butyl ester of acid (S) -2-. { 4 '- [(4-methoxy-3,5-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric were added 2 ml of TFA / dichloromethane (1: 1) and the solution was stirred at room temperature for 3 hours. When the reaction was completed, the solvent was removed under vacuum and the residue with acetonitrile. Filtration of the suspension gave 64 mg of acid (S) -2-. { 4 '- [(4-methoxy-3,5-dimethyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.3 (s, 3H) 2.7 (s, 3H) 3.6 (dd, J = 9.3 , 5.8 Hz, 1H) 3.8 (s, 3H) 7.4 (m, 2H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.5 (s, 1H).

Example 126: (S) -2- acid. { 4 '- [(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-b-tyric Step 1: To 1.24 g (5 mmol) of 4-hydroxy-benzofuran-2-carboxylic acid tert-butylester was added 9.5 g of magnesium methoxide / methanol solution (6-10% by weight) and 25 ml of toluene . The mixture was heated to reflux for 45 minutes. The methanol was distilled off. Then an additional 10 ml of toluene was added for further distillation, to ensure complete removal of the methanol. Then 2.4 g of paraformaldehyde was added in small portions over 35 minutes. The reaction mixture was stirred at 130 ° C for another 30 minutes. The mixture was washed with HCl 2 N and extracted with ethyl acetate. On removal of the solvents gave the crude product, which was purified by column chromatography to give 440 mg of 5-formyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester. Step 2: To 5-formyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (430 mg, 1.56 mmol) was added 8 mL of THF, followed by sodium cyanoborohydride (117 mg, 1.87 mmol ) in one portion. The solution was stirred at room temperature for 1 hour and then placed in an oil bath at 65 ° C overnight. The solvent was removed under vacuum and water was added. The mixture was extracted with ethyl acetate. On removal of the solvent gave the crude product, which was purified by column chromatography to give 200 mg of 4-hydroxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a semi-solid of yellow color. Step 3: To 190 mg of 4-hydroxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 1 ml of iodomethane, 200 mg of K2C0 and 3 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. When the solvent was removed, it gave 200 mg of 4-methoxy-5-hydroxymethyl-3-methyl-tert-butylester. benzofuran-2-carboxylic acid in the form of a light yellow oil. Step 4: To 190 mg of 4-methoxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butylester was added 4 ml of TFA / dichloromethane (1: 1) and the solution was stirred at room temperature during 3 hours. When the reaction was completed, the solvents were removed in vacuo and the residue was triturated with acetonitrile. Filtration of the suspension gave 184 mg of 4-methoxy-3-methyl-5- (2,2,2-trifluoroacetoxymethyl) -benzofuran-2-carboxylic acid as a white solid. Step 5: To 100 mg (0.42 mmol) of 4-methoxy-3-methyl-5- (2,2,2-trifluoroacetoxymethyl) -benzofuran-2-carboxylic acid was added 256 mg (1.5 eq.) Of tert. -butyl ester of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid, BOP (185 mg, 1 eq.), N, N-diisopropylethylamine (54 mg, 1 eq) .) and 4 mi of DMF. The mixture was stirred at room temperature for 48 hours. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2 N HCl and water. Removing the solvent from the organic solution gave the crude product, which was purified by column chromatography on silica gel to give 89 mg of tert-butylester of (S) -2- acid. { 4 '- [(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a solid whitish Step 6: To 81 mg tert-butylester of (S) -2- acid. { 4 '- [(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid 2 ml of TFA / dichloromethane (1: 1) were added and the solution was stirred at room temperature for 3 hours. When the reaction was complete, the solvent was removed in vacuo and the residue was triturated with acetonitrile / water. Filtration of the suspension gave a mixture of (S) -2- (4 '- { [4-methoxy-3-methyl-5- (2, 2,2-trifluoroacetoxymethyl) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid and (S) -2- acid. { 4'-. { (5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric. To the mixture was added 1 ml of THF and 2 ml of LiOH solution (3.6 g LiOH / 50 ml MeOH / 50 ml H20). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was dissolved in 3 ml of water. The solution was acidified and filtered the resulting suspension. The solid product was dried in vacuo to give 68 mg of (S) -2- acid. { 4 '- [(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of an off-white solid. ^? NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 2.0 (m, 1H) 2.8 (s, 3H) 3.6 (dd, J = 9.1, 6.1 Hz, 1H) 3.9 (s, 3H) 4.6 (d, J = 5.3 Hz, 2H) 5.2 (t, J = 5.6 Hz, 1H) 7.5 (d, J = 8.6 Hz, 1H ) 7.6 (d, J = 8.6 Hz, 1H) 7. 8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 9.1 Hz, 2H) 8.1 (d, J = 9.1 Hz, 1H) 10.5 (s, 1H) 12.6 (s, 1H) ).

Example 127: (S) -3-methyl-2- acid. { 4 '- [(benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 2-aminophenol (437 mg, 4 mmol) was added ethyl triethoxyacetate (3.5 g, 4 eq.). The mixture was stirred at 110 ° C overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 516 mg of benzooxazole-2-carboxylic acid ethyl ester as a white solid. Step 2: To benzooxazole-2-carboxylic acid ethyl ester (437 mg, 4 mmol) was added 2 mL of THF and 4 mL of NaOH solution (2 N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid dried in vacuo to give 160 mg of benzooxazole-2-carboxylic acid saditic salt as an off-white solid. Stage 3: A benzooxazole-2-benzoic acid salt carboxylic acid (161 mg, 1 mmol) were added (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butylester (405 mg, 1 eq.), BOP ( 550 mg, 1.2 eq.), N, N-diisopropylethylamine (155 mg, 1.2 eq.) And 4 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were washed with brine and water. On removal of the solvent gave the crude product, which was purified by column chromatography on silica gel to give 126 mg of (S) -3-methyl-2-tert-butylester. { 4 '- [(benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid.

Step 4: A (S) -3-methyl-2-tert-butylester. { 4 '- [(benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric 4 ml of TFA / CH2C12 (1: 1) was added. The solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo and the residue was triturated with ether. Filtration gave 90 mg of (S) -3-methyl-2- acid. { 4 '- [(benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. XE NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.6, 6.8 Hz, 6H) 1.9 (, 1H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.6 (m, 1H) 7.6 (m, 1H) 7.8 (m, 6H) 8.0 (m, 2H) 8.1 (m, 3H) 11.4 (s, 1H).

Example 128: (S) -3-methyl-2- acid. { 4 '- [(4-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 2-amino-3-methylphenol (1 g, 8.1 mmol) was added ethyl triethoxyacetate (5.4 g, 3 eq.). The mixture was stirred at 110 ° C overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 1.36 g of 4-methyl-benzooxazole-2-carboxylic acid ethyl ester as a white solid.

Step 2: To 4-methyl-benzooxazole-2-carboxylic acid ethyl ester (140 mg) was added 2 ml of THF and 0.93 ml (2 eq.) Of NaOH solution (2 N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid dried in vacuo to give 200 mg (100%) of the sodium salt of 4-methyl-benzooxazole-2-carboxylic acid as an off-white solid.

Step 3: Sodium salt of 4-methyl-benzooxazole-2-carboxylic acid (180 mg, 0.93 mmol) was added with (S) -2- (4 '-amino-biphenyl-4-tert-butylester. sulfonylamino) -3-methyl-butyric acid (450 mg, 1.2 eq.), BOP (490 mg, 1.2 eq.), N, N-diisopropylethylamine (144 mg, 1.2 eq.) and 4 ml of DMF. The mixture was stirred at room temperature overnight. The mixture was poured into brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removing the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 158 mg of (S) -3-methyl-2-tert-butylester. { 4 '- [(4-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid.

Step 4: A (S) -3-methyl-2-tert-butylester. { 4 '- [(4-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric (135 mg) was added 4 ml of TFA / CH2C12 (1: 1). The solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo and the residue was triturated with ether. Filtration gave 140 mg of (S) -3-methyl-2- acid. { 4 '- [(4-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. 1 H NMR (400 MHz, DMSO-d 5) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.4 (d, J = 8.3 Hz, 1H) 7.5 (m, 1H) 7.7 (d, J = 8.3 Hz, 1H) 7.8 (m, 6H) 8.1 (t, J = 8.8 Hz, 3H) 11.3 (s, 1H) ).

Example 129: (S) -3-methyl-2- acid. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 2-amino-4-methylphenol (1 g, 8.1 mmol) was added ethyl triethoxyacetate (5.4 g, 3 eq.). The mixture was stirred at 110 ° C overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 850 mg (91%) of 5-methyl-benzooxazole-2-carboxylic acid ethyl ester as a white solid.

Step 2: To 5-methyl-benzooxazole-2-carboxylic acid ethyl ester (170 mg) were added 2 ml of THF and 0.83 ml (2 eq.) Of sodium hydroxide solution (2 N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid dried in vacuo to give 144 mg of 5-methyl-benzooxazole-2-carboxylic acid sodium salt as an off-white solid.

Step 3: A sodium salt of 5-methyl-benzooxazole-2-carboxylic acid (130 mg, 0.83 mmol) was added (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butylester (400 mg, -1.2 eq.), BOP (430 mg, 1.2 eq.), N , -diisopropylethylamine (126 mg, 1.2 eq.) and 4 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Upon removal of the solvent gave the crude product, which was purified by column chromatography on silica gel to give 60 mg of (S) -3-methyl-2-tert-butylester. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid.

Step 4: A (S) -3-methyl-2-tert-butylester. { 4'- [(5-methyl-benzooxazole-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric (30 mg) was added 2 ml of TFA / CH2CI2 (1: 1). The solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo and the residue triturated with ether. Filtration gave 14 mg of (S) -3-methyl-2- acid. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. XR NMR (400 MHz, DMSO-d6) d ppm 0.76-0.93 (m, 6H) 1.84-2.07 (m, 6H) 3.56 (dd, 1H) 7.70-7.95 (m, 8H) 7.98-8.14 (m, 3H) 11.32-11.41 (m, 1H).

Example 130: (S) -3-methyl-2- acid. { 4 '- [(5-chloro-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 2-amino-4-chloro-benzenethiol (1 g) was added ethyl triethoxyacetate (3 eq.). The mixture was stirred at 110 ° C overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 392 mg of 5-chloro-benzothiazole-2-carboxylic acid ethyl ester as a white solid.

Step 2: To 5-chloro-benzothiazole-2-carboxylic acid ethyl ester (200 mg, 0.83 mmol) were added 3 mL of THF and 0.83 mL (2 eq.) Of NaOH solution (2 N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid dried in vacuo to give 170 mg of 5-chloro-benzothiazole-2-carboxylic acid sodium salt as an off-white solid.

Step 3: A sodium salt of 5-chloro-benzothiazole-2-carboxylic acid (150 mg, 0.64 mmol) was added (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butylester (310 mg, 1.2 eq.), BOP (340 mg, 1.2 eq.), N, N-diisopropylethylamine (99 mg, 1.2 eq.) And 4 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Upon removal of the solvent gave the crude product, which was purified by column chromatography on silica gel to give 136 mg of tert-butylester of (S) -3-methyl-2- acid. { 4 '- [(5-chloro-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid.

Step 4: A (S) -3-methyl-2-tert-butylester. { 4 '- [(5-chloro-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric (30 mg) was added 3 ml of TFA / CH2C12 (1: 1). The solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo and the residue triturated with ether. Filtration gave 105 mg of (S) -3-methyl-2- acid. { 4 '- [(5-chloro-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a yellow solid. aH NMR (400 MHz, DMSO-d6) d ppm 0.79-0.88 (m, 6H) 1.85-2.07 (m, 1H) 3.56 (dd, 1H) 7.70 (dd, 1H) 7.76-7.94 (m, 6H) 8.03- 8.12 (m, 3H) 8.26 (d, 1H) 8.35 (d, 1H) 11.36-11.40 (m, 1H).

Example 131: (S) -3-methyl-2- acid. { 4 '- [(5-trifluoromethyl-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: To 2-amino-4-trifluoromethyl-benzenethiol (0.7 g) was added ethyl triethoxyacetate (3 eq.). The mixture was stirred at 110 ° C overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 460 mg of 5-trifluoromethyl-benzothiazole-2-carboxylic acid ethyl ester as a white solid. Step 2: To 5-trifluoromethyl-benzothiazole-2-carboxylic acid ethyl ester (200 mg, 0.73 mmol) was added 3 mL of THF and 0.73 mL (2 eq.) Of NaOH solution (2 N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid dried in vacuo to give 270 mg of 5-trifluoromethyl-benzothiazole-2-carboxylic acid sodium salt as an off-white solid. Step 3: Sodium salt of 5-trifluoromethyl-benzothiazole-2-carboxylic acid (260 mg, 0.97 mmol) was added (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butylester (469 mg, 1.2 eq.), BOP (515 mg, 1.2 eq.) and 5 ml of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were washed with brine and water. Upon removal of the solvent gave the crude product, which was purified by column chromatography on silica gel to give 230 mg of (S) -3-methyl-2-tert-butylester. { 4 '- [(5-trifluoromethyl-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. Step 4: A (S) -3-methyl-2-tert-butylester. { 4 '- [(5-trifluoromethyl-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric (210 mg) was added 3 ml of TFA / CH2CI2 (1: 1). The solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo and the residue triturated with ether. Filtration gave 181 mg of (S) -3-methyl-2- acid. { 4 '- [(5-trifluoromethyl-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a yellow solid. XR NMR (400 MHz, DMSO-d6) d ppm 0.83 (dd, J = 12.63, 6.82 Hz, 6H) 1.92-2.00 (m, 1H) 3.56 (dd, J = 9.35, 6.06 Hz, 1H) 7.80-7.86 ( m, 4H) 7.88-7.92 (m, 2H) 7.97 (dd, J = 8.59, 1.52 Hz, 1H) 8.05-8.07 (m, 1H) 8.09 (d, J = 2.78 Hz, 1H) 8.49 (s, 1H) 8.57 (d, J = 8.59 Hz, 1H) 11. 41 (s, 1H) Example 132: 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid Step 1: To 3-methyl-benzofuran-2-carboxylic acid (500 mg, 2.84 mmol, 1 eq.) In 5 ml of dichloromethane under an argon atmosphere, 2,6-dimethyl-4- (4,4) were added. , 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol (704 mg, 2.84 mmol, 1 eq.), 1,3-dicyclohexylcarbodiimide (1.17 g, 5.68 mmol, 2 eq.) , and 4- (dimethylamino) pyridine (173 mg, 1.42 mmol, 0.5 eq.). The resulting mixture was stirred at room temperature for 6 hours. The reaction was then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified using flash column chromatography on silica gel to provide 2,6-dimethyl-4- (4,4,5,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) ester. 3-methyl-benzofuran-2-carboxylic acid phenyl with a yield of 28%. 1 H NMR (400 MHz, DMSO-dg) d ppm 1.3 (s, 12H) 2.2 (s, 6H) 2.7 (s, 3H) 7. 4 (m, 1H) 7.5 (s, 2H) 7.6 (m, 1H) 7.8 (d, J = 8.3 Hz, 1H) 7.9 (m, 1H). Step 2: A 2,6-dimethyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) phenyl ester of 3-methyl-benzofuran-2-carboxylic acid (310 mg, 0.76 mmol, 1 eq.), D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid (300 mg, 0.76 mmol, 1 eq) was added under an argon atmosphere. , Example 74, Step 2), tetrakis (triphenylphosphine) palladium (0) (44 mg, 0.0387 mmol, 0.05 eq.) And ethylene glycol dimethyl ether (10 ml) and stirred for 10 minutes. Then potassium carbonate was added (211 mg, 1.53 mmol, 2 eq.) In water (4 ml). The reaction was heated to reflux for 16 hours. After aqueous treatment and extraction with ethyl acetate, purification by flash column chromatography afforded 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of the acid D-3-methyl-benzofuran-2-carboxylic acid with a yield of 69%. XH NMR (400 MHz, DMSO-d6) d ppm 0.9 (m, 6H) 1.2 (s, 9H) 1.9 (m, 1H) 2.2 (s, 6H) 2.7 (s, 3H) 3.5 (dd, J = 9.9, 6.3 Hz, 1H) 7.4 (t, 3 = 1. 6 Hz, 1H) 7.6 (s, 2H) 7.6 (t, J = 7.7 Hz, 1H) 7.8 (d, J = 8.3 Hz, 1H) 7.9 (m, 5H) 8.2 (d, J = 9.6 Hz, 1H). Step 3: A 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid in dichloromethane (6) my) add TFA (3 mL) and stir the reaction at room temperature for 2 hours. After work-up, 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid was obtained in quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.2 (s, 6H) 2.7 (s, 3H) 3.6 (dd, J = 9.3 , 6.1 Hz, 1H) 7.4 (m, 1H) 7.6 (s, 2H) 7.6 (m, 1H) 7.8 (d, J = 8.3 Hz, 1H) 7.9 (m, 5H) 8.1 (d, J9.3 Hz, 1 HOUR) .

Example 133: 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid Step 1: The coupling of benzofuran-2-carboxylic acid with 2,6-dimethyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol to obtain 2 , 6-dimethyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ester of benzofuran-2-carboxylic acid was made in accordance with Example 132, Step 1, to provide 2,4,6-dimethyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ester of benzofuran-2-carboxylic acid with a yield of 50%. ? E NMR (400 MHz, DMSO-d6) d ppm 1.3 (s, 12H) 2.2 (s, 6H) 7.4 (m, 1H) 7.5 (s, 2H) 7.6 (m, 1H) 7.8 (dd, J = 8.3, 0.8 Hz, 1H) 7.9 (m, 1H) 8.1 (d, J = 1.0 Hz, 1H). Step 2: The coupling of 2,4,6-dimethyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ester of benzofuran-2-carboxylic acid with tert. -butyl ester of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid to obtain 4 '- (l-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4- The ester of D-benzofuran-2-carboxylic acid was made according to Example 132 ,. Step 2, to provide 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid in 81% yield. 1 H NMR (400 MHz, DMSO-de) d ppm 0.9 (m, 6H) 1.2 (s, 9 H) 1.9 (, 1H) 2.2 (s, 6H) 3.5 (dd, J = 9.7, 6.4 Hz, 1H) 7.4 (t, J = 7.6 Hz, 1H) 7.6 (s, 2H) 7.6 (m, 1H) 7.9 (m, 6 H) 8.2 (t, J = 4.8 Hz, 2H). Step 3: Deprotection of 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid to provide 4' - ( 1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid was made according to Example 132, Step 3, in quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 2.0 (m, 1H) 2.2 (s, 6H) 3.6 (dd, J = 9.3, 5.8 Hz, 1H) 7.4 (m, 1H) 7.6 (, 3H) 7.9 (m, 6H) 8.1 (d, J = 9.3 Hz, 1H) 8.2 (s, 1H) 12.6 (s, 1H).

Example 134: 4 '- (l-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid Step 1: The coupling of tert-butylester of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid (Example 74, Step 2) with 4- (4, 4, 5, 5-tetramethyl-l) , 3, 2-dioxaborolan-2-yl) phenol was made according to Example 132, Step 2, to provide D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3- tert-butylester. methyl-butyric with quantitative yield. 2 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 8.2, 6.9 Hz, 6H) 1.2 (s, 9H) 1.9 (m, 1H) 3.5 (dd, J = 9.6, 6.3Hz, 1H ) 6.9 (d, J = 8.6 Hz, 2H) 7.5 (m, J = 8.8 Hz, 2H) 7.8 (d, J = 2.3 Hz, 4H) 8.1 (d, J = 9.9 Hz, 1H) 9.7 (s, 1H) ). Step 2: A mixture of tert-butylester of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid (305 mg, 0.75 mmol, 1 eq.), 3-methyl- benzofuran-2-carboxylic acid (131 mg, 0.74 mmol, 1 eq.), 4- (dimethylamino) pyridine (95 mg, 0.77 mmol, 1 eq.) and 1,3-dicyclohexylcarbodiimide (DCC, 240 mg, 1.17 mmol, 1.6 eq.) in 5 ml of dichloromethane under a nitrogen atmosphere, was stirred at room temperature for 3.5 hours. After aqueous treatment and extraction with ethyl acetate, column chromatography (10% ethyl acetate / hexane) provided 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%. XH NMR (400 MHz, CDC13) d ppm 0.9 (d, J = 7.1 Hz, 3H) 1.0 (d, J = 6.8 Hz, 3H) 1.2 (s, 9H) 2.1 (m, 1H) 2.7 (s, 3H) 3.7 (dd, J = 10.0, 4.4 Hz, 1H) 5.1 (d, 3 = 9, 9 Hz, 1H) 7.4 (m, 3H) 7.5 (m, 1H) 7.6 (t, J = 8.0 Hz, 3 H) 7.7 (m, 3H) 7.9 (d, J = 8.3 Hz, 2H).

