Serine protease inhibitors

A method of preparing a compound of the formula (A):

• wherein
• R1 is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl;
• -alkyl-C(O)OCH3;
• alkylamino, dialkylamino, alkyldialkylamino;
• or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, (C5-C12)arylalkenyl, fused(C5-C12)aryl-cycloalkyl or fused(C5-C12)aryl-cycloalkylalkyl optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, —O—(C5-C6)aryl, (C5-C6)arylcarboxamido, alkylthio or haloalkylthio;
• X and Y are independently O, S, or N, wherein N is optionally substituted with alkyl or alkynyl optionally substituted with 1-3 halo atoms;
• (C5-C6)aryl, (C5-C6)arylalkyl or (C5-C6)arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O, and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)arylcarboxamide, alkylthio or haloalkylthio;
• and
• R1 and R3 are independently or together H;
• alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine;
• —RCOR′, —RCOOR′, —RNR′R″ Ro or —RC(O)NR′R′ where R is alkyl or alkenyl, and R′, R″ and Ro are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl;
• or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxy(C5-C12)aryl, alkyl-thio(C5-C12)aryl, alkyl-amino(C5-C12)aryl, (C5-C12)aryl, (C5-C12)arylalkyl, or (C5-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, —O—(C5-C6)aryl, (C5-C6)arylcarboxamide, alkylthio, or haloalkylthio;
• Z′ is one of:
• A. a group of the formula
• wherein
• A is a direct bond, —C(O)—, —NH—C(O)—, —S(O)2—, —NH—S(O)2—, —OC(O)—, —CH2— or an amino acid selected from proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)arylcarboxamide, alkylthio or haloalkylthio;
• phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;
• tetrahydroisoquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)arylcarboxamide, alkylthio or haloalkylthio;
• tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or (C5-C6)aryl;
• histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid;
• asparagine, glutamine, omithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or (C5-C12)aryl, (C5-C12)arylalkyl, cycloalkyl, alkylcycloalkyl, fused (C5-C12)aryl-cycloalkyl or alkyl fused (C5-C12)aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O, and S;
• and
• R4 is H, alkyl, alkenyl or a alkynyl;
• or cycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, fused (C5-C12)aryl-cycloalkyl or fused (C5-C12)aryl-cycloalkylalkyl optionally comprising one or more heteroatoms selected from N, O, and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, (C5-C5)arylalkyl, (C5-C6)arylcarboxamido, alkylthio or haloalkylthio or is absent;
• or
• B. a group of the following formula (I-VI)
• wherein
• W is as defined in section D, below;
• R′2 and R′3 are independently or together H;
• alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine;
• —RCOR′, —RCOOR′, —RNR′R″Ro or —RC(O)NR′R′ where R is alkyl or alkenyl, and R′, R″ and Ro are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl;
• or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxy(C5-C12)aryl, alkyl-thio(C5-C12)aryl, alkyl-amino(C5-C12)aryl, (C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C12)aryl, —O—(C5-C12)aryl, (C5-C12)arylcarboxamide, alkylthio or haloalkylthio;
• R13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or (C5-C12)aryl, (C5-C12)arylalkyl, cycloalkyl, alkylcycloalkyl, fused (C5-C12)aryl-cycloalkyl or fused (C5-C12)aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
• R14 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino;
• or (C5-C12)aryl, (C5-C12)arylalkyl, cycloalkyl, alkylcycloalkyl, fused (C5-C12)aryl-cycloalkyl, alkyl fused (C5-C12)aryl-cycloalkyl, or (C5-C12)aryloxycarboxamide optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, (C5-C6)arylalkyl, (C5-C6)arylcarboxamide, alkylthio or haloalkylthio;
• and
• R15 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino;
• or (C5-C12)aryl, (C5-C12)aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S;
• C. a group of the formula
• where
• m is 0 or 1;
• n is 0 or 1;
• D is a direct bond or an amino acid selected from proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)arylcarboxamide, alkylthio or haloalkylthio;
• phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;
• tetrahydroisoquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)arylcarboxamide, alkylthio or haloalkylthio;
• tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or (C5-C6)aryl;
• histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid, asparagine, glutamine, omithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl, or (C5-C12)aryl, (C5-C12)arylalkyl, cycloalkyl, alkylcycloalkyl, fused (C5-C12)aryl-cycloalkyl or alkyl fused (C5-C12)aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S;
• and
• A′ is a direct bond, —C(O)—, —NH—C(O)—, —S(O)2—, —NH—S(O)2—, —OC(O)— or —CH2—;
• D. a group of the formula
• wherein
• W is S or O;
• R8 is H, alkylamino, dialkylamino or amino;
• and
• R9 is H, alkyl or halo;
• E. a group of the formula
• wherein
• R10 is (C5-C6)aryl, (C5-C6)arylalkyl, (C5-C6)arylalkenyl, cycloalkyl, alkylcycloalkyl, fused (C5-C12)aryl-cycloalkyl or alkyl fused (C5-C12)aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio;
• and
• F. a group of the formula
• wherein
• R11, R12 and E together form a monocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, S and O;
• said ring containing 1 or more keto groups;
• and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, ((C5-C12)arylalkyl)OC(O)NH— or (C5-C12)arylalkenyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, —C(O)O(alkyl), —C(O)(alkyl), alkylcarboxamide, alkylthio or haloalkylthio;
• the method comprising the steps of:
• (i) reacting a compound of formula (B):
• wherein M is Li or MgBr,
• with an aldehyde of formula (C):
• where PGr1 is a protecting group to give an alcohol of formula (D):
• (ii) removing the protecting group from the alcohol (D)
• (ii) coupling the alcohol obtained from step (ii) with an acid of formula (B):
• Z′—COOH (E)
• and
• (iv) either:
• (a) oxidizing the alcohol moiety of the product of step (iii);
• or
• (b) oxidizing the alcohol moiety of the product of step (iii) and removing any other protecting group to yield the compound of the formula (A).