Matriptase inhibitors and uses thereof against orthomyxoviridae infections

A method of inhibiting matriptase activity in a cell, comprising contacting the cell with an effective amount of:

• (i) a compound of formula (1):
• or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein
• R12 is NHR7;
• wherein R7 is
• R13 is H, NH2 or NHR7;
• wherein R7 is an alkyl, aryl, (C═O)-alkyl, (C═O)-aryl, SO2-alkyl or SO2-aryl, C(═NH)—NH2, C(═NH)—NHalkyl, C(═NH)—NHaryl or one or more amino acids residues;
• R1 is H, NH2 or NHR7;
• wherein R7 is an alkyl, aryl, (C═O)-alkyl, (C═O)-aryl, SO2-alkyl or SO2-aryl, C(═NH)—NH2, C(═NH)—NHalkyl, C(═NH)—NHaryl or one or more amino acids residues;
• R2 and R5 are independently —CH2—R8 or
• wherein R8 is (CH2)n-NH(C═NH)NH—R14 or (CH2)n-NH—R14, wherein,
• n is 1 to 4;
• m is 0 to 3;
• R10 is —C(═NH)—NH2, NH2 or NH alkyl;
• and
• R14 is H, alkyl, NH2, NO2 or COalkyl;
• R3 is a linear alkyl;
• an alkyl substituted with (CO)NH2, (CO)OH, NH2, NHCO-alkyl, NHCO-aryl, NHSO2-alkyl, NHSO2-aryl or heteroaryl;
• an aryl, a substituted aryl, an heteroaryl or a substituted heteroaryl;
• R4 is an alkyl, an aryl, a substituted alkyl, a substituted aryl, an heteroaryl, a substituted heteroaryl, a side chain of an amino acid residue or a substituted side chain of an amino acid residue;
• R6 is
• CF3, CO2H, CONH2, CONH-alkyl, CONH-aryl or CO-(amino acid residue)p, wherein p is 1 to 3;
• wherein W, X, Y and Z are independently N or CH;
• V and U are independently O, NH, NCH3 or S;
• and
• R11 is H, CO2H, CONH-alkyl, CONH-aryl, aryl, heteroaryl, halide or CO-(amino acid residue)q, wherein q is 1 or 2;
• wherein the amino acid residue is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, proline, serine, tyrosine, 3-amino-propionic acid, 2,3-diamino propionic acid, alpha-aminoisobutyric acid (Aib), 4-amino-butyric acid, N-methylglycine (sarcosine), hydroxyproline, ornithine, citrulline, t-butylalanine, t-butylglycine, N-methylisoleucine, phenylglycine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norleucine (Nle), norvaline, 2-napthylalanine, pyridylalanine, 3-benzothienyl alanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, penicillamine, 1,2,3,4-tetrahydro-isoquinoline-3-carboxylix acid, beta-2-thienylalanine, methionine sulfoxide, L-homoarginine (hArg), N-acetyl lysine, 2-amino butyric acid, 2-amino butyric acid, 2,4,-diaminobutyric acid, p-aminophenylalanine, N-methylvaline, selenocysteine, homocysteine, homoserine (HoSer), cysteic acid, epsilon-amino hexanoic acid, delta-amino valeric acid, or 2,3-diaminobutyric acid;
• and wherein said amino acid residue is in the (L) or (D) configuration;
• or
• (ii) a composition comprising
• a compound of formula (1) as defined above and a pharmaceutically acceptable excipient;
• whereby said matriptase activity is inhibited.