Step 3: Deprotection of the 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid was done according to Example 132 , Step 3. After 1 hour of reaction, the solvent was removed and the product was further extracted with toluene. The solid obtained in this way was dissolved in a minimum amount of acetonitrile. About the same amount of water was added to the mixture. The mixture was frozen in a dry ice-acetone bath and subjected to removal of the lyophilization solvent to give 4'- (1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-3 acid. methyl-benzofuran-2-carboxylic acid. XH NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6H) 2.0 (m, 1H) 2.7 (s, 3H) 3.6 (dd, J = 9.2, 5.9 Hz, 1H) 7.4 (t, J = 7.6 Hz, 1H) 7.5 (d, J8.8 Hz, 2H) 7.6 (t, J = 8.2 Hz, 1H) 7.8 (d, J = 8.3 Hz, 1H) 7.9 (m, 7H) 8.1 (d, J = 9.3 Hz, 1H).

Example 135: 4 '- (l-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid Step 1: To benzofuran-2-carboxylic acid (0.401 g, 2.47 mmol, 1 eq.) Dissolved in dry dichloromethane (50 mL) was added dicyclohexylcarbodiimide (1019 g, 4.94 mmol, 2 eq.) And the mixture was stirred under an atmosphere of nitrogen for 15 minutes. Then 2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid tert-butylester (1.0 g, 2.47 mmol, 1 eq, Example 134, Step 1) was added to the reaction mixture, followed by the addition of 4- (dimethylamino) -pyridine (0.050 g, 0.41 mmol). The mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with water and brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated in vacuo. The residue was dissolved in ethyl acetate and purified by column chromatography on silica gel, eluting with 20% ethyl acetate / hexane, to yield 325 mg of 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl. ) -biphenyl-4-yl ester of benzofuran-2-carboxylic acid with a yield of 31%. ^? NMR (400 MHz, CDC13) d ppm 0.87 (d, J = 6.82 Hz, 3H) 1.03 (d, J = 6.82 Hz, 3H) 1. 21 (s, 9H) 2.07 (m, 1H) 3.68 (dd, J = 9.85, 4.55 Hz, 1H) 5.15 (d, J = 9.85 Hz, 1H) 7.37 (m, 3H) 7.53 (t, J = 7.83 Hz , 1H) 7.66 (m, 5H) 7.77 (m, 2H) 7.92 (d, J = 8.34 Hz, 2H).

Step 2: 4 '- (1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of benzofuran-2-carboxylic acid (325 mg) gave 214 mg of 4' - (1-carboxy-2) -methyl-propylsulfamoyl) -biphenyl-4-yl ester of benzofuran-2-carboxylic acid (76% yield), according to the procedure of Example 132, Step 3, after column chromatography, eluting with 5-20% methanol / ethyl acetate. XH NMR (400 MHz, DMSO-d6) d ppm 0.80 (d, J = 6.57 Hz, 3H) 0.87 (d, J = 6.82 Hz, 3H) 2.04 (m, 1H) 3.24 (m, 1H) 7.43 (t, J = 7.58 Hz, 1H) 7.49 (d, J = 8.84 Hz, 2H) 7.60 (t, J = 7.96 Hz, 1H) 7.70 (d, J = 9.85 Hz, 1H) 7.85 (m, 7H) 8.08 (s, 1 HOUR) .

Example 136: D-2- [4 '- (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: A solution of 5-bromo-4-methoxy-3-methyl-benzofuranr-2-carboxylic acid (286 mg, 1.0 mmol, 1 eq, Example 119, Step 3) in 5 mL of THF under nitrogen atmosphere was placed in a water bath. To this solution, 1.4 ml of BH3 were added dropwise. THF (1.0 M in THF, 1.4 mmol, 1.4 eq.). After 24 hours the reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl) -methanol (220 mg) in 81% yield. XH NMR (400 MHz, CDC13) d ppm 2.4 (s, 3H) 3.9 (s, 3H) 4.7 (s, 2H) 7.1 (d, J = 8.6 Hz, 1H) 7.4 (d, J = 8.8 Hz, 1H) .

Step 2: To a solution of (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl) -methanol in 7 ml of dichloromethane was added 0.5 ml of thionyl chloride at room temperature. After 2 hours the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give 216 mg (92%) of 5-bromo-2-chloromethyl-4-methoxy-3-methyl-benzofuran. aH NMR (400 MHz, CDC13) d ppm 2.4 (s, 3H) 3.9 (s, 3H) 4.7 (s, 2H) 7.1 (d, J = 8.8 Hz, 1H) 7.4 (d, J = 8.6 Hz, 1H) .

Step 3: A mixture of D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methylester (155 mg, 0.43 mmol, 1 eq.), 5-bromo-2-chloromethyl -4-methoxy-3-methyl-benzofuran (120 mg, 0.42 mmol, 1 eq.) And K2C03 (137 mg, 0.99 mmol, 2.4 eq.) In 8 ml of DMF, was heated at 90 ° C for 18 hours. After working-up and column chromatography, eluting with 20% ethyl acetate / hexane, D-2- [4 '- (5-bromo-4-methoxy-3-methyl-benzofuran-2-ylmethoxy) methyl ester was obtained ) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid (102 mg) with a yield of 40%. XH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 31.8, 6.8 Hz, 6H) 2.1 (m, 1H) 2.5 (s, 3H) 3.4 (s, 3H) 3.8 (dd, J = 10.2, 5.2 Hz, 1H) 3.9 (s, 3H) 5.1 (d, J = 10.1 Hz, 1H) 5.2 (s, 2H) 7.1 (dd, J = 12.6, 8.8 Hz, 3H) 7.4 (d, J = 8.6 Hz, 1H ) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (d, J = 8.6 Hz, 2H) 7.9 (d, J = 8.6 Hz, 2H).

Stage 4: Hydrolysis of D-2- [4 '- (5-bromo-4-methoxy-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methylester was carried out performed according to Example 20, Step 5, with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.1, 6.8 H, 6H) 2.0 (, 1H) 2.4 (s, 3H) 3.5 (dd, J = 9.2, 5.9 Hz, 1H) 3.9 (s, 3H) 5.3 (s, 2H) 7.2 (d, J = 8.8 Hz, 2H) 7.4 (d, J = 8.8 Hz, 1H) 7.5 (d, J = 8.8 Hz, 1H) 7.7 (d, J = 9.1 Hz, 2H) 7.8 (d, J = 3.0 Hz, 4H) 8.0 (d, J = 9.3 Hz, 1H).

Example 137: D-2- [4 '- (benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-yl-butyric acid Step 1: Alkylation of 2-bromomethyl-benzothiazole with D-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester was carried out according to Example 136, Step 3, to give D- 2- [4 '- (benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester in 20% yield. ^? NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 15.0, 6.7 Hz, 6H) 1.9 (m, 1H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 5.7 (s, 2H) 7.2 (m, J = 8.8 Hz, 2H) 7.5 (m, 1H) 7.6 (m, 1H) 7.7 (m, 4H) 7.8 (m , 2H) 8.0 (d, 3 = 1. 3 Hz, 1H) 8.1 (d, J = 7.8 Hz, 1H) 8.3 (d, J = 9.6 Hz, 1H).

Step 2: Hydrolysis of D-2- [4 '- (benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester was carried out according to Example 20, Step 5, with quantitative performance. 1 H NMR (400 MHz, DMSO-de) ppm 0.8 (dd, J = 12.4, 6.8 Hz, 6H) 1.9 (m, 1H) 3.5 (dd, J = 9.3, 5.8 Hz, 1H) 5.7 (s, 2H) 7.2 (d, J = 8.8 Hz, 2H) 7.5 (m, 1H) 7.6 (m, 1H) 7.7 (d, J = 8.8 Hz, 2H) 7.8 (d, J = 2.3 Hz, 4H) 8.0 (dd, J = 9.1, 4.5 Hz, 2H) 8.1 (d, J = 8.6 Hz, 1H).

Example 138: D-3-methyl-2- [4 '- (1-methyl-lH-benzomidazol-2-ylmethoxy) -biphenyl-4-sulfonylamino acid} -butyric Step 1: To 432 mg of l-methyl-lH-benzoimidazole-2-carbaldehyde (2.7 mmol, 1 eq.) Dissolved in a mixture of THF (10 ml) and methanol (10 ml), 340 mg of sodium borohydride was added (9.0 mmol, 3.33 eq.) In several portions. After 12 hours the reaction mixture was quenched with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (1-methyl-lH-benzimidazol-2-yl) -methanol in quantitative yield. XH NMR (400 MHz, DMS0-d6) d ppm 3.8 (s, 3H) 4.7 (d, J = 5.6 Hz, 2H) 5.6 (t, J = 5.7 Hz, 1H) 7.2 (m, 1H) 7.2 (m, 1H) 7.5 (m, 1H) 7.6 (m, 1H). Step 2: The conversion of (1-methyl-lH-benzoimidazol-2-yl) -methanol into 2-chloromethyl-l-methyl-lH-benzoimidazole was carried out according to Example 136, Step 2, with a yield 48% XR NMR (400 MHz, CDC13) d ppm 3.9 (s, 3H) 4.9 (s, 2H) 7.3 (m, 3H) 7.8 (m, 1H). Step 3: Alkylation of 2-chloromethyl-1-methyl-1H-benzoimidazole with D-2- (4'-hydroxy) methyl ester biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to Example 136, Step 3, to give methyl ester of D-3-methyl-2- [4 '- (l-methyl-lH- benzoimidazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric with a yield of 28%. aH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 15.4, 6.8 Hz, 6H) 1.9 (, 1H) 3.3 (s, 3 H) 3.6 (dd, J = 9.5, 7.2 Hz, 1H) 3.9 (s, 3H) 5.5 (s, 2H) 7.3 (m, 4H) 7.6 (d, J = 7.1 Hz, 1H) 7.7 (d, J = 7.8 Hz, 1H) 7.7 (m, 4H) 7.8 (m, 2H) 8.3 (d, J = 9.6 Hz, 1H). Step 4: The hydrolysis of methyl ester of D-3-methyl-2- [4 '- (l-methyl-lH-benzoimidazol-2-yl-methoxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out according to Example 20, Step 5, with quantitative yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 11.9, 6.8 Hz, 6H) 1.9 (m, 1H) 3.5 (dd, J = 9.3, 6.1 Hz, 1H) 4.0 (s, 3H) 5.7 (s, 2H) 7.3 (d, J = 9.1 Hz, 2H) 7.5 (m, 2H) 7.8 (m, 8H) 8.1 (d, 3 = 9. 1 Hz, 1H).

Example 139: D-3-methyl-2- [4 '- (3-methyl-benzofuran-2-ylmethoxy) -bifenyl-4-sulfonylamino] -butyric acid Stage 1: A solution of 3-methyl-benzofuran- acid 2-carboxylic acid (2.0 g, 11.4 mmol, 1 eq.) In 60 ml of THF under a nitrogen atmosphere was placed in a water bath. Then 30 ml of BH3.THF (1.0 M in THF, 30 mmol, 2.6 eq.) Was added dropwise. The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction was then quenched with methanol (10 ml). The solvent was removed in vacuo and the residue was subjected to column chromatography, eluting with 20% ethyl acetate / hexane to give (3-methyl-benzofuran-2-yl) -methanol (1.6 g) in 87% yield. %. 2 H NMR (400 MHz, DMSO-d 6) d ppm 2.2 (s, 3 H) 4.5 (d, J = 5.8 Hz, 2 H) 5.3 (t, J = 5.8 Hz, 1 H) 7.3 (m, 2 H) 7.5 (m, 1H) 7.6 (m, 1H).

Step 2: To a solution of (3-methyl-benzofuran-2-yl) -methanol (1.12 g, 6.9 mmol) in 12 ml of dichloromethane was added 2.8 ml of thionyl chloride. The color of the reaction changed from an initial pink to a pale yellow. After 2 hours the reaction was subjected to treatment and 2-chloromethyl-3-methyl-benzofuran was obtained with quantitative yield. 2 H NMR (400 MHz, CDC13) d ppm 2.3 (s, 3 H) 4.7 (s, 2H) 7.2 (m, 1H) 7.3 (m, 1H) 7.5 (m, 1H) 7.5 (m, 1H).

Step 3: The alkylation of 2-chloromethyl-3-methyl-benzofuran with 4- (4, 4, 5, 5-tetramethyl- [1, 2, 3] dioxaborolan-2-yl) -phenol was carried out in accordance with Example 136, Step 3, to give 3-methyl-2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran in 44% yield. 1 H NMR (400 MHz, CDC13) d ppm 1.3 (s, 12H) 2.3 (s, 3H) 5.2 (s, 2H) 7.0 (d, J = 8.6 Hz, 2H) 7.3 (m, 2H) 7.5 (dd, J = 21.6, 7.7 Hz, 2H) 7.8 (d, J = 8.8 Hz, 2H).

Stage 4: The Suzuki stockpiling of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester with 3-methyl-2-. { 4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran was carried out according to Example 38, Step 3, with a yield of 75%. %. - "? NMR (400 MHz, CD30D) d ppm (d, J = 6.8 Hz 6H) 1.9 (m, 1H) 2.2 (s, 3H) 3.2 (s, 3H) 3.5 (d, J = 6.6 Hz, 1H) 5.1 (s, 2H) 7.0 (m, J = 9.1 Hz, 2H) 7.1 (m, 1H) 7.2 (m, 1H) 7.3 (m, 1H) 7.4 (m, 1H) 7.5 (d, J = 9.1 Hz, 2H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (m, 2H).

Step 5: The hydrolysis of methyl ester of D-3-methyl-2- [4 '- (3-methyl-benzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -butyric acid was carried out in accordance with Example 20, Step 5, with quantitative yield. '' "H NMR (400 MHz, CD3OD) d ppm 0.8 (dd, J = 30.3, 6.8 Hz, 6H) 2.0 (m, 1H) 2.2 (s, 3H) 3.5 (d, J = 5.3 Hz, 1H) 5.1 (s, 2H) 7.1 (d, J = 9.1 Hz, 2H) 7.1 (m, 1H) 7.2 (m, 1H) 7.3 (d, J = 8.3 Hz, 1H) 7. 5 (d, J = 8.3 Hz, 1H) 7.5 (d, J = 9.1 Hz, 3H) 7.6 (d, J = 8.6 Hz, 2H) 7.8 (d, J = 8.8 Hz, 2H).

Example 140: D-2- (4 '- (benzofuran-2-yl-methoxy) -3'-methoxy-biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: To benzofuran-2-carbaldehyde (4 g, 27.4 mmol, 1 eq.) THF (50 mL) and methanol (50 mL) were added under an argon atmosphere, and the reaction was cooled using an ice bath /Salt. Then sodium borohydride (3.11 g, 82.1 mmol, 3 eq.) Was added in several portions, and the reaction was allowed to warm slowly to room temperature for 1 hour. After treatment, benzofuran-2-yl-methanol was obtained with quantitative yield. XH NMR (400 MHz, DMSO-de) d ppm 4.6 (d, J = 5.8 Hz, 2H) 5.5 (t, J = 5.9 Hz, 1H) 6.8 (s, 1H) 7.3 (m, 2H) 7.6 (m, 2H).

Step 2: Alkylation of 2-bromomethyl-benzofuran with 2-methoxy-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol was carried out according to Example 136, step 3, to give 2- [2-methoxy-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran in a yield of 29% 1 H NMR (400 MHz CDC13) d ppm 1.3 (s, 12H) 3.9 (s, 3 H) 5.3 (s, 2H) 6.8 (d, J = 0.8 Hz, 1H) 7.0 (d, J = 8.1 Hz, 1H) 7.2 (m, 1H) 7.3 (m, 2H) 7.4 (dd, J = 8.0, 1.4 Hz, 1H) 7.5 (dd, J = 8.1, 0.8 Hz, 1H) 7.5 (dd, J = 8.0, 1.1 Hz, 1H).

Step 3: Suzuki coupling of D-2- (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid methyl ester with 2- [2-methoxy-4- (4,4,5,5-tetramethyl- [1] 2,3] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran was carried out according to example 38, Step 3, to provide 2- [4'-benzofuran-2-ylmethoxy) -3'-ethoxy acid methyl ester. -biphenyl-4-sulfonylamino] -3-methyl-butyric in a yield of 53%. ^? NMR (400 MHz DMSO-de) d ppm 0.8 (dd, J = 14.1, 6.8 Hz, 6 H) 1.9 (m, 1H) 3.6 (dd, J = 9.2, 6.9 Hz, 1H) 3.9 (s, 3 H) 5.3 (s, 2H) 7.1 (s, 1H) 7.3 (m, 5 H) 7.6 (d, J = 8.3 Hz, 1H) 7.7 (d, J = 8.6 Hz, 1H) 7.8 (d, J = 8.6 Hz, 2H) 7.9 (m, 2H) 8.3 (d, J = 9.3 Hz, 1H).

Step 4: Hydrolysis of 2- [4'- (benzofuran-2-ylmethoxy) -3 '-methoxy-biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester was carried out according to Example 20, Step 5, to provide 2- [4 '- (benzofuran-2-ylmethoxy) -3'-methoxy-biphenyl-4-sulfonylamino] -3-methyl-butyric acid in a quantitative yield XH NMR (400 MHz, DMSO-d6) pm 0. 8 (dd, J = 12.1, 6.8 Hz, 6H) 1.9 (m, 1H) 3.5 (dd, J = 9.3, 6.1 Hz, 1H) 3.9 (s, 3 H) 5.3 (s, 2H) 7.1 (s, 1H) 7.3 (m, 5H) 7.6 (d, J = 8.3 Hz, 1H) 7.7 (d, J = 6.3 Hz, 1H) 7.8 (d, J = 8.6 Hz, 2H) 7.9 (m, 2H) 8.0 (d, J = 9.3 Hz, 1H).

Example 141: D-2- [4'-benzofuran-2-ylmethoxy) -bifenil-4-sulfonylamino] -3-methyl-butyric acid Step 1: To benzofuran-2-yl-methanol (4.3 g, 29.0 mmol, 1 eq, Example 140, Step 1), dichloromethane was added. (200 ml) and the solution was cooled using an ice / ethanol bath. Then carbon tetrabromide was added (10.6 g, 31.9 mmol, 1.1 eq.) And 1,3-bis (diphenylphosphino) -propane (6.6 g, 16.0 mmol, 0.55 eq.) Under an argon atmosphere, and then the reaction was slowly allowed to warm to room temperature for 2.5 hours. After treatment and flash column chromatography, 2-bromomethyl-benzofuran was obtained in quantitative yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 4.9 (s, 2H) 7.0 (dd, J = 5.3, 0.5 Hz, 1H) 7.3 (dd, 1H) 7.4 (m, 1H) 7.6 (m, 2H). Step 2: To 2-bromomethyl-benzofuran (1.5 g, 7.1 mmol, 1 eq.) Was added 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol (1.56 g, 7.1 mmol, 1 eq.), Potassium carbonate (1.96 g, 14.2 mmol, 2 eq.) And acetonitrile (50 ml) under an argon atmosphere, and the reaction was heated at 70 ° C for 16 hours. . After treatment and flash column chromatography, it was obtained 2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl} -benzofuran with a 63% yield. 1 H NMR (400 MHz, DMSO-de) d ppm 1.3 (s, 12H) 5.3 (s, 2H) 7.1 (m, 3H) 7.3 (m, 1H) 7.3 (m, 1H) 7.6 (, 4H). Step 3: The coupling of 2- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -benzofuran with tert-butylester of D-2- acid (4-bromo-benzenesulfonylamino) -3-methyl-butyric acid was carried out according to Example 132, Step 2, to provide D-2- [4 '- (benzofuran-2-yl-methoxy) tert-butyl ester - biphenyl-4-sulfonylamino] -3-methyl-butyric with a 33% yield. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 8.3, 7.1 Hz, 6H) 1.2 (s, 9H) 1.9 (m, 1H) 3.5 (dd, J = 9.7, 6.2 Hz, 1H) 5.3 (s, 2H) 7.1 (s, 1H) 7.2 (d, J = 8.6 Hz, 2H) 7.3 (, 1H) 7.3 (m, 1H) 7.6 (dd, J = 8.2, 0.6 Hz, 1H) 7.7 (m , 3H) 7.8 (d, J = 3.3 Hz, 4H) 8.1 (d, J = 9.9 Hz, 1H). Step 4: A tert-butylester of D-2- acid [4 '~ (benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid (126 mg, 0.23 mmol, 1 eq.) in acetonitrile (10 ml) under an argon atmosphere, cerium chloride heptahydrate ( 175 mg, 0.47 mmol, 2 eq.) And potassium iodide (51 mg, 0.30 mmol, 1.3 eq.) And the reaction was heated at 70 ° C for 16 hours. After treatment and flash column chromatography, D-2- [4 '- (benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid was obtained with a % yield. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 2.0 (m, 1H) 3.5 (dd, J = 9.2, 5.9 Hz, 1H) 5.3 (s, 2H) 7.1 (s, 1H) 7.2 (d, J = 8.8 Hz, 2H) 7.3 (dd, J = 8.1, 0.8 Hz, 1H) 7.3 (m, 1H) 7.6 (d, J = 8.1 Hz, 1H) 7.7 (m , 1H) 7.7 (d, J = 8.3 Hz, 2H) 7.8 (d, 4H) 8.0 (d, J = 9.3 Hz, 1H).

Example 142: L-2- [4 '- (5-chloro-4-methoxy-3-methylbenzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: At 0.31 g (1.3 mmol) of 5-chloro-4-methoxy-3-methylbenzofuran-2-carboxylic acid (Example 116, Step 3) in 10 ml of THF under a nitrogen atmosphere was added 1.0 M solution of BH3 / THF (1.8 mL, 1.8 mmol, 1.4 eq.). The reaction was stirred overnight and then carefully quenched with water and extracted twice with ethyl acetate. The combined organic phases were washed with 1N sodium hydroxide and then with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give (5-chloro-4-methoxy-3-methylbenzofuran-2-yl) -methanol as solid white crystalline (0.29 g, 99% yield).

Step 2: To a 0 ° C solution of (5-chloro-4-methoxy-3-methylbenzofuran-2-yl) -methanol (0.29 g, 1.3 mmol) in dichloromethane (5 mL) was added pure phosphorus tribromide ( 0.18 ml, 0.52 g, 1.9 mmol, 1.5 eq.) And pyridine (3 drops). The ice bath was removed and the reaction was allowed to warm to room temperature overnight. Additional phosphorus tribromide (0.09 ml, 0.26 g, 0.95 mmol, 0.75 eq.) Was added and stirring was continued at room temperature. After two hours, the reaction was quenched with ice and extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated sodium bicarbonate, followed by drying over magnesium sulfate, filtration and concentration in vacuo to give essentially pure 2-bromomethyl-5-chloro-4-methoxy-3-methyl-benzofuran (0.37. g, 99% yield). Step 3: To a flask loaded with L-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (0.49 g, 1.3 mmol, 1.05 eq.) And 2-bromomethyl-5 Chloro-4-methoxy-3-methyl-benzofuran (0.37 g, 1.2 mmol, 1 eq.) was added reactive-grade acetone (20 ml) and solid potassium carbonate (0.18 g, 1.2 mmol, 1 eq.). After stirring at room temperature for 12 hours, the acetone was removed in vacuo and the residue diluted with water. Mix The resulting mixture was extracted twice with ethyl acetate and the combined organic phases were washed successively with water, 1N sodium hydroxide, and brine, dried over magnesium sulfate., filtered and concentrated in vacuo to give the crude product as a yellowish brown solid. This was chromatographed on silica gel, eluting with 20% to 30% ethyl acetate / hexanes, to give methyl ester of L-2- [4 '- (5-chloro-4-methoxy-3-methylbenzofuran- 2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid in the form of an off-white solid (0.41 g, 57%). Step 4: To a solution of L-2- [4 '- (5-chloro-4-methoxy-3-methylbenzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester. (0.41 g, 0.72 mmol) dissolved in methanol / THF 1: 1 (10 mL), 7.2 mL of 1 N sodium hydroxide (7.2 mmol, 10 eq.) Was added and the resulting solution was stirred at room temperature overnight. The organic solvents were removed in a stream of nitrogen, the aqueous layer acidified to pH -3 with concentrated HCl, and extracted twice with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give L-2- [4 '- (5-chloro-4-methoxy-3-methylbenzofuran-2-yl-methoxy) -biphenyl- acid. 4-sulfonylamino] -3-methyl-butyric in the form of an off-white solid (0.32 g, 79% yield). Mass Spectrometry: M-H "556.1, 558.1.

Example 143: L-2- [4 '- (5-cyano-4-methoxy-3-methylbenzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: A suspension of (5-bromo-4-methoxy-3-methylbenzofuran-2-yl) -methanol (0.31 g, 1.1 mmol, Example 136, Step 1) and CuCN (0.21 g, 2.3 mmol, 2 eq. ) in N-methylpyrrolidinone (1.5 ml), was subjected to microwave radiation at 200 ° C for 10 minutes. The reaction was diluted with water and ethyl acetate (10 ml each) and filtered. The layers were separated and the aqueous phase was washed with a second portion of ethyl acetate. The combined organic layers were washed twice with water and once with brine. After drying over magnesium sulfate, filtering and concentrating in vacuo, the crude product was obtained. Chromatography on silica gel, eluting with 20% to 30% ethyl acetate / hexanes, gave pure 2-hydroxymethyl-4-methoxy-3-methylbenzofuran-5-carbonitrile (0.17 g, 67% yield).

Step 2: A solution of 2-hydroxymethyl-4-methoxy-3-methylbenzofuran-5-carbonitrile (0.17 g, 0.76 mmol) in dichloromethane (5 ml) was cooled to 0 ° C. To this solution was added successively pure phosphorus tribromide (0.11 ml, 0.32 g, 1.2 mmol, 1.5 eq.) And pyridine (2 drops). The ice bath was removed and the reaction was allowed to warm to room temperature overnight with stirring. After the reaction was quenched with ice, the crude product was isolated by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-bromomethyl-4-methoxy-3-methylbenzofuran-5-carbonitrile (0.20 g, 95% yield).

Step 3: To a vial loaded with L-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (0.28 g, 0.76 mmol, 1.05 eq.) And 2-bromomethyl-4 -methoxy-3-methylbenzofuran-5-carbonitrile (0.20 g, 0.72 mmol, 1 eq.) was added reactive-grade acetone (5 ml) and solid cesium carbonate (0.23 g, 0.72 mmol, 1 eq.). The reaction preceded overnight and concentrated in vacuo when TLC analysis indicated that the starting materials had been consumed. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, 1N sodium hydroxide, and brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to give crude ether in vacuo. form of a yellowish brown solid. This was chromatographed on silica gel, eluting with 20% to 30% ethyl acetate / hexanes, followed by recrystallization from ethyl acetate / hexanes, to give methyl ester of L-2- [4 '- (5-cyano-4-methoxy-3-methylbenzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino} -3-methyl-butyric acid in the form of a crystalline white solid (0.28 g, 68% yield).

Stage 4: To a solution of acid methyl ester L-2- [4 '- (5-cyano-4-methoxy-3-methylbenzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid (0.16 g, 0.28 mmol) dissolved in methanol / THF 1: 1 (5 mL), 1N sodium hydroxide solution (3 mL, 3.0 mmol, 10 eq.) Was added and the reaction was stirred at room temperature overnight. The temperature was then raised to 40 ° C for 4 hours whereupon the organic solvent was removed in a stream of nitrogen and the resulting aqueous residue was acidified to pH-3 with concentrated HCl. It was then extracted with ethyl acetate (2x) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give L-2- [4 '- (5-cyano-4-methoxy-3-methylbenzofuran -2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid in the form of an off-white solid (0.20 g, 73% yield). Mass Spectrometry: M-H "= 547.1.

Example 144: N-. { [4 '- (2-furoyloxy) -1,1' -biphenyl-4-yl] sulfonyl} -D-valina According to the procedure of Example 134, N- was obtained from furan-2-carbonyl chloride. { [4 '- (2-furoyloxy) -l, 1-biphenyl-4-yl] sulfonyl} -D-valina. aH NMR (400 MHz, DMSO-d6) d ppm 0.82 (d, J = 6.82 Hz, 3H) 0.85 (d, J = 6.82 Hz, 3H) 1.96 (m, 1H) 3.57 (dd, J = 9.35, 6.06 Hz , 1H) 6.83 (dd, J = 3.54, 1.77 Hz, 1H) 7.42 (d, J = 8.84 Hz, 2H) 7.61 (dd, J = 3.66, 0.88 Hz, 1H) 7.86 (m, 6H) 8.09 (d, J = 9.35 Hz, 1H) 8.13 (dd, J = 1.77, 0.76 Hz, 1H).

Example 145: N-. { [4 '- (3-f-roxylo) -1,1' -bif nyl-4-yl] sulfonyl} -D-valina According to the procedure of Example 134, N- was obtained from furan-3-carbonyl chloride. { [4 '- (3- furoyloxy) -l, 1-biphenyl-4-yl] sulfonyl} -D-valina. XH NMR (400 MHz, CD3OD) d ppm 0.82 (d, J = 6.82 Hz, 3H) 0.88 (d, J = 6.82 Hz, 3H) 1.96 (m, 1H) 3.59 (d, J = 5.56 Hz, 1H) 6.81 (s, 1H) 7.23 (d, J = 8.84 Hz, 2H) 7.59 (d, J = 2.02 Hz, 1H) 7.66 (d, J = 8.84 Hz, 2H) 7.70 (d, J = 8.84 Hz, 2H) 7.83 (d, J = 8.59 Hz, 2H) 8.30 (d, J = 0.76 Hz, 1H).

Example 146: L-2- [4 '- (4-ethyl-3-methylbenzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: To 3-methyl-4-ethylbenzofuran-2-carboxylic acid ethyl ester (0.795 g, 3.43 mmol) in tetrahydrofuran (20 mL) cooled to 0 ° C, diisopropylaluminium hydride (13.7 mL of anhydrous) was added dropwise. 1.0 M solution in toluene). After stirring for 1 hour, methanol (10 mL) was added, followed by saturated aqueous sodium potassium tartrate (10 mL). The resulting mixture was stirred for 15 minutes and then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, reduced to dryness and the resulting residue was chromatographed. gradient snap on silica gel (hexanes / ethyl acetate 10: 1-3: 1), which yielded 0.6124 g (94%) of (4-ethyl-3-methyl-benzofuran-2-yl) -methanol in shape of a white solid. MS (ES) m / z: 190.1 (M +).

Step 2: To a solution of (4-ethyl-3-methylbenzofuran-2-yl) -methanol (77 mg, 0.403 mmol) in dichloromethane (4 mL) at 0 ° C, pyridine (0.1 mL) was added followed by tribromide of phosphorus (0.057 ml, 0.604 mmol). The cooling bath was removed and the solution was stirred for 1 hour at room temperature. After cooling again to 0 ° C, the reaction cooled rapidly by adding ice chips. The mixture was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium bromide. The solution was dried over sodium sulfate, filtered and reduced to dryness to provide 83 mg (82%) of 4-ethyl-3-methyl-2-bromomethyl-benzofuran as a white solid.

Stage 3: To a solution of acid methyl ester L-2- (4'-Hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric (165 mg, 0.454 mmol) in DMF (3 mL) was added cesium carbonate (444 mg, 1362 mmol). After 10 minutes, 4-ethyl-3-methyl-2-bromomethyl-benzofuran (82 mg, 0.324 mmol) in dimethylformamide (3 mL) was added dropwise. After 1 hour add water (30 mL) and extract the solution with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, reduced to dryness and the resulting residue was subjected to flash chromatography on a silica gel gradient (hexanes / ethyl acetate 20: 1: 3: 1), which gave 89 mg ( 51%) of L-2- [4 '- (4-ethyl-3-methylbenzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester in the form of a white solid. MS (ES) m / z: 536.2 (M + H) +, 1071.4 (2M + H).

Step 4: To a solution of L-2- [4 '- (4-ethyl-3-methylbenzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester (70 mg, 0.131 mmol ) in tetrahydrofuran (6 mL), methanol (4 mL) and water (2 mL), lithium hydroxide (125 mg, 5.23 mmol) was added. After stirring for 2.5 days at room temperature, hydrochloric acid (5.23 ml, 1 N solution) was added, followed by ethyl acetate (50 ml). The layers were separated and the organic phase was washed with water, dried over sodium sulfate, filtered and reduced to dryness. The solid material was recrystallized from a minimum amount of boiling isopropanol, to give 54 mg (79%) of L-2- [4 '- (4-ethyl-3-methylbenzofuran-2-ylmethoxy) -biphenyl-4 acid. -sulfonylamino] -3-methyl-butyric acid in the form of a white solid. MS (ES) m / z: 520.1 (M-H) -, 1041.4 (2M-H).

Example 147: N- [(4 '- { [4- (3-methoxypro) yl) -3-methyl-l-benzofuran-2-yl] methoxy.] -!, 1' -biphenyl-4- il) sulfonyl] -L-valine Step 1: A mixture of 4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.6566 g, 0.00977 mol, Example 22, Step 1), 10% palladium on activated carbon (705 mg) and tetrahydrofuran (60 ml) was stirred under a hydrogen atmosphere (balloon) for 20 hours. After filtering the mixture through a pad of celite, the resulting solution was reduced to dryness, yielding 2.46 g (91%) of 4- (3-methoxy-propyl) -3-methyl-benzofuran-2- ethyl ester. carboxylic acid in the form of a clear oil. MS (ES) m / z: 277.1 (M + H) +, 553.3 (2M + H). Step 2: To a solution of 4- (3-methoxy-propyl) -3-methylbenzofuran-2-carboxylic acid ethyl ester (2.213 g, 8.018 mmol) in tetrahydrofuran (25 mL) and methanol (9 mL) at room temperature, 1 N LiOH (16 838 ml) was added. The resulting yellow solution was stirred at room temperature for 2.5 hours, neutralized with 1 N HCl and then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and reduced to dryness, yielding 1.98 g (98%) of 4- (3-methoxy-propyl) -3-methylbenzofuran-2-carboxylic acid as a white solid. MS (ES) m / z: 249.11214 (M + H) +, 497.21700 (2M + H). Step 3: 4- (3-methoxy-propyl) -3-methylbenzofuran-2-carboxylic acid (0.2354 g, 0.853 mmol) in tetrahydrofuran (10 mL) cooled to 0 ° C, diisopropylaluminum hydride was added dropwise ( 3.41 ml of a 1.0 M solution in toluene). After stirring for 1 hour, methanol (5 mL) was added, followed by saturated aqueous sodium potassium tartrate (5 mL). The resulting mixture was stirred for 15 minutes and then extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, reduced to dryness, and the resulting residue was subjected to flash gradient chromatography on silica gel (hexanes / ethyl acetate 10: 1-3: 1), which afforded 0.192 g (96%) of [4- (3-methoxypropyl) -3-methyl-1-benzofuran-2-yl] -methanol as a white solid. MS (ES) m / z: 234.1 (M +). Step 4: To a solution of [4- (3-methoxypropyl) -3-methyl-1-benzofuran-2-yl] -methanol (181 mg, 0.774 mmol) in dichloromethane (4 mL) at 0 ° C was added pyridine (0.1 ml), followed by phosphorus tribromide (0.109 ml, 1.16 mmol). The cooling bath was removed and the solution was stirred for 1 hour at room temperature. After re-cooling to 0 ° C, the reaction rapidly cooled by the addition of pieces of ice. The mixture was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium bromide. The solution was dried over sodium sulfate, filtered and reduced to dryness to give 188 mg (82%) of 4- (3-methoxypropyl) -3-methyl-2-bromomethyl-1-benzofuran, which was taken directly to the next step . Step 5: To a solution of L-2- (4'-hydroxy-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (240 mg, 0.66 mmol) in acetone (5 mL) was added cesium carbonate. (206 mg, 0.633 mmol). After 10 minutes, 4- (3-methoxypropyl) -3-methyl-2-bromomethyl-1-benzofuran (188 mg, 0.633 mmol) in acetone (5 mL) was added dropwise. After 1 hour water (20 ml) was added and the solution was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, reduced to dryness and the resulting residue was subjected to flash gradient chromatography on silica gel (hexanes / ethyl acetate 20: 1-3: 1), yielding 210 mg ( 57%) of N- [(4 '- { [4- (3-methoxypropyl) -3-methyl-l-benzofuran-2-yl] -methoxy.} -1, 1'-biphenyl-4- il) sulfonyl] -L-valinate in the form of a white solid. MS (ES) m / z: 580.2 (M + H). Step 6: To a solution of N- [(4 '- { [4- (3-methoxypropyl) -3-methyl-1-benzofuran-2-yl] methoxy.] -1, 1'-biphenyl- 4-yl) sulfonyl] -L-valinate (192 mg, 0.331 mmol) in tetrahydrofuran (12 ml), methanol (8 ml) and water (4 ml), lithium hydroxide (317 mg, 13.25 mmol) was added. After stirring for 2.5 days at room temperature, hydrochloric acid (13.25 ml, 1 N solution) was added, followed by ethyl acetate (80 ml). The layers were separated and the organic phase was washed with water, dried over sodium sulfate, filtered and reduced to dryness. The solid material was recrystallized from a minimum amount of boiling isopropanol, which yielded 171 mg (91%) of N - [(4'-. {[4- (3-methoxypropyl) -3-methyl- 1-benzofuran-2-yl] -methoxy.! -! 1 '-biphenyl-4-yl) sulfonyl] -L-valine as a white solid. MS (ES) m / z: 564.2 (M-H), 1129.4 (2M-H).

Example 148: N- (. {4 '- [(5-bromo-4-methoxy-3-methyl-1-benzofuran-2-yl) -methoxy] -1,1' -biphenyl-4-yl} sulfonyl) -L-valine According to the procedure of Example 136, N- (. {4 '- [(5-bromo-4-methoxy-3-methyl-1-benzof ran-2-yl) methoxy] -1,1' was obtained -biphenyl-4-yl.}. sulfonyl) -L-valine from 5-bromo-2-chloromethyl-4-methoxy-3-methyl-benzofuran and methyl ester of L-2- (4'-hydroxy) biphenyl-4-sulfonylamino) -3-methyl-butyric pf 198-200 ° C; MS: 600.0 (M-H) -.

Example 149: N- (. {4 '- [(5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl) methoxy] -1,1' -biphenyl-4-yl}. sulfonyl) -D-valine Step 1: At 0.50 g (1.7 mmol) of ethyl 5-bromo-4-hydroxy-3-methyl-1-benzofuran-2-carboxylate (Example 119, Step 1) in 7 ml of DMF was added 0.51 g (3.75 g). mmol) of potassium carbonate and 0.48 ml (3 mmol) of 2-bromopropane and the reaction was stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.58 g of ethyl 5-bromo-4-isopropoxy-3-methyl-l-benzofuran-2-carboxylate. 100% performance; p.f. 48-50 ° C; MS: 341.0 (M + H) +.

Step 2: To 0.58 g (1.7 mmol) of ethyl 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylate in 15 ml of THF and 15 ml of MeOH was added 8.5 ml of 1 N NaOH and the reaction was stirred at room temperature for 1 hour. HE The solvent was concentrated in vacuo, the residue neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.46 g of 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylic acid. Yield 86.8%; p.f. 182-184 ° C; MS: 311.0 (M-H). " Step 3: A solution of 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylic acid (0.43 g, 1.37 mmol) in 25 ml of THF under a nitrogen atmosphere was placed in a water bath . To this solution was added dropwise 2 ml of BH3.THF (1.0 M in THF, 2.06 mmol, 1.4 eq.). After 24 hours, the mixture was rapidly cooled with water, the solvent was concentrated in vacuo and the residue was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated to provide 0.33 g of acid (5-bromo-4-isopropoxy-3-methyl-1-benzofü-8-2-). il) -methanol. Performance 80.5%. Atonic spectrum: theoretical C: 52.15H: 5.05; found C: 52.26; H: 4.80.

Step 4: To a solution of (5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl) -methanol (0.3 g, 1 mmol) in 10 mL of dichloromethane was added 0.73 mL of thionyl chloride And the reaction was stirred at room temperature for 2 hours. HE The solvent was concentrated in vacuo and toluene was added to the residue to provide 0.33 g of 5-bromo-4-isopropoxy-3-methyl-2-chloromethyl-1-benzofuran. Step 5: A mixture of the above chlorine compound (0.31 g, 1.03 mmol), N- [(4'-hydroxy-1, 1'-biphenyl-4-yl) sulfonyl] -D-valinate methyl (0.37 g, 0.98 mmol) and potassium carbonate (0.34 g, 2.45 mmol) in 20 ml of DMF, was heated in an oil bath (~90 ° C) for 18 hours. The solvent was concentrated in vacuo and the residue was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.61 g of crude product. After column chromatography, eluting with hexane / ethyl acetate (2: 1), 0.13 g of N- (. {4 '-. {(5-bromo-4-isopropoxy-3-methyl- methyl l-benzofuran-2-yl] -methoxy] -1, 1 '-biphenyl-4-yl.} sulfonyl) -L-valinate, yield 20.6%, mp 154-156 ° C; MS: 661 (M + NH4) +.

Step 6: According to the procedure of Example 136, Step 4, 0.11 g of N- (. {4 '- { (5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl. ) methoxy] -1, 1'-biphenyl-4-yl.} sulfonyl) -D-valinate gave 0.1 g of N- (. {4 '- [(5-bromo-4-isopropoxy-3- methyl-l-benzofuran-2-yl) -methoxy] -1,1 '-biphenyl-4-yl}. sulfonyl) -D-valine. Yield -100%; p.f. 137-140 ° C; MS: 628 (M-H) ~.

Example 150: N- [(4 '-. {[[(5-bromo-4-methoxy-3-methyl-l-benzofuran-2-yl) methyl] amino]} -1,1' -biphenyl-4 -il) sulfonyl] -L-valine Step 1: To a solution of 0.21 g (0.77 mmol) of (5-bromo-4-methoxy-3-methyl-1-benzofuran-2-yl) methanol (Example 136, Step 1) in 6 ml of dichloromethane, added 0.36 g (0.85 mmol, 1.1 eq.) Of Dess-Martin periodinane. The reaction was stirred at room temperature for 2 hours and then diluted with 15 ml of ether. To the reaction was added 5 ml of 1 N NaOH and the mixture was stirred for 30 minutes. The reaction was diluted with ether and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.19 g of 5-bromo-4-methoxy-3-methyl-1-benzofuran-2-carbaldehyde. Performance 90.4%; p.f. 81-82 ° C; ES: 268.9 (M + H) +. Step 2: A 0.14 g (0.52 mmol) of 5-bromo-4-methoxy-3-methyl-1-benzofuran-2-carbaldehyde and 0.20 g (0.55 mmol) of methyl ester of L-2- (4'-amino) -biphenyl-4-sulfonylamino) -3-methyl-butyric acid in 8 ml of dichloromethane, 0.15 g was added (0.68 mmol) of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 1.5 hours. It was diluted the reaction with ethyl acetate and then neutralized with 1 N NaOH to pH -8. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. After chromatography on silica gel, eluting with hexane: ethyl acetate (2: 1), 0.21 g of N- [(4'- { [(5-bromo-4-methoxy-3-methyl) was obtained. methyl-l-benzofuran-2-yl) methyl] amino.} - l, 1'-biphenyl-4-yl) sulfonyl] -L-valinate. Performance 66.7%; p.f. 144-146 ° C; MS: 615.2 (M + H) +. Step 3: According to the procedure of Example 136, Step 4, 0.22 g of N- [(4 '- { [(5-bromo-4-methoxy-3-methyl-1-benzofuran-2-yl) methyl] amino.}. -1. 1'-biphenyl-4-yl) sulfonyl] -L-valinate afforded 0.20 g of N- [(4'-. {[[(5-bromo-4-methoxy) 3-methyl-1-benzofuran-2-yl) methyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine. Yield 90.9%; p.f. 194-198 ° C; MS: 601.0 (M + H) + Example 151: L-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-buyric Step 1: L-2- (4'-amino-biphenyl-4-sulfonylamino) -methyl ester was added to an oven-dried flask. 3-methyl-butyric (0.552 g), anhydrous methylene chloride (10 ml), and N, N-diisopropylethylamine (2.0 eq.). The solution was cooled in an ice bath before the addition of 2-benzothioxazolecarboxylic acid chloride (1.0 eq.), Prepared according to a literature procedure: Romero et al., J. Med. Chem. 1993. 37. 999 The reaction was left stirring at 0 ° C for 4 hours, after which it was judged complete. Water was added and the resulting mixture was extracted with CH2C12 (2 x 15 mL). The organic layers were combined, dried over magnesium sulfate, and evaporated under reduced pressure to provide methyl ester of L-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid, with quantitative yield.

Stage 2: Hydrolysis of methyl ester of L-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure described in Example 20, Step 5, produced the final product, L-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 13.3, 6.7 Hz, 6H) 2.0 (m, 1H) 3.6 (t, J = 6.6 Hz, 1H) 7.7 (m, 2H) 7.8 ( m, 4H) 7.9 (m, 2H) 8.1 (d, J = 8.8 Hz, 3H) 8.3 (dd, J = 17.9, 7.8 Hz, 2H) 11.3 (s, 1H) 12.6 (s, 1H).

Example 152: D-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] bifenil-4-sulfonylamino} -3-me til-butírico Step 1: D-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester (0.552 g), anhydrous methylene chloride (10 ml), was added to an oven-dried flask. and N, N-diisopropylethylamine (2.0 eq.). The solution was cooled in an ice bath before the addition of 2-benzothiazolecarboxylic acid chloride (1.0 eq.). The reaction was allowed to stir at 0 ° C for 4 hours, after which it was judged complete. Water was added and the resulting mixture was extracted with dichloromethane (2 x 15 mL). The organic layer was combined, dried over magnesium sulfate, and evaporated under reduced pressure to yield methyl ester of D-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid, with quantitative yield. Step 2: The hydrolysis of methyl ester of D-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure described in Example 20, Step 5, produced D-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4- sulfonylamino} -3-methyl-butyric in the form of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 2.0 (m, 1H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 7.7 (m, 2H) 7.9 (m, 6H) 8.1 (m, 3H) 8.3 (m, 2H) 11.3 (s, 1H) 12.6 (s, 1H).

Example 153: L-3-methyl-2- acid. { 4 '- [(naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: The Naphtho [2,1-b] furan-2-carboxylic acid stockpiling (Emmont and Livingstone, J. Chem. Soc., 1957, 3144) with L-2- tert-butylester (4 '- amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to the procedure described in Example 21, Step 3. t-butylester of L-3-methyl-2- acid. { 4 '- [(naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was obtained in the form of a white solid with a yield of 75%. Step 2: Removal of the t-butyl group was carried out using 40% TFA in methylene chloride at room temperature in 4 hours. The acid L-3-methyl-2-. { 4 '- [(naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric it was isolated in the form of a white solid with a yield of 90%. XH NMR (400 MHz, DMSO-d6) d ppm 0.8 (dd, J = 12.9, 6.8 Hz, 6H) 2.0 (m, 1H) 3.6 (dd, J = 9.1, 6.1 Hz, 1H) 7.7 (m, 2H) 8.0 (m, 11 H) 8.4 (m, 2H) 10.8 (s, 1H).

Example 154: L-3-methyl-2- acid. { 4 '- [(1-methyl-naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: The coupling of 1-methyl-naphtho [2, 1-b] furan-2-carboxylic acid (prepared according to Emmont &Livingstone, J. Chem. Soc., 1957. 3144) with L-t-butylester -2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid was carried out according to the procedure described in Example 21, Step 3. T-butylester of L-3-methyl- 2-. { 4 '- [(1-methyl-naphtho [2, 1-b] furan-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -butyric was obtained in the form of a white solid. Step 2: Removal of the t-butyl group was conducted using 40% TFA in methylene chloride at room temperature in 4 hours. The acid L-3-methyl-2-. { 4 '- [(1-methyl-naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was isolated in the form of a solid white color with a 90% yield. XH NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 13.4, 6.8 Hz, 6H) 2.0 (m, 1H) 3.1 (s, 3H) 3.6 (d, J = 6.1 Hz, 1H) 7.6 ( m, 1H) 7.7 (m, 1H) 7.8 (m, 7H) 8.0 (m, 3H) 8.1 (d, J = 8.1 Hz, 1H) 8.5 (d, J = 8.1 Hz, 1H) 10.6 (s, 1H) .

Example 155: L-3-methyl-2- acid. { 4 '- [(3-methyl-4-phenoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: 3-Methyl-4-phenoxy-benzofuran-2-carboxylic acid ethyl ester was prepared from phenylboronic acid and 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester in the presence of copper acetate (II) according to the procedure of Evans et al., Tetrahedron ett. , 1998. 39. 2937, with a yield of 50%. Stage 2: Hydrolysis of the acid ethyl ester 3-methyl-4-phenoxy-benzofuran-2-carboxylic acid was carried out according to Example 20, Step 3, producing acid 3-methyl-4-phenoxy-benzofuran-2-carboxylic acid in the form of a white solid, with a yield of 75%. Stage 3: The coupling of 3-methyl-4-phenoxy acid benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid t-butylester was carried out according to the procedure described in Example 21, Step 3 Methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-phenoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was obtained in the form of a white solid. Step 4: The hydrolysis of methyl ester of L-3-methyl-2- acid. { 4 '- [(3-methyl-4-phenoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was carried out according to Example 20, Step 5, to produce L-3-methyl-2- acid. { 4 '- [(3-methyl-4-phenoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. XE NMR (400 MHz, DMSO-de) d ppm 0.8 (dd, J = 12.5, 6.7 Hz, 6H) 2.0 (m, 1H) 2.6 (s, 3H) 3.6 (dd, J = 9.3, 6.1 Hz, 1H) 6.8 (dd, J = 5.7, 2.9 Hz, 1H) 7.1 (dd, J = 8.7, 1.1 Hz, 2H) 7.2 (m, 1H) 7.5 (m, 4H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (m, 4H) 8.0 (d, J = 8.8 Hz, 2H) 8.1 (d, J = 9.3 Hz, 1H) 10.6 (s, 1H).

Example 156: L-2- (4 '- { [4- (1-methoxycarbonyl-l-methyl-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -3-methyl-butyric Step 1: A solution of 2,6-dihydroxyacetophenone (35.37 g, 0.23 moles), potassium carbonate (51.4 g, 0.37 moles) and t-butyl bromoacetate (28.4 ml, 0.23 moles) in 440 ml of acetone was heated at reflux for 1.5 hours. Then it was cooled to room temperature and filtered. The filter cake was washed with acetone, and the combined mother liquors were concentrated in vacuo. The (2-acetyl-3-hydroxy-phenoxy) -acetic acid tert-butylester was isolated in the form of a viscous yellow oil, which was used directly in the next step. Step 2: (2-Acetyl-3-hydroxy-phenoxy) -acetic acid tert-butylester The DMF was dissolved and heated to 110-130 ° C in the presence of potassium carbonate for 4 hours. The resulting suspension was poured slowly into cold water. The product precipitated and was collected by filtration. Recrystallization from toluene afforded 34.26 g of the desired tert-butylester of the desired 4-hydroxy-3-methylbenzofuran-2-carboxylic acid in the form of a light yellow solid (overall yield 60%). Step 3: The 4- (1-ethylperoxycarbonyl-1-methyl-ethoxy) -3-methyl-benzofuran-2-carboxylic acid tert-butylester compound was prepared from 4-hydroxy-3-methyl tert-butylester -benzofuran-2-carboxylic acid according to the procedure of Bencze et al., Tetrahedron, 1970. 26, 5407, in the form of a white solid.

Step 4: The removal of the t-butyl group of tert-butylester from 4- (1-ethylperoxycarbonyl-1-methyl-ethoxy) -3-methyl-benzofuran-2-carboxylic acid was carried out using 40% TEA in chloride of methylene at room temperature for 4 hours. The monoacid, 4- (1-ethylperoxycarbonyl-1-methyl-ethoxy) -3-methylbenzofuran-2-carboxylic acid, was isolated as a white solid with a total yield of 40%. Step 5: The coupling of 4- (l-ethylperoxycarbonyl-1-methyl-ethoxy) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl) 4- t-butylester sulfonylamino) -3-methyl-butyric acid was carried out according to the procedure described in Example 21, Step 3. T-butylester of L-2- (4 '- { [4- (1-methoxycarbonyl- l-methyl-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino.) -3-methyl-butyric acid was obtained in the form of a viscous oil. elimination of the t-butyl group of t-butylester of L-2- (4 '- { [4- (1-methoxycarbonyl-l-methyl-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino .} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid according to the procedure described in Step 2, produced L-2- (4'- { [4- (1-methoxycarbonyl-1- methyl-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid as a white solid XH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 46.6, 6.7 Hz, 6H) 1.7 (s, 6H) 2.1 (m, 1H) 2.9 (s, 3H) 3.8 (s, 3H) 3.8 (dd, J = 9.9, 4.5 Hz, 1H ) 5.1 (d, J = 9.9 Hz, 1H) 6.4 (d, J = 8.1 Hz, 1H) 7.1 (d, J = 8.3 Hz, 1H) 7.6 (dd, J = 29.1, 8.6 Hz, 4H) 7.8 (dd) , J = 20.5, 8.8 Hz, 4H) 8.4 (s, 1H).

Example 157: L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methylbenzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid t-butylester (1 mmol), ethyl 2-bromoacetate (1.1 eq.), potassium carbonate (5 eq.), and 10 ml of DMF. The reaction mixture was stirred overnight and then added slowly, dropwise, to water (10 ml), with stirring. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), brine (20 mL) and dried over magnesium sulfate. Filtration and evaporation of the solvent gave 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a viscous oil, in 90% yield. Stage 2: 4- Tert-butyl ester Previous ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid was dissolved in a 40% solution of TFA / methylene chloride, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 4-ethoxycarbonylmethoxy-3-methylbenzofuran-2-carboxylic acid in quantitative yield. Stage 3: Acquisition of 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid t-butylester was carried performed according to the procedure described in Example 21, Step 3. The t-butylester of L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid was obtained in the form of a viscous oil.

Step 4: The elimination of the t-butyl group of t-butylester of L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure described in Step 2, produced L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. XH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 45.0, 6.8 Hz, 6H) 1.3 (t, J = 7.1 Hz, 3H) 2.1 (, 1H) 2.9 (s, 3H) 3.8 (dd, J = 9.9, 4.8 Hz, 1H) 4.3 (g, 3 = 1. 1 Hz, 2H) 4.7 (s, 2H) 5.5 (d, J = 10.1 Hz, 1H) 6.5 (d, J = 7.8 Hz, 1H) 7.1 (d, J = 7.8 Hz, 1H) 7.3 (m, 1H) 7 5 (dd, J = 25, 5, 8, 6 Hz, 4H) 7. 8 (dd, J = 24.5, 8.6 Hz, 4H) 8. 3 (s, 1H).

Example 158: L-2- acid. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-me til-butírico Step 1: To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid t-butylester (1 mmol), methyl 2-bromoacetate (1.1 eq.), potassium carbonate (5 eq.), and 10 ml of DMF. The reaction mixture was stirred overnight and then added slowly, dropwise, to water (10 ml), with stirring. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), brine (20 mL) and dried over magnesium sulfate. Filtration and evaporation of the solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a viscous oil, with a yield of 92%. Step 2: 4-Methoxycarbonylmethoxy-3-methylbenzofuran-2-carboxylic acid tert-butylester was dissolved in a methylene chloride solution of TFA 40% /, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.

Stage 3: The coupling of 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid t-butylester was carried performed according to the procedure described in Example 21, Step 3. T-butylester of L-2- acid. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid was obtained in the form of a viscous oil.

Step 4: The elimination of the t-butyl group of t-butylester of L-2- acid. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure described in Step 2, produced L-2- acid. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. "" "H NMR (400 MHz, CDCl 3) d ppm 0.9 (dd, J = 45.0, 6.8 Hz, 6H) 2.1 (m, 1H) 2.8 (s, 3H) 3.8 (m, 4H) 4.7 (s, 2H) 5.5 (d, J = 10.1 Hz, 1H) 6.5 (d, J = 8.1 Hz, 1H) 7.1 (d, J8.1 Hz, 1H) 7.3 (t, J = 8.2 Hz, 1H) 7.5 (dd, J = 23.9, 8.7 Hz, 4H) 7.8 (m, 4H) 8.3 (s, 1H).

Example 159: L-2- acid. { 4 '- [(4-carboxymethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric The hydrolysis of L-2- acid. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric (Example 158) according to the procedure of Example 20, Step 5, produced L-2- acid. { 4 '- [(4-carboxymethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric in the form of a white solid. 1 H NMR (400 MHz, CD30D) d ppm 0.8 (dd, J = 23.6, 6.7 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.6 (d, J = 5.8 Hz, 1H) 4.7 (s, 2H) 6.6 (d, J = 8.1 Hz, 1H) 7.1 (d, J = 8.3 Hz, 1H) 7.3 (t, J = 8.2 Hz, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (d, J = 8.6 Hz, 2H) 7.8 (m, 4H) 9.9 (s, 1H).Example 160: L-3-methyl-2- (4 '- { [3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carbonyl] -amino acid} -bifenyl- 4-sulfonylamino.} - butyric Step 1: To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid t-butylester (1 mmol), 3-picolyl chloride (1.1 eq.), potassium carbonate (5 eq.), and 10 ml of DMF. The reaction mixture was stirred overnight and then added slowly, dropwise, to water (10 ml), with stirring. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), brine (20 mL) and dried over magnesium sulfate. Filtration and evaporation of the solvent afforded 3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carboxylic acid t-butylester in the form of a viscous oil, with a yield of 90%. Step 2: 3-Methyl-4- (pyridin-3-ylmethoxy) benzofuran-2-carboxylic acid t-butylester was dissolved in a 40% solution of TEA / methylene chloride, and stirred at room temperature for 4 hours . Evaporation of the solvent gave 3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carboxylic acid in quantitative yield.

Step 3: The coupling of 3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-butylester -methyl-butyric was carried out according to the procedure described in Example 21, Step 3. T-butylester of L-3-methyl-2- (4 '- { [3-methyl-4- ( pyridin-3 ilmethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -butyric acid was obtained as a white solid.

Step 4: Removal of the t-butyl group according to the procedure described in Step 2, produced L-3-methyl-2- (4 '- { [3-methyl-4- (pyridin-3) acid ylmethoxy) -benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -butyric acid in the form of a white solid. aH NMR (400 MHz, CD30D) d ppm 0.9 (dd, J = 24.0, 6.8 Hz, 6H) 2.1 (m, 1H) 2.8 (s, 3H) 3.7 (d, J = 5.6 Hz, 1H) 5.5 (s, 2H) 6.9 (d, J = 8.1 Hz, 1H) 7.3 (d, J = 8.3 Hz, 1H) 7.4 (t, J = 8.2 Hz, 1H) 7.7 (d, J = 8.8 Hz, 2H) 7.7 (d, J = 8.6 Hz, 2H) 7.9 (m, 4H) 8.1 (dd, J = 8.2, 5.7 Hz, 1H) 8.7 (d, J = 7.8 Hz, 1H) 8.8 (d, J = 4.0 Hz, 1H) 9.0 (s, 1H).

Example 161: L-2- acid. { 4 '- [(4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric Step 1: 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester (Example 156, Step 2) is dissolved in a 40% solution of TFA / methylene chloride, and stirred at room temperature for 4 hours. 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid was isolated as a white powder by evaporation of the solvent.

Step 2: Coupling of 4-hydroxy-3-methylbenzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid t-butylester was carried out according to the procedure described in Example 21, Step 3. T-butylester of L-2- acid. { 4 '- [(4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} 3-methyl-butyric acid was obtained as a white solid.

Step 3: The elimination of the t-butyl group of t-butylester of L-2- acid. { 4 '- [(4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric is to form the L-2- acid. { 4 '- [(4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric was carried out according to the procedure described in Step 1. The final product was isolated as a gray powder. 1 H NMR (400 MHz, CD 3 OD) d ppm 0.8 (dd, J = 23.5, 6.8 Hz, 6H) 1.9 (m, 1H) 2.7 (s, 3H) 3.5 (d, J = 5.6 Hz, 1H) 6.5 (d, J = 7.8 Hz, 1H) 6.9 (d, J8.8 Hz, 1H) 7.1 (m, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (dd, J = 13.8, 8.7 Hz, 4H). Example 162: L-2- (4-. {5- [(L-Ethyl-lH-benzoimidazole-2-carbonyl) -amino] -? Iridin-2-yl} -benzenesulfonylamino) -3-methyl acid -butyric Step 1: To a solution containing 2-methylbenzimidazole (10 mmol) in DMF (100 mL) at 0 ° C was slowly added sodium hydride (1.3 eq.). The evolution of the gas was observed. After completing the addition, the resulting suspension was stirred at room temperature for 30 minutes, and then cooled to 0 ° C. Then ethyl iodide was added slowly, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with brine (50 ml) and dried over MgSO4. Filtration and evaporation of the solvents gave the product in the form of a viscous oil. Step 2: Oxidation of l-ethyl-2-methylbenzimidazole to the corresponding aldehyde using selenium dioxide was conducted according to a literature procedure (erner et al., Tetrahedron, 1995. 51, 4779). 1- was isolated ethyl-lH-benzimidazole-2-carboxaldehyde in the form of a yellow oil, with a total yield of 52%. Step 3: Oxidation of l-ethyl-lH-benzimidazole-2-carboxaldehyde to the corresponding carboxylic acid was conducted according to a similar procedure from the literature (Burtner and Cusic, J. Am. Chem. Soc., 1943. 65 . 265). The l-ethyl-lH-benzoimidazole-2-carboxylic acid was isolated as a white solid, with a yield of 80%. Step 4: Coupling of 1-ethyl-lH-benzimidazole-2-carboxylic acid with L-2- (4- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid t-butylester carried out according to the procedure described in the Example 21, Step 3. L-2- (4- {5 - [(1-ethyl-lH-benzimidazole-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino acid t-butylester ) -3-methyl-butyric was obtained as a white solid. Step 5: The elimination of the t-butyl group of t-butyl ester of L-2- (4- {5- (l-ethyl-lH-benzimidazole-2-carbonyl) -amino] -pyridin-2-acid il. β-benzenesulfonylamino) -3-methyl-butyric was carried out using 40% TFA in methylene chloride. L-2- (4-. {5- [(1-Ethyl-lH-benzoimidazole-2-carbonyl) -amino] -pyridin-2-yl] -benzenesulfonylamino) -3-methyl acid t-butylester -butyric was isolated in the form of a light brown solid. 1 H NMR (400 MHz, CD3OD) d ppm 0. 9 (dd, J = 23.7, 6.8 Hz, 6H) 1.5 (t, J = 7.2 Hz, 3H) 2.1 (m, 1H) 3.7 (d, J = 5.6 Hz, 1H) 4.8 (m, 2H) 5.5 (s) , 1H) 7.5 (m, 2H) 7.7 (m, 3H) 7.8 (m, 3H) 7.9 (, 4H).

Example 163: N- (. {4 '- [(1,2,3-thiadiazol-4-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -L-valine N- (. {4 '-. {(1,2,3-thiadiazol-4-ylcarbonyl) -amino] -1,1-biphenyl-4-yl.} Sulfonyl) -L-valine was prepared from Fmoc-L-Vai-ang resin and 1,2, 3-thiadiazole-4-carboxylic acid, using the same procedure as in Example 4. CLEM MH + (m / z) 461. 2 H NMR (300 MHz, DMSO- d6) d ppm 10.96 ppm (s, 1H), 9.67 ppm (s, 1H), 7.84 ppm (d, 2H, J = 8.7 Hz), 7.68-7.60 ppm (m, 6H), 3.36 ppm (d, 1H J = 6.0 Hz), 1.75 ppm (, 1H), 0.63 ppm (m, 6H). Example 164: D-2- [4 '- (benzofuran-2-sulfonyl-methyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: A mixture of 2- [1, 2, 3] thiadiazole-4-yl- phenol (241 mg, 1.35 mmol, 1 eq, prepared according to MA Abramov, W. Dehaen, B. D'hooge, ML Petrov, S. Smeets, S. Toppet and M. Voeta, Tetrahedron, 2000. 56. 3933 -3940), 2- (4-bromomethyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborlane (406 mg, 1.37 mmol, 1 eq.) And potassium carbonate (396 mg , 2.87 mmol, 1.9 eq.), Was dissolved in 8 ml of acetonitrile and heated to 90 ° C under a nitrogen atmosphere. After the reaction was complete, as monitored by TLC, the mixture was filtered and the solvent removed in vacuo. The resulting crude material was chromatographed on silica gel, eluting with 20% ethyl acetate / hexane, to give 2- [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan -2-yl) -benzylsulphane] -benzofuran (198 mg) with a yield of 40%. 1 H NMR (400 MHz, CDC13) d ppm 1.3 (s, 12H) 4.1 (s, 2H) 6.6 (d, J = 1.0 Hz, 1H) 7.2 (m, 4H) 7.4 (d, J = 7.8 Hz, 2H) 7.7 (d, J = 8.1 Hz, 2H). Step 2: 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) -benzylsulfañil} -benzofuran was carried out according to Example 38, Step 3, to give D-2- [4'- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester with a yield of 54%. XH NMR (400 MHz, Benzene-de) d ppm 0.7 (d, J = 6.8 Hz, 3H) 0.9 (d, J = 6.8 Hz, 3H) 1.9 (m, 1H) 3.0 (s, 3H) 4.0 (m, 3H) 5.0 (d, J = 10.1 Hz, 1H) 6. 6 (d, J = 1.0 Hz, 1H) 7.1 (m, 4H) 7.3 (m, 6H) 7.3 (s, 1H) 7.4 (m, 1H). Step 3: A solution of D-2- [4 '- (benzofuran-2-ylsulfanylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester (75 mg, 0.15 mmol, 1 eq.) In 4 My THF, was placed in an ice bath. M-Chloroperoxybenzoic acid (125 mg of 77%) was added dropwise0.55 mmol, 3.7 eq. ) in 3 ml of THF. After 10 minutes at 0 ° C, the ice bath was removed and the reaction was allowed to proceed for 12 hours. After working-up and column chromatography, eluting with 20% ethyl acetate / hexane, D-2- [4 '- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl- methyl ester was obtained. butyric (56 mg) with a 70% yield. XE NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 33.3, 6.8 Hz, 6H) 2.0 (m, 1H) 3.4 (s, 3H) 3.8 (dd, J = 10.1, 5.3 Hz, 1H) 4.6 ( s, 2H) 5.1 (d, J = 10.1 Hz, 1H) 7.4 (m, 4H) 7.5 (m, 3H) 7.6 (m, 1H) 7.7 (m, 3H) 7.9 (d, J = 8.8 Hz, 2H) . Step 4: Hydrolysis of D-2- [4 '- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester was carried out according to Example 20, Step 5 , with quantitative performance. 1 HOUR NMR (400 MHz, DMSO-d5) d ppm 0.8 (dd, J = 12.1, 6.8 Hz, 6H) 1.9 (m, 1H) 3.5 (dd, J = 9.3, 6.1 Hz, 1H) 5.0 (s, 2H) 7.4 (d, J = 8.3 Hz, 2H) 7.4 (m, 1H) 7.6 (m, 1H) 7.7 (d, J = 1.0 Hz, 1H) 7.7 (d, J = 8.3 Hz, 2H) 7.8 (m, 6H) 8.1 (d, J = 9.1 Hz, 1H).

Example 165: D-2- [4 '- (benzofuran-2-sulfinylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid Step 1: A solution of methyl ester of D-2- acid. { 4 '- (benzofuran-2-ylsulfanylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid (190 mg, 0.37 mmol, 1 eq, prepared according to Example 164, Step 2) in 5 ml of dichloromethane, It was placed in an ice bath. M-Chloroperoxybenzoic acid (88 mg of 77%, 0.39 mmol, 1.05 eq.) In 3 ml of dichloromethane was added dropwise. After 45 minutes, the reaction was treated by washing with saturated sodium carbonate solution. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was subjected to column chromatography, eluting with 25% ethyl acetate / hexane, to give methyl ester of D-2- [4 '- (benzofuran-2-sulfinyl-methyl) -biphenyl-4-sulfonylamino ] -3-methyl-butyric with a yield of 83%. aH NMR (400 MHz, CDC13) d ppm 0.9 (dd, J = 33.2, 6.7 Hz, 6H) 2.0 (m, 1H) 3.4 (s, 3H) 3.8 (dd, J = 10.1, 5.1 Hz, 1H) 4.5 ( m, 2H) 5.1 (d, J = 10.1 Hz, 1H) 7.1 (s, 1H) 7.3 (s, 2H) 7.3 (dd, J = 8.2, 7.2 Hz, 1H) 7.5 (m, 3H) 7.6 (m, 4H) 7.9 (d, J = 8.6 Hz, 2H).

Step 2: Hydrolysis of D-2- [4 '- (benzofuran-2-sulfinylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid methyl ester was carried out according to Example 20, Step 5 , with quantitative performance. 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.8 (dd, J = 12.0, 6.7 Hz, 6H) 1.9 (m, 1H) 3.5 (dd, J = 9.3, 6.1 Hz, 1H) 4.7 (m, 2H) 7.4 (m, 3H) 7.5 (m, 2H) 7.7 (d, J = 8.3 Hz, 2H) 7.8 (m, 6H) 8.1 (d, J = 9.6 Hz, 1H) 12.6 (s, 1H).

Example 166: (S) -2- (4 '- { [3- (4-Chloro-phenyl) -isoxazole-5-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl -butyric Step 1: The coupling of 3- (4-chloro-phenyl) -isoxazole-5-carboxylic acid (commercially available) with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl acid methyl ester -butyric was carried out according to the procedure described in Example 21, Step 3. Methyl ester of (S) -2- (4 '- { [3- (4-chloro-phenyl) -isoxazole-5 -carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid was obtained as a white solid with a yield of 70%.

Step 2: Hydrolysis of (S) -2- (4 '- { [3- (4-chloro-phenyl) -isoxazole-5-carbonyl} -amino} -biphenyl-4-methyl ester. -sulfonylamino) -3-methyl-butyric acid according to the procedure described in Example 20, Step 5, produced (S) -2- (4 '- {. {3- (4-chloro-phenyl)) acid -isoxazole-5-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid in the form of a white solid. MS: calculated for [M-H] ~: 553.02; found: 552.36.

Example 167: (S) -3-methyl-2- acid. { 4 '- [(1-methyl-3-phenyl-1H-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: The coupling of l-methyl-3-phenyl-1H-thieno [2,3-c] pyrazole-5-carboxylic acid (commercially available) with L-2- (4'-amino-biphenyl) methyl ester 4-sulfonylamino) -3-methyl-butyric acid was carried out according to the procedure described in Example 21, Step 3. Methyl ester of (S) -3-methyl-2- acid. { 4 '- [(1-methyl-3-phenyl-1H-thieno [2,3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was obtained in the form of a solid of white color with a yield of 72%.

Step 2: The hydrolysis of the methyl ester of (S) -3-methyl-2- acid. { 4 '- [(1-methyl-3-phenyl-1H-thieno [2, 3-c.] Pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric according to the procedure described in Example 20, Step 5, produced (S) -3-methyl-2- acid. { 4 '- [(1-methyl-3-phenyl-1H-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. MS: calculated for [M + H] +: 589.71; found: 589.16.

Example 168: (S) -3-methyl-2- acid. { 4 '- [(5-methyl-l-phenyl-lH-pyrazole-3-carbonyl) -amino] -biphenyl-4-sullynylamino} -butyric Step 1: The coupling of 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (commercially available) with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl acid methyl ester -butyric was carried out according to the procedure described in Example 21, Step 3. Methyl ester of (S) -3-methyl-2- acid. { 4 '- [(5-methyl-l-phenyl-lH-pyrazole-3- carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was obtained in the form of a white solid with a yield of 72%.

Step 2: The hydrolysis of methyl ester of (S) -3-methyl-2- acid. { 4 '- [(5-methyl-l-phenyl-lH-pyrazole-3-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric according to the procedure described in Example 20, Step 5, produced (S) -3-methyl-2- acid. { 4 '- [(5-methyl-l-phenyl-lH-pyrazole-3-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. MS: calculated for [M + H] +: 533.62; found: 533.19.

Example 169: (S) -3-methyl-2- acid. { 4 '- [(2-pyridin-4-yl-thiazole-4-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Step 1: The coupling of 2-pyridin-4-yl-thiazole-4-carboxylic acid (commercially available) with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester was carried out according to the procedure described in Example 21, Step 3. Methyl ester of the acid (S) -3-methyl-2-. { 4 '- [(2-pyridin-4-yl-thiazole-4-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric was obtained in the form of a white solid with a yield of 79%.

Step 2: The hydrolysis of methyl ester of (S) -3-methyl-2- acid. { 4 '- [(2-pyridin-4-yl-thiazole-4-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric according to the procedure described in Example 20, Step 5, produced (S) -3-methyl-2- acid. { 4 '- [(2-pyridin-4-yl-thiazole-4-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric in the form of a white solid. MS: calculated for [M-H] +: 535.64; found: 535.70.

Example 170: (S) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino acid} -butyric (S) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino] -butyric acid was prepared according to the procedure of Example 166, using 2-thiophenesulfonyl. HRMS: calculated for [M + H] +: 495,071; found: 495,071.

Example 171: (R) -3-Methyl-2- [4 '- (thiophen-2-sulfonylamino) -bifenyl-4-sulfonylamino] -butyric acid (R) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino] -butyric acid was prepared according to the procedure of Example 166, using 2-thiophenesulfonyl. MS: calculated for [M-H] ": 493.1, found: 493.5.

Example 172: acid (R) -2-. { 4 '- [(furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino) -3-methyl-butyric Acid (R) -2- was prepared. { 4 '- [(furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure of Example 166, using 2-furoyl chloride. MS: calculated for [M-H] ": 441.1, found: 441.5.

Example 173: (R) -3-methyl-2- acid. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric Acid (R) -3-methyl-2- was prepared. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric according to the procedure of Example 166, using 2-thiophenecarbonyl. MS: calculated for [M-H] ": 457.1, found: 457.5.

Example 174: (S) -3-methyl-2- acid. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric (S) -3-methyl-2- acid was prepared. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric according to the procedure of Example 166, using 2-thiophenecarbonyl chloride. MS: calculated for [M-H] ~: 457.1; found: 457.5.

Example 175: (S) -2- acid. { 4 '- [(furan-2-carbonyl) -amino] bifenyl-4-sulfonylamino} -3-me til-butírico Acid (S) -2- was prepared. { 4 '- [(furan-2-carbonyl) -amino] -bifenil-4-sulfonylamino} -3-methyl-butyl according to the procedure of Example 166, using 2-furoyl chloride. MS: calculated for [M-H] ": 441.1, found: 441. 6.

Example 176: (S) -2- acid. { 4 '- [(4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -3-methyl-buty rich Step 1: To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid t-butylester (1 mmol), a-bromo-N, N-dimethylacetamide (1.1 eq.), potassium carbonate (5 eq.), and 10 ml of DMF. The reaction mixture was stirred overnight and then added slowly, dropwise, to water (10 ml), with stirring. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), washed with brine (20 mL) and dried over magnesium sulfate. Filtration and evaporation of the solvent gave 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butylester in the form of a viscous oil, in 90% yield. Step 2: 4-Dimethylcarbamoylmethoxy-3-methylbenzofuran-2-carboxylic acid tert-butylester was dissolved in 40% TFA / methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield. Stage 3: The coupling of the acid 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-bifenyl-4-sulphonylamino) -3-methyl-butyric acid t-butylester was carried out in accordance with the procedure described in Example 21, Step 3. Tert-butylester of (S) -2- acid. { 4 '- [(4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -3-methyl-butyric acid was obtained in the form of a viscous oil. Step 4: The elimination of the t-butyl group of t-butylester of (S) -2- acid. { 4 '- [(4-dimethylcarbamoylmethoxy-3-methylbenzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid according to the procedure described in Step 2, produced or (S) -2- acid. { 4 '- [(4-dimethylcarbamoylmethoxy-3-methylbenzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonylamino} -3-methyl-butyric in shape of a white solid. MS: calculated for [M + H] +: 608.68; found: 608.30.

Example 177: (S) -2- (4 '- { [4- (2-tert-butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -3-methyl-butyric Step 1: The preparation of 4- (2-tert-butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carboxylic acid ethyl ester was made according to the procedure described in Example 176, Step 1, using tert-butylester of (2-bromoethyl) carbamic acid, obtained in the form of a white solid with a yield of 90%. Step 2: The hydrolysis of 4- (2-tert-butoxycarbonylamino-ethoxy) -3-methylbenzofuran-2-carboxylic acid ethyl ester with LiOH was done according to the process described in Example 20, Step 3, to give acid 4 - (2-tert-butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carboxylic acid in the form of a white solid. Step 3: The coupling of 4- (2-tert-butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl) 4- methyl ester sulfonylamino) -3-methyl-butyric acid was carried out according to the procedure described in Example 21, Step 3 to give (S) -2- (4 '-. {[4- (2-tert. -butoxycarbonylamino-ethoxy) -3-methylbenzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid in the form of a white solid. Step 4: Hydrolysis of methyl ester of (S) -2- (4 '- { [4- (2-tert-butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid with LiOH according to the process described in Example 20, Step 5, produced (S) -2- (4 '- { [4- (2- tert-butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino.} - biphenyl-4-sulfonylamino) -3-methyl-butyric acid in the form of a white solid. MS: calculated for [M-H] ~: 664.77; found: 664.61.

Example 178: (S) -3-Methyl-2- (4 '- { [3-methyl-4- (pyridin-2-ylmethoxy) -benzofuran-2-carbonyl] -amino acid} -biphenyl- 4-sulfonylamino) -butyric This compound was prepared according to a procedure similar to that described in Example 160, using 2-picolyl chloride. MS: calculated for [M + H] +: 614.69; found: 614.22.

Example 179: (S) -3-Methyl-2- (4 '- { [3-methyl-4- (pyridin-4-ylmethoxy) -benzofuran-2-carbonyl] -amino acid} -biphenyl- 4- sulfonylamino) -butyric This compound was prepared according to a procedure similar to that described in Example 160, using 4-picolyl chloride. MS: calculated for [M + H] +: 614. 69; found: 614.26.

Example 180: acid (S) -2-. { 4 '- [(4-carbamoylmethoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric This compound was prepared according to a procedure similar to that described in Example 176, using 2-bromoacetamide. MS: calculated for [M + H] +: 580. 63; found: 580. 32. Example 181: (S) -2- (4 '- { [4- (2-amino-ethoxy) -3-methyl- acid benzof uran-2 -carbonyl] -amino} -bif enyl-4-sul-onylamino) -3-me til-bu tí rico The product of Example 177, (S) -2- (4 '- { [4- (2-tert-butoxycarbonylamino-ethoxy) -3-methylbenzofuran-2-carbonyl] -amino acid.} - biphenyl-4 -sulfonylamino) -3-methyl-butyric acid, was treated with 40% TFA / methylene chloride solution at room temperature for 4 hours to produce acid (S) -2- (4 '- { [4- (2-amino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl -butyric in the form of a brown solid (salt of TFA). MS: calculated for [M-H] ": 564.65, found: 564.51.

Example 182: (S) -2- (4 '- { [4- (2-dimethylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid) -3-methyl-butyric Stage 1: To a solution of t-butylester of acid 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid dissolved in THF (30 ml / g) under a nitrogen atmosphere was added N, N-dimethylethanolamine and triphenylphosphine, followed by the dropwise addition of diisopropylcarbodiimide. The resulting mixture was allowed to stir overnight. The crude product was isolated by concentrating the reaction mixture in vacuo. Step 2: Tert-butyl ester from Step 1 was dissolved in a 40% TFA / methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 4- (2-dimethylamino-ethoxy) -3-methyl-benzofuran-2-carboxylic acid as a white solid, in quantitative yield. Step 3: The coupling of 4- (2-dimethylamino-ethoxy) -3-methylbenzofuran-2-carboxylic acid with L-2- (4'-amino-biphenyl-4-sulfonylamino) -3-methyl-butyric acid methyl ester was carried out according to the procedure described in Example 21, Step 3, to give methyl ester of L-2- (4 '- { [4- (2-dimethylamino-ethoxy) -3-methyl-benzofuran -2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid in the form of a white solid, with a yield of 65%. Stage 4: Hydrolysis of methyl ester of acid L-2- (4 '- { [4- (2-dimethylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino.}. -biphenyl-4-sulfonylamino) -3-methyl-butyric from According to the process described in Example 20, Step 5, it produced L-2- (4 '- { [4- (2-dimethylamino-ethoxy) -3-methylbenzofuran-2-carbonyl] -amino acid. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid in the form of a white solid. MS: calculated for [M + H] +: 594.70; found: 594.29.

Examples 183-193: Step 1: To a solution of methyl ester of (4'-amino-biphenyl-4-sulfonyl) -L-valine (0.055 mmol, 20 mg) and carboxylic acid (0.75 mmol) in THF, diisopropylcarbodiimide was added (0.1 mmol, 12.6 mg) and the solution was heated at 60 ° C for 16 hours. After cooling to room temperature, the solvent was removed. The crude product was used in the next step. Stage 2: To a solution of the product of Stage 1 (0.55 mmol) in water / methanol (1: 1) was added lithium hydroxide (0.15 mmol, 7 mg). The resulting solution shook 50 ° C overnight, and then concentrated in vacuo. The residue was dissolved in water / methanol / DMSO (1.5 ml) and purified by semi-preparative HPLC-FI (Gilson preparative HPLC conditions: Gilson preparative HPLC system, YMC Pro C18, 20 mm x 50 mm internal diameter, 5 uM column 2 ml injection, Solvent A: 0.02% TFA / water, B solvent: 0.02% TFA / acetonitrile, Gradient: Time 0: 95% A, 2 minutes: 95% A, 14 minutes: 10% A, 15 minutes: 10% A; 16 minutes: 95% A; flow rate: 22.5 ml / min; Detection: DAD at 254 nm). Table 1 shows the acids used in Step 1 for Examples 183-193.

TABLE 1 LCMS: EM Waters Xterra C18, 2 mm (d.i.) x 50 mm (length), 3.5 mm column, adjusted to 50 ° C; flow rate: 1.0 ml / min; Solvent A: 0.02% formic acid in water; Solvent B: 0.02% formic acid in ACN; Gradient: Time 0: 10% B; 2.5 minutes 90% B; 3 minutes: 90% B; Sample concentration: ~ 2.0 mM; Injection volume: 5 uL; Detection: DAD at 220 nm, 254 nm.

Table 2 lists the chemical name of the compounds produced in Examples 183-193.

TABLE 2 Examples 194-247: N- (. {47- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1-biphenyl-4-yl.} Sulfonyl) -D-alanine WAC-549937 Step 1: Bifenyl (46.3 g, 0.3 moles) was dissolved in 500 ml of chloroform. The solution was cooled in a water / ice bath. Chlorosulfonic acid (19.9 ml, 1 eq.) Was added dropwise over 30 minutes. The ice / water bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solid was washed with CHC13 to provide 41.2 g of bifenyl-4-sulfonic acid as a white solid. Step 2: Biphenyl-4-sulfonic acid (30 g) was mixed with trifluoroacetic acid and a suspension formed. The mixture was cooled to -5 ° C. Steamy nitric acid (12.8 ml) was added dropwise over 30 minutes. The reaction mixture was stirred at 0 ° C for 2 hours. The chloroform was removed in vacuo and the residue was recrystallized from acetic acid to provide 15 g of 4'-nitro-bifenyl-4-sulfonic acid, obtained as white crystals. Step 3: 4'-Nitro-biphenyl-4-sulfonic acid (1.12 g, 4 mol) was mixed with tin (II) chloride (5.2 g, 32 mmol) and 40 mL of THF. The mixture was refluxed overnight. The reaction mixture was poured into 80 ml of water and stirred room temperature for 8 hours. The mixture was filtered and dried in vacuo to give 0.73 g (73%) of 4'-amino-biphenyl-4-sulfonic acid, obtained as an off-white solid. Step 4: Benzofuran-2-carboxylic acid (310 mg, 1.9 mmol) was mixed with 3 ml of oxalyl chloride, refluxed for 1 hour in the presence of a catalytic amount of DMF, and then excess chloride was removed of oxalyl by vacuum. The residue was dissolved in 4 ml of dichloromethane and added to a mixture of 400 mg (1.6 mmol) of 4'-amino-biphenyl-4-suifonic acid, N, N-diisopropylethylamine (0.92 ml, 4 eq.) And 4 g. my THF in an ice / water bath. The mixture was stirred at room temperature for 4 hours. The reaction mixture was mixed with 2 N HCl, and a suspension formed during the process. The solid was collected by centrifugation and washed with chloroform and 2 N HCl to give 540 mg of 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonic acid, obtained as a solid of color light brown. Step 5: To 75 mL of DMF cooled to -20 ° C, oxalyl chloride (6.7 mL, 76 mmol) was carefully added dropwise. A white suspension formed and the smoke produced by blowing N2 through the flask was removed. A solution of 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonic acid (15 g, 38 mmol) in 100 ml of DMF was slowly added and the temperature was maintained at < 0 ° C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at that temperature for 3 hours. The reaction mixture was poured into 4 1 of ice / water, and the suspension. The solid was collected and dried under vacuum to provide 7.3 g of 4 '- [(benzofuran-2-carbonyl) -amino] -bifinyl-4-sulfonyl chloride, obtained as an off-white solid. Step 6: To a solution of D-alanine (0.15 mmol, 14 mg) in water (0.5 ml) and DMF (0.1 mil) was added N, N-diisopropylethylamine (52 uL, 0.3 mmol) and sodium chloride. 4 '- [(benzofuran-2-carbonyl) -amino] -bifenil-4-sulf onyl (0.1 mmol, 41 mg) as a solution in acetonitrile (0.4 ml). The resulting solution was stirred at room temperature for 4 hours and purified by semi-preparative HPLC-FI (Gilson preparative HPLC conditions: Gilson preparative HPLC system, YMC Pro C18, 20 mm x 50 mm ID, 5 uM column; 2 ml; Solvent A: TFA / 0.02% water, Solvent B: TEA / acetonitrile 0.02%, Gradient: Time 0: 95% A, 2 minutes: 95% A, 14 minutes: 10% A, 15 minutes: 10 % A, 16 minutes: 95% A, flow rate: 22. 5 ml / minute; Detection: DAD at 254 nm), to provide N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -bifinyl-4-yl.} Sulfonyl) -D -Alanin. Using essentially the same procedures described for Example 194, Step 6, and using the appropriate amino acid, the compounds of Examples 195-247, shown in Table 3, were prepared and purified by reverse phase preparative HPLC2.

TABLE 3 2CLEM: EM Waters Xterra C18, 2 mm (d.i.) x 50 mm (length), 3.5 mm column, adjusted to 50 ° C; flow rate: 1.0 ml / min; Solvent A: 0.02% formic acid in water; Solvent B: 0.02% formic acid in ACN; Gradient: Time 0: 10% B; 2.5 minutes 90% B; 3 minutes: 90% B; Concentration of the sample: -2.0 mM; Injection volume: 5 uL; Detection: DAD at 220 nm, 254 nm.

Table 4 lists the chemical names of the compounds produced in Examples 194-247. TABLE 4 246 N- ( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.}. Sulfonyl) -1-benzyl-L-histidine 247 N- ( {.4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1"biphenyl-4-yl.} Sulfonyl) -O-benzyl-L-tyrosine Example 248: Activity The activity of the compounds of the invention was tested through enzymatic inhibition in vi tro assays, using MMP-1, MMP-2, MMP-7, MMP-9, MMP-12, MMP-13 and Agrecanase-1. The inhibitory potencies of some of the compounds of the invention are shown in Table 5. The values are given as IC 50 in nanomolar, or as percentage of inhibition at a given micromolar concentration. to. In vitro fluorescence assay of MMP-1 activity: A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group (7-methoxycoumarin; Mea), which rapidly cools by energy transfer to a 2,4-dinitrophenyl group. When the peptide is divided by MMP, a large increase in fluorescence is observed. The enzyme source in the assay was the recombinant human catalytic domain of MMP-1, prepared at Wyeth-Research in Cambridge. The substrate used was Mca-PQGL- (3- (2,4-dinitrophenyl) -L-2,3-diaminopropionyl) -AR-OH (designated Wammp-5, synthesized at client's request by AnaSpec, Inc.). The assay buffer consists of 50 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM CaCl2, and Brij-35 at 0.005%. Each well of the black 96-well polystyrene plates contained a 200 μl reaction mixture which consisted of a test buffer, purified MMP (at a final concentration of 25 ng / ml, prepared by dilution with the assay buffer), and varying concentrations of inhibitor (prepared by serial dilution of a given inhibitor in DMSO in a 96-well polypropylene plate). The plates were then incubated at 30 ° C for 15 minutes. Enzymatic reactions were initiated by adding substrate to a final concentration of 20 μM, and mixing 10 times with a pipette. The final concentration of DMSO in the assay was 6.0%. The initial rate of the cleavage reaction at a temperature of 30 ° C was determined with a fluorescence plate reader (excitation filter 330 nm and emission filter 395 nm), immediately after adding the substrate. The graphs of inhibitor concentration vs. the percentage of inhibition was adjusted to the following equation: y = (a-d) / [1+ (x / c) b] + d, a general sigmoid curve with Hill slope, from a to d. x is the concentration of the inhibitor under test. and is the inhibition percentage, a is the limit response when x approaches zero. As x increases in an unlimited way, and tends towards its limit d. c is the inflection point (IC50) for the curve, that is, "y" is at the midpoint between the lower and upper asymptotes when x = c, b is the slope factor or Hill coefficient. b. In vitro fluorescence assay of MMP-2 activity: A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group (7-methoxycoumarin; Mea), which rapidly cooled by energy transfer to a 2,4-dinitrophenyl group. When the peptide is divided by MMP, a large increase in fluorescence is observed. The source of the enzyme in the assay was recombinant human MMP-2 (66 kDa), purchased from Oncogene Research Products (catalog number PF023 from Calbiochem). The substrate used was Mca-PQGL- (3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -AR-OH (designated Wammp-5, synthesized at the request of the client by AnaSpec, Inc.). The assay buffer consists of 50 M HEPES (pH 7.4), 100 mM NaCl, 5 mM CaCl 2, and Brij-35 at 0.005%. Each well of the black 96-well polystyrene plates contained a 200 μl reaction mixture consisting of a test buffer, MMP (final concentration of 25 ng / ml, prepared by dilution with the assay buffer), and varying concentrations of inhibitor (prepared by serial dilution of a given inhibitor in DMSO on a plate of 96-well polypropylene). The plates were then incubated at 30 ° C for 15 minutes. Enzymatic reactions were initiated by adding substrate to a final concentration of 20 μM, and mixing 10 times with a pipette. The final concentration of DMSO in the assay was 6.0%. The initial rate of the division reaction at 30 ° C was determined with a fluorescence plate reader (330 nm excitation filter and 395 nm emission filter), immediately after adding substrate. 10. Graphs of inhibitor concentration vs. the percentage of inhibition was adjusted to the following equation: y = (a-d) / [1+ (x / c) b] + d, a general sigmoid curve with Hill slope, between a and d. "x" is the concentration of the inhibitor under test. "and" is the percentage of inhibition. ? a "is the limit response when x" approaches zero. As? X "increases unlimitedly, ?? and" tends towards its limit d. ?? c "is the inflection point (IC50) for the curve, that is," y "is at the midpoint between the lower and upper asymptotes when 0 x = c. ?? b" is the slope factor or coefficient of Hill. c. Xn vitro Fluorescence Assay of MMP-13 Activity: A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group 5 (7-methoxycoumarin; Mea), which rapidly cools by transfer of energy to a 2,4-dinitrophenyl group. When the peptide is divided by MMP, a large increase in fluorescence is observed. The source of the enzyme in the assay was the recombinant human catalytic domain of MMP-13 (165 amino acids, residues 104-268, 19 kDa), prepared at Wyeth Research in Cambridge. The substrate used was Mca-PQGL- (3- [2, 4-dinitrophenyl] -L-2,3-diaminopropionyl) -AR-OH (designated Wammp-5, synthesized at the request of the client by AnaSpec, Inc.) . The assay buffer consisted of 50 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM CaCl2, and Brij-35 at 0.005%. Each well of the 96 black polystyrene well plates contained a 200 μl reaction mixture consisting of assay buffer, purified MMP (final concentration 0.5 nM, prepared by dilution with the assay buffer), and varying concentrations of inhibitor (prepared by serial dilution of a given inhibitor in DMSO in a 96-well polypropylene plate). The plates were then incubated at 30 ° C for 15 minutes. Enzymatic reactions were initiated by adding substrate to a final concentration of 20 μM, and mixing 10 times with a pipette. The final concentration of DMSO in the assay was 6.0%. The initial rate of the division reaction at 30 ° C was determined with a fluorescence plate reader (excitation filter 330 nm and emission filter 395 n), immediately after adding substrate.

The graphs of inhibitor concentration vs. the percentage of inhibition was adjusted to the following equation: y = (a-d) / [1+ (x / c) b] + d, a general sigmoid curve with Hill slope, between a and d. "x" is the concentration of the inhibitor under test. "y" is the percentage of inhibition. "a" is. the limit response when "x" approaches zero. As x increases unlimitedly, X? Y "tends toward its limit d." C "is the inflection point (CI50) for the curve, that is," y "is at the midpoint between the lower asymptotes and higher when x = c. "b" is the slope factor or Hill coefficient. d. In vitro fluorescence assay of M-P-14 activity: A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group (7-methoxycoumarin; Mea), which rapidly quenches by energy transfer to a Group 2, 4-dinitrophenyl. When the peptide is divided by the MMP, a large increase in fluorescence is observed. The source of the enzyme in the assay was the recombinant human catalytic domain of MMP-14 (177 amino acids corresponding to Tyr89-Gly265 of the mature human enzyme, 20 kDa), purchased from Chemicon International, Inc. (catalog number CC1041). The substrate used was Mca-PQGL- (3- [2, 4-dinitrophenyl] -L-2, 3- diaminopropionyl) -AR-OH (designated Wammp-5, synthesized at the request of the client by AnaSpec, Inc.). The assay buffer consisted of 50 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM CaCl2, and Brij-35 at 0.005%. Each well of the black 96-well polystyrene plates containing a 200 μl reaction mixture consisting of a test buffer, purified MMP (final concentration of 25 ng / ml, prepared by dilution with the assay buffer), and varying concentrations of inhibitor (prepared by serial dilution of a given inhibitor in DMSO in a 96-well polypropylene plate). The plates were then incubated at 30 ° C for 15 minutes. Enzymatic reactions were initiated by adding substrate to a final concentration of 20 μM, and mixing 10 times with a pipette. The final concentration of DMSO in the assay was 6.0%. The initial rate of the cleavage reaction at a temperature of 30 ° C was determined with a fluorescence plate reader (excitation filter of 330 nm and emission filter of 395 nm), immediately after the substrate addition. The graphs of inhibitor concentration vs. the percentage of inhibition was adjusted to the following equation: y = (a-d) / [1+ (x / c) b] + d, a general sigmoid curve with Hill slope, between a and d. x "is the inhibitor concentration tested." and "is the percent inhibition," a "is the limit response when x" approaches zero. TO measure that? x "increases in an unlimited way, and tends towards its limit? d". "c" is the inflection point (IC50) for the curve. That is, "y" is at the midpoint between the lower and upper asymptotes when x = c. "b" is the slope factor or Hill coefficient. and. MMP-7 activity assay: A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group (7-methoxycoumarin; Mea), which rapidly cools by energy transfer to a 2-dinitrophenyl group . When the peptide is divided by MMP, a large increase in fluorescence is observed. Active recombinant human MMP-7 was purchased from Calbiochem (catalog No. 444270, expressed in E. coli, 19 kDa). The substrate used was Mca-PLG L- (3- [2, 4-dinitrophenyl] -L-2,3-diaminopropionyl) -AR-NH 2 (purchased from Bache or AnaSpec, Inc., first described by Knight, CG, Willenbrock, F., and Murphy, G., FEBS Lett. (1992) 296. 263-266). The initial substrate concentration was determined spectrophotometrically using 7500 M "1ci? F1 as the extinction coefficient at 410 nm. The assay buffer (pH 7.4) consisted of 50 mM HEPES, 100 M NaCl, 5 mM CaCl2, and Brij. -35 to 0.005% Each well of the 96 black polystyrene well plates consisted of a reaction mixture that was filled with assay buffer, purified MMP (final concentration of 1.0 nM, prepared by dilution with the assay buffer), and varying concentrations of inhibitor (prepared by serial dilution of a given inhibitor in DMSO in a 96-well polypropylene plate). The plates were then incubated at room temperature for 30 minutes. Enzymatic reactions were initiated by adding substrate to a final concentration of 15 μM, and were mixed by pipetting. The final concentration of DMSO in the assay was 10% and the total final assay volume was 200 μl. The initial rate of the cleavage reaction at room temperature was determined with a fluorescence plate reader (excitation at 325 nm with a bandwidth of 12 nm and emission at 395 nm with a bandwidth of 12 nm), immediately after to add substrate. The graphs of inhibitor concentration vs. the initial division rate was adjusted to the following equation to determine IC50 values: y = Vmax * (1- (Xn / (Kn + Xn))), whereby "x" = inhibitor concentration,? and " = initial velocity, Vmax = initial velocity in the absence of inhibitor, "n" = slope factor, and X? K "= IC50 for the inhibition curve.

F. MP-9 activity assay: Active recombinant human MMP-9 (83 kDa) was purchased from Calbiochem (catalog No. PF024). He Test procedure was identical to that described for MMP-7, except that the final enzyme concentration was 0.5-1.0 nM and the final substrate concentration was 20 μM. g. In vitro fluorescence assay of MMP-12 activity: A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group (7-methoxycoumarin; Mea), which is rapidly cooled by energy transfer to a group 2,4-dinitrophenyl. When the peptide is divided by MMP, a large increase in fluorescence is observed. The enzyme source in the assay was recombinant human MMP-12 (19 kDa; "A280" form), purified in Wyeth Research (Biological Chemistry, Cambridge). The substrate used was Mca-PLGL- (3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -AR-NH2 (purchased from Bachem or AnaSpec, Inc., described for the first time by Knight, C.G., Wilienbrock, F., and Murphy, G., FEBS Lett. (1992) 296, 263-266). The initial substrate concentration was determined spectrophotometrically using 7500 M-1cm-1 as the extinction coefficient at 410 nm. The assay buffer (pH 7.4) consisted of 50 mM HEPES, 100 mM NaCl, 5 mM CaCl2, and Brij-35 at 0.005%. Each well of the black 96-well polystyrene plates contains a reaction mixture consisting of assay buffer, purified MMP (final concentration of 1.5 nM, prepared by dilution with assay buffer), and varying concentrations of inhibitor (prepared by serial dilution of a given inhibitor in DMSO in a 96-well polypropylene plate). The plates were then incubated at room temperature for 30 minutes. Enzymatic reactions were initiated by adding substrate to a final concentration of 20 μM, and were mixed by pipette. The final concentration of DMSO in the assay was 10% and the total final assay volume was 200 μl. The initial rate of the cleavage reaction at room temperature was determined with a fluorescence plate reader (excitation at 325 nm with a bandwidth of 12 nm and emission at 395 nm with a bandwidth of 12 nm), immediately after to add substrate. The graphs of inhibitor concentration vs. The initial division velocity was adjusted to the following equation: y = Vmax * (1- (xn / (Kn + x))), whereby x = concentration of the inhibitor, y = initial velocity, Vma? = initial velocity in the absence of inhibitor, n = slope factor, and K = IC50 for the inhibition curve. g. FRET assay of aggrecanase-1: The following protocol was used: The fluorimeter was started and the temperature was adjusted to 30 ° C, approximately 30 minutes before preparing the test. The following reagents were used: Buffer: 50 mM HEPES, pH 7.5, 100 mM NaCl, 5 mM CaCl2, 0.1% CHAPS, 5% glycerol. rAqql: 5 μg / ml (final concentration in the assay). Substrate: WAAG-3R (MWT = 1645.8, Anaspec, stored at 4 ° C). An initial mixture of 2 mg / ml in 100% DMSO was made. The absorbance at 354 nm (e = 18172 M "^" 1) was measured to determine the exact concentration. It was diluted to 62.5 μM in buffer. The initial mixture not used in 100% DMSO was stored at -80 ° C. The final concentration of the substrate in the assay is 25 μM. This concentration is much lower than Km (Km = 1.1 +/- 0.2 mM, determined by Jin and Cowling). Inhibitors: The inhibitors were made at an initial concentration of 10x in 100% DMSO. Serial dilutions (in duplicate) were made in 100% DMSO, along a Nunc well plate. Dilution plates: Nunc, low adsorption polypropylene (Nalgene) Test plate: Fluoronunc (Nalgene) Fluorimeter: GeminiXS (Molecular Devices); The assay was performed as follows: The plates were adjusted so that the final column (12) is used for the controls. The total reaction volume is 100 μl. Each compound is tested in duplicate, so they are analyzed 4 compounds per plate. 1) Buffer was added to the entire 96-well plate (30 μl / well). 2) Agg-lr was diluted to 25 μg / ml in buffer just before adding to the plate. 20 μl / well was added to all wells. It was mixed 6 times. 3) 10 μl / well of lOx inhibitors was added from the work plate, except in column 12. Mixed 6 times. To wells 12A-F, 10x controls were added (see reference compounds below). 4) 10 μl of 100% DMSO was added to the 12G-H wells. 5) It was incubated for 10-15 minutes at 30 ° C. 6) 40 μl / well of WAAG-3R substrate was added. It was mixed 6 times. The reaction was monitored for 30-40 minutes at 30 ° C (? Ex: 340 nm and? Em = 420 nm). The fluorescence is linear during this time and the slope of the line (Vmax / s) represents the initial reaction speed, v. The maximum substrate cleavage rate is determined in the absence of inhibitor. The percentage of inhibition of activity in the presence of an inhibitor is calculated as follows: % inhibition = (l-v (Velocity, RFU / sec) / Maximum Velocity (RFU / sec)) * 100 IC50 was obtained by adjusting the initial velocity, v, or% inhibition of each inhibitor concentration to the Next equation in Excel: y = (a-d) / (l + C / IC5o)? Ji} + d This model describes a sigmoid curve with an adjustable baseline, "a". "and" is the% inhibition or initial reaction rate, "C" is the inhibitor concentration under test. N? A "is the limit response when ?? C" approaches zero. As "C" increases unlimitedly and tends toward its lower limit,? D ". N? Y" is at the midpoint between the lower and upper asymptotes when C = Clso. Vn "is the Hill coefficient.The sign of" n "is positive when the response increases when the dose increases, and it is negative when the response decreases when the dose increases (inhibition) Table 5 lists the activities of the compounds of Examples 1-179 All values are IC50 in nanomolar, or% inhibition at a concentration (uM).

TABLE 5 The descriptions of each patent, patent application or publication cited or described in this document are incorporated herein by reference, in their entirety. In addition to those described herein, various modifications of the invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be within the scope of the appended claims.

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

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Method for modulating the activity of a metalloproteinase, characterized in that it comprises contacting the metalloproteinase with an effective amount of a biaryl sulfonamide bound to a heteroaryl radical.

2. Method according to claim 1, characterized in that it additionally comprises determining the activity of the metalloproteinase.

Method according to claim 2, characterized in that the determination is made before the contact stage.

Method according to claim 2, characterized in that the determination is made after the contact stage.

Method according to claim 1, characterized in that the metalloproteinase is Gelatinase A, Macrophage metalloelastase, Collagenase-3 or Agrecanase-1.

Method according to claim 1, characterized in that the metalloproteinase is macrophage metalloelastase or collagenase-3.

7. Method according to claim 1, characterized in that the compound has the formula 1 wherein: R1 and R2 are, independently, H, CH (OH) R4, phenyl, heteroaryl, or C? -C6 alkyl, with the proviso that, when R1 or R2 is CH (OH) R4, then Z is replaced with NR4S02R5, S02NR4R5, heterocycloalkyl, heteroaryl or C3-C6 cycloalkyl; R3 is H or C6-C6 alkyl; R4 and R5 are, independently with respect to each event, a bond with the other, H, C? -C6 alkyl, or phenyl; G and E are, independently, S, O, N (R4), C (R6) = C (R6), or N = C (R6); R6 is, independently with respect to each event, H, halogen, NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NRS02R5, NR4C (= 0) R5, NHC (= 0) OR4 , N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl, heteroaryl, d-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; X is N (R3) C (= 0), OC (= 0), OS (0) 2, NHS02, OCH2, CH2S (0), or CH2S (0) 2; and Z is at least one heteroaryl radical.

8. Method according to claim 7, characterized in that R1 is substituted with halogen, CO2R4, C (= 0) NR4R5, phenyl or heteroaryl.

9. Method according to claim 7, characterized in that R3 is substituted with NR4R5, N [(CH2) 2] 2? N [(CH2) 2] 2NR4, NR4S02R5, NRC (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

10. Method according to claim 7, characterized in that R6 is optionally substituted with NRR5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NRC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4 , COOR4, CONR4R5, CN, phenyl or heteroaryl.

Method according to claim 7, characterized in that Z is a 5-membered ring.

12. Method according to claim 7, characterized in that Z is bicyclic.

13. Method according to claim 7, characterized in that Z is furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, thiazole, 1,2,5-thiadiazole, 1, 2, 3-triazole, 1, 3, -thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and furazane, or U is selected from S, O and N (R4); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R4); R7 is selected from a bond with R6, H, halogen, 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, C? -C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally substituted with NR4R5, N [( CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R5 , CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C3 alkyl, optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NRS02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

14. Method according to claim 7, characterized in that Z is: U is selected from S, O and N (R); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N, and N (R4); R7 is selected from a bond with R6, H, halogen, 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 and Ci-Ce alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2 ] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NR4S02R5, NRC (= 0) R5 , NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

15. Method according to claim 7, characterized in that: R3 is H; G is C (H) = C (H); E is C (H) = C (H) or N = C (H); X is NHC (= 0), or OCH2; Y wherein: U is selected from S, O and N (R4); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R4); R7 is selected from a bond with R6, H, halogen, NR4R3, N [(CH2) 2] 20, N [(CH2) 2] 2NR, NHS02R \ NR * C (= 0) R3, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) ) R4, COOR4, CONR4R5, CN, phenyl, heteroaryl and C! -C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally substituted with NR4R5, N [(CH2)] 2 ?, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR8, C (= 0) R4, COOR4, C0NRR5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

16. Method according to claim 15, characterized in that: E is C (H) = C (H); U is 0; W is C (H), or C (CH3); M is C (R9), where R9 is H, halogen, C? -C6 alkyl, or CN; and L is C (H) = C (H).

17. Method according to claim 7, characterized in that R1 and R2 are each d-C6 alkyl.

Method according to claim 7, characterized in that R3 is H.

19. Method according to claim 7, characterized in that R4 and R5 are a Ci-Ce alkyl.

Method according to claim 7, characterized in that G and E are each C (H) = C (H).

21. Method according to claim 7, characterized in that U is 0 or S.

22. Method according to claim 7, characterized in that W is C (H) or C (CH3).

23. Method according to claim 7, characterized in that M is CR6.

24. Method according to claim 7, characterized in that L is CH = CH.

25. Method according to claim 7, characterized in that R7 is different from H.

26. Method for treating a patient suspected of suffering from a disease associated with excessive metalloproteinase activity, characterized in that it comprises the step of administering to the patient a therapeutically effective amount of a biaryl sulfonamide attached to a heteroaryl radical.

27. Method according to claim 26, characterized in that the disease is cancer, ost eoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, macular degeneration related to age, myocardial infarction, corneal ulcer and other diseases of the ocular surface, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft-versus-host disease, diabetes, inflammatory bowel disease, shock, degeneration of discs intervertebral, apoplexy, osteopenia, or periodontal diseases.

28. Method according to claim 25, characterized in that the compound is formula 1: R1 and R2 are, independently, H, CH (OH) R4, phenyl, heteroaryl, or C? -C6 alkyl, with the proviso that, when R1 or R2 is CH (OH) R4, then Z is substituted with NR4S02R5, S02NR4R5, heterocycloalkyl, heteroaryl or C3-Cd cycloalkyl; R3 is H or C6-C6 alkyl; R4 and R5 are, independently with respect to each event, a bond with the other, H, CX-C6 alkyl, or phenyl; G and E are, independently, S, 0, N (R4), C (R6) = C (R6), or N = C (R6); • R6 is, independently with respect to each event, H, halogen, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR C (= 0) R5, NHC (= 0) 0R4, N02, S02NR4R5, S02R4, OR 4, C (= 0) R 4, COOR 4, CONR 4 R 5, CN, phenyl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; X is N (R3) C (= 0), 0C (= 0), 0S (0) 2, NHS02, 0CH2, CH2S (0), or CH2S (0) 2; and Z is at least one heteroaryl radical.

29. Method according to claim 28, characterized in that R1 is optionally substituted with halogen, C02R4, C (= 0) NR R5, phenyl or heteroaryl.

30. Method according to claim 28, characterized in that R3 is optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0 ) OR4, N02, S02NR R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

31. Method according to claim 28, characterized in that R6 is optionally substituted with NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NR S02R5, NR4C (= 0) R5, NR4C ( = 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl or heteroaryl.

32. Method according to claim 28, characterized in that Z is a 5-membered ring.

33. Method according to claim 28, characterized in that Z is bicyclic.

34. Method according to claim 28, characterized in that Z is furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, thiazole, 1, 2, 5-thiadiazole, 1,2,3-triazole, 1,3-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1, 2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and furazane, or wherein: U is selected from S, O and N (R4); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R4) R7 is selected from a bond with Rf H, halogen, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR R5, CN, phenyl, heteroaryl, C? -C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally 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, CONR R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C1-C6 alkyl, optionally substituted with NR R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR 'NR4S02R5 NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NR R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

35. Method according to claim 28, characterized in that Z is: U is selected from S, 0 and N (R); W is selected from C (R6) and N; M is selected from C (R6) and N; is selected from C (R6) = C (R6) C (R6) = N, and N (R4); R7 is selected from a bond with R6, H, halogen, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR C (= 0) R5, NHC (= 0) 0R4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, phenyl, heteroaryl and Ci-Cß alkyl, C2-C6 alkenyl, and C2-Ce alkynyl, each optionally substituted with NR4R5, N [ (CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NR R5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; Y R8 is selected from H, phenyl, heteroaryl, and Ci-Ce alkyl, optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR S02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

36. Method according to claim 28, characterized in that: R3 is H; G is C (H) = C (H); E is C (H) = C (H) or N = C (H); X is NHC (= 0), or 0CH2; Y U is selected from S, 0 and N (R); W is selected from C (RS) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R- R7 is selected from a bond with R6, H, halogen, NR R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR R5, C, phenyl, heteroaryl and C? -C5 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally substituted with NR4R5, N [(CH2) 2] 2? , N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR R5, S02R4, OR8, C (= 0) R4, COOR4, CONR R5, CN, cycloalkyl , heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and Ci-Cg ^ alkyl optionally 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, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

37. Method according to claim 36, characterized in that: E is C (H) = C (H); U is O; W is C (H), or C (CH3); M is C (R9), where R9 is H, halogen, C? -C6 alkyl, or CN; and L is C (H) = C (H).

38. Method according to claim 28, characterized in that R1 and R2 are each C? -C6 alkyl.

39. Method according to claim 28, characterized in that R3 is H.

40. Method according to the claim 28, characterized in that R4 and R5 are each C? -C6 alkyl.

41. Method according to claim 28, characterized in that G and E are each C (H) = C (H).

42. Method according to claim 28, characterized in that U is 0 or S.

43. Method according to claim 28, characterized in that W is 0 (H) or C (CH3).

44. Method according to claim 28, characterized in that M is CR6.

45. Method of compliance with the claim 28, characterized in that L is CH = CH.

46. Method according to claim 28, characterized in that R7 is different from H.

47. Compound of formula 1: characterized in that R1 and R2 are, independently, H, CH (0H) R4, phenyl, heteroaryl, or Ci-Ce alkyl, with the proviso that, when R1 or R2 is CH (OH) R4, then Z is substituted with NR4S02R5 , S02NR4R5, heterocycloalkyl, heteroaryl or C3-C6 cycloalkyl, "R3 is H or C? -C6 alkyl; R4 and R5 are, independently with respect to each event, a bond with the other, H, C? -C6 alkyl, or phenyl; G and E are, independently, S, 0, N (R4), C (R6) = C (R6), or N = C (R6); R6 is, independently with respect to each event, H, halogen, NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NR R5, S02R4, OR 4, C (= 0) R 4, COOR 4, CONR 4 R 5, CN, phenyl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 5 alkenyl or C 2 -C 6 alkynyl; X is N (R3) C (= 0), OC (= 0), 0S (0) 2, NHS02, 0CH2, CH2S (O), or CH2S (0) 2; and Z is at least one heteroaryl radical.

48. Compound according to claim 47, characterized in that R1 is substituted with halogen, C02R4, C (= 0) NR4R5, phenyl or heteroaryl.

49. Compound according to claim 47, characterized in that R3 is substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) 0R4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

50. Compound according to claim 47, characterized in that R6 is optionally substituted with NR4R5, N [(CH2) 2-2 ?, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NR4C (= 0) OR4, N02, S02NR4R5, S02R4, OR4, C ( = 0) R4, COOR4, CONR4R5, CN, phenyl or heteroaryl.

51. Compound according to claim 47, characterized in that Z is a 5-membered ring.

52. Compound according to claim 47, characterized in that Z is bicyclic.

53. Compound according to claim 47, characterized in that Z is furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, thiazole, 1, 2, 5-thiadiazole, 1, 2, 3-triazole, 1, 3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and furazane, or wherein U is selected from S, O. and N (R); it is selected from C (R6) and N; M is selected from C (R) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R4); R7 is selected from a bond with R6, H, halogen, NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NHS02R4, NR C (= 0) R5, NHC (= 0) OR4 , N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, C0NR4R5, CN, phenyl, heteroaryl, Ci-Ce alkyl, C2-Cd alkenyl and C2-C6 alkynyl, each optionally substituted with NR R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR8, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NR4R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5 , NHC (= 0) OR4, N02, S02NR R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

54. Compound according to claim 47, characterized in that Z is: where U is selected from S, 0 and N (R); it is selected from C (R6) and N; M is selected from C (R6) and N; is selected from C; R6) = C (R6) C (R6) = N, and N (R4) R7 is selected from a bond with R6, H, halogen, NR R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR C (= 0) R5, NHC ( = 0) OR4, N02, S02NR4R5, S02R4, OR4, C (= 0) R4, COOR4, CONR R5, CN, phenyl, heteroaryl and C! -C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with NR4R5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, OR8, C ( = 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally substituted with NR R5, N [(CH2) 2] 2 ?, N [(CH2) 2] 2NR4, NR4S02R5, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR4R5, S02R4, C (= 0) R4, COOR4, CONR4R5, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

55. Compound in accordance with the claim 47, characterized in that: R3 is H; G is C (H) = C (H); E is C (H) = C (H) or N = C (H); X is NHC (= 0), or OCH2; Y where: ü is selected from S, O and N (R4); W is selected from C (R6) and N; M is selected from C (R6) and N; L is selected from C (R6) = C (R6), C (R6) = N and N (R4); R7 is selected from a bond with R6, H, halogen, NRR5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NR? IlnR5D, CN, phenyl, heteroaryl and C?-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, each optionally substituted with NRR5, N [(CH2) 2] 20, N [(CH2) 2] 2NR4, NHS02R4, NR4C (= 0) R5, NHC (= 0) OR4, N02, S02NRR5, S02R4, OR8, C (= 0) R4, COOR4, CONRR ?, CN, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl; and R8 is selected from H, phenyl, heteroaryl, and C? -C6 alkyl, optionally 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, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl.

56. Compound according to claim 55, characterized in that: E is C (H) = C (H); U is O; W is C (H), or C (CH3); M is C (R9), where R9 is H, halogen, Ci-Ce alkyl, or CN; and L is C (H) = C (H).

57. Compound according to claim 47, characterized in that R1 and R2 are each a C? -C6-58 alkyl.

Compound according to claim 47, characterized in that R3 is H.

59. Compound in accordance with the claim 47, characterized in that R4 and R5 are each Ci-Cß alkyl.

60. Compound according to claim 47, characterized in that G and E are each C (H) = C (H).

61. Compound according to claim 47, characterized in that U is O or S.

62. Compound according to claim 47, characterized in that W is 0 (H) or C (CH3).

63. Compound according to claim 47, characterized in that M is CR5.

64. Compound in accordance with the claim 47, characterized in that L is CH = CH.

65. Compound according to claim 47, characterized in that R7 is different from H.

66. Compound according to claim 47, characterized in that N- ( { '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) glycine; L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] biphenyl-4-sulfonylamino} -3-methyl-butyric; N- (. {4 '- [(1H-indol-2-ylcarbonyl) amino] -1, 1' -biphenyl-1, yl] sulfonyl) glycine; (4 '- { [(5-chloro-l-benzofuran-2-yl) carbonyl] amino.} -1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(7-methoxy-l-benzofuran-2-yl) carbonyl] amino] -! -! 1'-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '-. {[[(5-nitro-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-amino-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- (. {4 '- [( { 5- [(methylsulfonyl) amino] -l-benzofuran-2-yl} .carbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-valine; N-. { [4 '- ( { [5- (acetylamino) -l-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; 4 '- [(5-benzenesulfonylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine; N- [(4 '- { [(4-methoxy-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; 4 '- [(benzo [ß] thiophen-2-carbonyl) -amino] -biphenyl-4-sulfonyl-L-valine; 4 '~ [(4-benzyloxy-benzofuran-2-carbonyl) -amino] - biphenyl-sulfonyl-L-valine; 4' -. { [4- (1-carboxy-ethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonyl-L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-asparagine; L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-histidine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -L-leucine; L-2- acid. { 4 '- [(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-prop-1-ynyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- (4 '- { [4- (3-methoxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - 3-methyl-butyric; 2- acid. { 4 '- [(4-cyclopropylethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4'- { [4- (2-cyclopropyl-ethyl) -3-methyl- acid benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid; L-2- (4'- { [4- (3-methoxy-Z-propenyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3- acid methyl-butyric; L-2- (4'- { [4- (3-hydroxy-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - 3-methyl-butyric; L-2- (4 '- { [4- (3-hydroxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-ethyl acid butyric; L-3-methyl-2- (4'- { [3-methyl-4- (4-methyl-pent-1-ynyl) -benzofuran-2-carbonyl] -amino} -biphenyl-4 acid -sulfonylamino) butyric; L-3-Methyl-2- (4'- { [3-methyl-4- (4-methyl-pentyl) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) butyric acid; L-2- (4 '- { [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-2- (4 '- { [4- (3-Dimethylamino-prop-1-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - 3-methyl-butyric; L-2- (4'- { [4- (3-dimethylamino-propyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3- acid methyl-butyric; L-2- acid. { 4 '- [(4-ethynyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4'- { [4- (3, 3-dimethyl-but-l-ynyl) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino ) -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] -amino] -biphenyl-4 acid sulfonylamino) butyric; L-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4 '- { [4- (methanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-3-hydroxy-2- (4-. {5 - [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl}. -benzenesulfonylamino) -butyric acid; L-2- (4- { 5- [(4-Methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl-butyric acid; L-2- (4- { 5- [(4-Cyano-3-methyl-benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl-butyric acid; D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl- benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- ( {4 '- [(4-cyano-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl} - methyl-amino) -3-methyl- butyric; triethylamine salt of L-3-methyl-2 ~ acid. { 4 '- [(3-methyl-4-methylcarbamoyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; triethylamine salt of 2- acid. { 4 '- [(4-dimethylcarbamoyl-3-methyl-benzofuran-2-carbonyl) -amino} -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4,6-Dimethoxy-3,7-dimethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; 2- acid. { 4 '- [(5-bromo-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-carbamoyl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid _ L-2- (4 '- { [4- (cyclopropancarbonyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl-butyric acid; L-2- acid. { 4 '- [(4-acetylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-propionylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} - butyric; L-2- acid. { 4 '- [(4-isobutyrylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3- ethyl-butyric; L-2- acid. { 4 '- [(1H-benzimidazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-sec-butoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- (4'- { [4- (Acetyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-3-methyl-2- (4'- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino -butyric; L-2- (4 '- { [4- (3, 3-dimethyl-butyl) -3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino acid} -3-methyl-butyric; L-2- acid. { 4 '- [(3-ethyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-tert-butoxycarbonylamino-3-methyl- benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-methylamino-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- acid. { 4 '- [(4-amino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { '- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- ( { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonyl.} - ethyl-amino) -3-methyl- butyric; L-3-hydroxy-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-Methyl-2- (4'- { [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl] -amino} -biphenyl-4-sulfonylamino acid -butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (2,2,2-trifluoro-acetylamino) -benzofuran-2-carbonyl] -amino acid} -biphenyl-4 -sulfonylamino) -butyric; L-2- acid. { 4 '- [(4-ethanesulfonylamino-3-methyl- benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (propane-2-sulfonylamino) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - butyric; L-2- (4'- { [4- (Ethanesulfonyl-methyl-amino) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) -3-methyl- butyric; L-2- acid. { 4 '- [(4-Benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - Butyric; L-2- (4 '- { [4- (1,1-dioxo-l, 6-isothiazolidin-2-yl) -3-methyl-benzofuran-2-carbonyl] -amino acid} -biphenyl -4-sulfonylamino) -3-methyl-butyric; D-3-methyl-2- acid. { 4 '- [(3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; D-2- acid. { 4 '- [(benzofuran-2-carbonyl) -methylamino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; 4- . { 5- [(benzofuran-2-carbonyl) -amino] -pyridin-2-yl} -benzenesulfonyl-L-valine N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) mino] -1,1' -biphenyl-4-yl.} sulfonyl) -N-methyl-D- valina; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) -N-methyl-L-valine; N- ( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -N-methylglycine; acid (S) -2-. { 4 '- [(1, 3-dimethyl-lH-thieno [2,3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1'-biphenyl-4-yl.} - sulfonyl) -N- (pyridin-3-ylmethyl) -L -valina; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} - sulfonyl) -N- (2-morpholin-4-ylethyl) - L-valine; N- [(4 '- { [(3-methyl-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-bromo-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [(4-methyl-3, 4,5,6-tetrahydrofuro [4,3,2-ef] [3] benzazepin-2-yl) carbonyl] amino.} - !, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-ethyl-4-methoxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino] .l, 1'-biphenyl-4- il) sulfonyl] -L-valine; N- [(4'- { [(4-ethyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L -valina; N- [(4'- { [(5-ethyl-4-isopropoxy-3-methyl-1-benzofuran-2-yl) carbonyl] aminoj-1,1 '-biphenyl-4-yl) sulfonyl} -L-valine; N-. { [4 '- ( { [4- (benzyloxy) -5-ethyl-3-methyl-l- benzofuran-2-yl] carbonyl} amino) -1,1 '-biphenyl-4-yl] sulfonyl} - L-valine; N- [(4 '- { [(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1'-biphenyl-4-yl] sulfonyl} -L-valine; N-. { [4 '- ( { [4- (hydroxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N- [(4'- { [(3, 4-dimethyl-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]: -! 1'-biphenyl-4-yl) sulfonyl] -L -valina; N- [(4 '- { [(1-hydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L -valina; N-. { (4 '- ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1, 1' -biphenyl-4-yl] sulfonyl .) .L-valine; N-methyl-N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino.}. -l, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- { [4' - ( { [4- (1, 2-dihydroxyethyl) -3-methyl-1-benzofuran-2-yl carbonyl.} amino) -1,1'-biphenyl-4-yl] sulfonyl.} - N-methyl-L-valine; N-. { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N-. { [4 '- ( { [4- (1-Methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N-. { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-Valinate; N- [(4 '- { [(4-isopropoxy-1-benzofuran-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-methoxy-l-benzofuran-2-yl) carbonyl] amino] -! -! 1'-biphenyl-4-yl) sulfonyl] -L-valine; acid (S) -2-. { '- [(4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(4-Ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-propoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-phenyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-Methyl-2- (4'- { [3-methyl-4- (3-nitro-phenyl) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid -butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} - butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (R) -2- acid. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3- methyl-butyric; acid (S) -2-. { 4 '- [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -2- (4'-. {[[5- (l-Chloro-vinyl) -4-methoxy-3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino ) -3-methyl-butyric; acid (S) -2-. { 4'- [(5-Acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-methyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4'- [(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (S) -3-methyl-2-. { '- [(benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(4-methyl-benzooxazol-2- carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-chloro-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-trifluoromethyl-benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -3,5-dimethyl-biphenyl-4-yl ester of D-benzofuran-2-carboxylic acid; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of D-3-methyl-benzofuran-2-carboxylic acid; 4 '- (1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester of benzofuran-2-carboxylic acid; D-2- acid. { 4 '- (5-Bromo-4-methoxy-3-methyl-benzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; D-2- [4 '- (benzothiazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; D-3-methyl-2- [4 '- (l-methyl-lH-benzoimidazol-2-ylmethoxy) -biphenyl-4-sulfonylamino] -butyric acid; D-3-methyl-2- [4 '- (3-methyl-benzofuran-2-ylethoxy) -biphenyl-4-sulfonylamino] -butyric acid; D-2- [4 '- (benzofuran-2-ylmethoxy) -3' -methoxy-biphenyl-4-sulfonylamino] -3-methyl-butyric acid; D-2- [4 '- (benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; L-2- [4 '- (5-chloro-4-methoxy-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; L-2- [4 '- (5-cyano-4-methoxy-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; N-. { [4'- (2-furoyloxy) -1,1 '-biphenyl-4-yl] sulfonyl} -D-Valine; N-. { [4 '- (3-furoyloxy) -l, 1-biphenyl-4-yl] sulfonyl} -D-Valine; L-2- [4 '- (4-ethyl-3-methyl-benzofuran-2-ylmethoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; N- [(4 '- { [4- (3-methoxypropyl) -3-methyl-1-benzofuran-2-yl] methoxy.] -! 1' -biphenyl-4-yl) sulfonyl] - L-valine; N- ( {4 '- [(5-bromo-4-methoxy-3-methyl-1-benzofuran-2-yl) methoxy] -1,1' -biphenyl-4-yl}. Sulfonyl) - L-valine; N- ( {4 '- [(5-bromo-4-isopropoxy-3-methyl-1-benzof ran-2-yl) methoxy] -1,1' -biphenyl-4-yl.} Sulfonyl) -D-Valine; N- [(4'- { [(5-bromo-4-methoxy-3-methyl-l-benzofuran-2-yl) methyl] amino.} -! 1 '-biphenyl-4-yl) sulfonyl] -L-valine; L-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; D-2- acid. { 4 '- [(benzothiazole-2-carbonyl) -amino] - biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- acid. { 4 '- [(naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-3-methyl-2- acid. { 4 '- [(1-methyl-naphtho [2, 1-b] furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-3-methyl-2- acid. { 4 '- [(3-methyl-4-phenoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; L-2- (4'- { [4- (1-methoxycarbonyl-l-methyl-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - 3-methyl-butyric; L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid L-2-. { 4 '- [(4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-carboxymethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - butyric; L-2- acid. { 4 '- [(4-hydroxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- (4- { 5- [(l-ethyl-lH-benzimidazole-2-acid carbonyl) -amino] -pyridin-2-yl} -benzenesulfonylamino) -3-methyl-butyric acid; N- (. {4 '- [(1,2,3-thiadiazol-4-ylcarbonyl) amino] -1,1'-biphenyl-4-yl) sulfonyl) -L-valine; D-2- [4 '- (benzofuran-2-sulfonylmethyl) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid-D-2- [4' - (benzofuran-2-sulfinylmethyl) -biphenyl-4-acid -sulfonylamino] -3-methyl-butyric; (S) -2- (4'- { [3- (4-Chloro-phenyl) -isoxazole-5-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3-methyl-butyric acid; (S) -3-methyl-2- acid. { 4 '- [(1-methyl-3-phenyl-1H-thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(5-methyl-l-phenyl-lH-pyrazole-3-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(2 ~ pyridin-4-yl-thiazole-4-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino] -butyric acid; (R) -3-Methyl-2- [4 '- (thiophene-2-sulfonylamino) -biphenyl-4-sulfonylamino] -butyric acid; (R) -2- acid. { 4 '- [(furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (R) -3-methyl-2- acid. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(thiophene-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(furan-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -2- (4 '- { [4- (2-tert-Butoxycarbonylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) - 3-methyl-butyric; (S) -3-Methyl-2- (4 '- { [3-methyl-4- (pyridin-2-ylmethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid -butyric; (S) -3-Methyl-2- (4'- { [3-methyl-4- (pyridin-4-ylmethoxy) -benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino acid ) -butyric acid- (S) -2-. { 4 '- [(4-carbamoylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -2- (4'- { [4- (2-Amino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3- acid methyl-butyric; (S) -2- (4'- { [4- (2-dimethylamino-ethoxy) -3-methyl-benzofuran-2-carbonyl] -amino} -biphenyl-4-sulfonylamino) -3- acid methyl-butyric; N- [(4 '- { [(5-chloro-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- ( {4 '- [(5-bromo-l-furoyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) -L-valine; N- [(4 '- { [(7-nitro-lH-indol-2-yl) carbonyl] amino.} - 1, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(2-pyridin-4-yl-l, 3-thiazol-5-yl) carbonyl}. Amino]} -l, 1'-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [5- (2-Nitrophenyl) -2-furoyl] amino} -l, 1'-biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [2- (2, 3-dihydro-l, 4-benzodioxin-2-yl) -1, 3-thiazol-4-yl] carbonyl} amino) -1, 1' -biphenyl-4-yl] sulfonyl} -L-valine; N- [(4 '- { [(5-Methyl-3-phenylisoxazol-4-yl) carbonyl] amino] -! -! 1'-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4'- { [(4-Methyl-1,2,8-thiadiazol-5-yl) carbonyl] amino]} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L -valina; N- [(4'-. {[[(L-tert-butyl-3-methyl-lH-pyrazol-5-yl) carbonyl] amino]} - l, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(3-chloro-l-benzothien-2-yl) carbonyl] amino]} - 1,1' -biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [3- (2-chlorophenyl) -5-methylisoxazol-4-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -D-alanine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -L-valine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.] Sulfonyl) -D-valine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-norvaline; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-norvaline; N- ( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] 1,1'-biphenyl-4-yl}. sulfonyl) -L-aspartic acid; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] 1,1'-biphenyl-4-yl.} sulfonyl) -D-aspartic acid; N-2- ( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-glutamine; N ~ 2 ~ (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -D-glutamine; N- ( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-histidine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -D-histidine; N- ( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -L-isoleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -D-isoleucine; N- ( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'- biphenyl-4-il} } sulfonyl) -L-leucine; N- (( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1-biphenyl-4-yl}.}. Sulfonyl) -D-leucine; N- (( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' biphenyl-4-yl}.}. Sulfonyl) -L-norleucine; N- ((. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.}.]. sulfonyl) -D-norleucine; N- ((. {4 '- [ (L-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}.,. sulfonyl) -L-phenylalanine; N- ((. {4 '- [(l- benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.}.]. sulfonyl) -D-phenylalanine; - ((. {- '- [(1-benzofuran-2- ylcarbonyl) amino] -1,1'-biphenyl-4-yl.}.]. sulfonyl) -L-proline;, - ((. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] ] -1,1'-biphenyl-4-yl.}.]. Sulfonyl) -D-proline; N- ((. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1 , 1'-biphenyl-4-yl.}.]. Sulfonyl) -L-tryptophan; N- ((. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl.}.}. sulfonyl) -D-tryptophan; N- ((. { 4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} } sulfonyl) -N-methylglycine; N- ((. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}.}. Sulfonyl) -2-methylalanine; N- (( j. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.}...... sulfonyl) -N-methyl-L-alanine; 1- [(. {4 '- [(1-Benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) amino] cyclopentanecarboxylic acid; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -N-methylvaline; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) -amino] -1,1'-biphenyl-4-yl} sulfonyl) -3-methyl-L-valine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -2-methyleucine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1/1' -biphenyl-4-yl} sulfonyl) -D-glutamic acid; (2R) - [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1-biphenyl-4-yl} sulfonyl) amino] (phenyl) acetic acid; [( { '- [(1-Benzofuran-2-ylcarbonyl) -amino] -1, 1-biphenyl-4-yl} sulfonyl) amino] (thien-2-yl) acetic acid; (2S) -2- [( {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. sulfonyl) amino] -5-methoxy- 5-oxopentanoic; 3- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) amino] -3-phenylpropanoic acid; 2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) amino] -4-phenylbutanoic acid; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -L-tyrosine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -D-tyrosine; (2S) -2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1'-biphenyl-4-yl}. sulfonyl) amino] -4-tert-acid butoxy-4-oxobutanoic; (2R) -2- [( {4 '- [(1-Benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. sulfonyl) amino] -4-tert-acid. butoxy-4-oxobutanoic; (2S) - [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.] sulfonyl) amino] (2,3-dihydro) lH-inden-2-yl) acetic; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -O-methyl-L-tyrosine; [( { 4 '- [(1-benzofuran-2-ylcarbonyl) amino-1,1'-biphenyl-4-yl.] sulfonyl) amino] (1-methyl-1H-indol-5-yl) ) acetic; [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl} sulfonyl) amino] (1-benzothien-5-yl) acetic acid; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -4-nitro-L-phenylalanine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -3- (2-naphthyl) alanine; N- ( { '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. Sulfonyl) -beta-methylphenylalanine; N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -N-methyl-L-tryptophan; N-2- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1, 1' -biphenyl-4-yl.} Sulfonyl) -N-5-phenylglutamine; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl.} Sulfonyl) -4,4,4,4', 4 ', 4'-hexafluorovaline; 4-amino-N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1' -biphenyl-4-yl}. Sulfonyl) -L-phenylalanine; (2R) -2- [(. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) amino] -5- (benzyloxy) -5-oxopentanoic; N- ({4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl} sulfonyl) -1-benzyl-L-histidine; and N- (. {4 '- [(1-benzofuran-2-ylcarbonyl) amino] -1,1'-biphenyl-4-yl}. sulfonyl) -O-benzyl-L-tyrosine.

67. The compound according to claim 47, characterized in that it is, L-2- (4 '- { [4- (3-methoxy-propyl) -3-methyl-benzofuran-2-carbonyl] -amino acid. .} - biphenyl-4-sulfonylamino) -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (3-methyl-isoxazol-5-yl) -benzofuran-2-carbonyl] -amino acid} -biphenyl-4 -sulfonylamino) -butyric; D-2- acid. { 4 '- [(4-methanesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-cyclopropylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4 '- { [3-methyl-4- (2H-tetrazol-5-yl) -benzofuran-2-carbonyl] -amino] -biphenyl-4-sulfonylamino -butyric; L-2- acid. { 4 '- [(4-dimethylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { '- [(4-benzenesulfonylamino-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (thiophene-2-sulfonylamino) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - butyric; N-. { (4'- { [(5-Ethyl-4-methoxy-3-methyl-l-benzofuran-2-yl) carbonyl] aminoj-l, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; Nt (4'- { [(4-ethyl-3-methyl-l-benzofuran-2-yl) carbonyl] amino.} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl) carbonyl] amino.} -!, 1' -biphenyl-4-yl) sulfonyl] -L-valine; N-. { [4 '- ( { [4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -3-methyl-l-benzofuran-2-yl] carbonyl} amino) -1, 1 '-biphenyl-4-yl] sulfonyl} -L-valine; N- [(4'- { [(3,4-Dimethyl-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1 '-biphenyl-4-yl) sulfonyl] -L-valine; N- [(4 '- { [(4-acetyl-3-methyl-1-benzofuran-2-yl) carbonyl] amino]: -! 1'-biphenyl-4-yl) sulfonyl] -L -valina; N- [(4 '- ( { [4- (1-hydroxyethyl) -3-methyl-l-benzofuran-2- il] carbonil} amino) -1,1 '-biphenyl-4-yl] sulfonyl} -L-valine; N- [(4 '- { [(3-methyl-4-vinyl-l-benzofuran-2-yl) carbonyl] amino]} - 1, 1' -biphenyl-4-yl) sulfonyl] -L -valina; N-. { [4 '- ( { [4- (methoxymethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N-. { [4 '- ( { [4- (1-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl] amino) -1,1' -biphenyl-4-yl] sulfonyl} -L-valine; N-. { [4 '- ( { [4- (2-methoxyethyl) -3-methyl-1-benzofuran-2-yl] carbonyl} amino) -1, 1-biphenyl-4-yl] sulfonyl) -L -valinato; acid (S) -2-. { 4 '- [(4-Ethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; (S) -3-methyl-2- acid. { 4 '- [(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; acid (S) -2-. { 4 '- [(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-Chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (R) -2- acid. { 4 '- [(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4- [(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; acid (S) -2-. { 4 '- [(5-methyl-4-methoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; (S) -3-methyl-2- acid. { 4 '- [(5-methyl-benzooxazole-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; D-2- [4 '- (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl-methoxy) -biphenyl-4-sulfonylamino] -3-methyl-butyric acid; L-2- acid. { 4 '- [(4-Ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-2- acid. { 4 '- [(4-carboxymethoxy-3-methyl-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric; L-3-methyl-2- (4'- { [3-methyl-4- (pyridin-3-ylmethoxy) -benzofuran-2-carbonyl] -amino}. -biphenyl-4-sulfonylamino) - butyric; (S) -3-methyl-2- acid. { 4 '- [(l-methyl-3-phenyl-lH- thieno [2, 3-c] pyrazole-5-carbonyl) -amino] -biphenyl-4-sulfonylamino} -butyric; and (S) -3-methyl-2- (4'- { [3-methyl-4- (pyridin-4-ylmethoxy) -benzofuran-2-carbonyl] -amino acid} -biphenyl-4- sulfonylamino) -butyric acid.

68. Composition, characterized in that it comprises at least one of the compounds according to claim 47 and one or more pharmaceutically acceptable carriers.

69. Method of compliance with the claim 26, characterized in that the disease is osteoarthritis, rheumatoid arthritis, asthma or chronic obstructive pulmonary disease.