Heterocyclic derivatives and their use as antithrombotic agents

A therapeutic compound comprising a serine protease inhibitor of the formula (I), wherein formula (I) is

• R1—Y—[NR2—A—C(O)]n—NR3—CHR4—C(O)—R5 (I)
• in which
• R1 is (1-8C)alkyl, (6-14C)aryl-(1-8C)alkenyl, (6-14C)aryl-(1-8C)alkanoyl, (6-14C)aryl, (7-15C)aralkyl, bisaryl, heteroaryl, heteroaralkyl, heterocycloalkyl, cycloalkyl or cycloalkyl substituted alkyl;
• R2 is H or (1-8C)alkyl;
• R3 is Q when R4 is H, or R3 is H or (1-8C)alkyl when R4 is Q;
• wherein Q has the formula
• wherein the substructure
• is a structure selected from
• wherein
• X is O or S;
• X′ being independently CH or N;
• and m is O, 1, 2 or 3;
• wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom;
• R5 is OH or OR6, R6being (1-8C)alkyl, (3-12C)cycloalkyl or (7-15C)aralkyl, or R5 is NR7R8, wherein R7 and R8 are the same or different being H, (1-8C)alkyl, (3-12C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl, optionally substituted with (1-8C)alkoxy, C(O)OH or C(O)OR6, or R7 and R8 together with the nitrogen atom to which they are bonded are a nonaromatic (4-8) membered ring optionally containing another heteroatom, which ring may be condensed with another optionally aromatic ring and may be substituted with OH, an oxo group, (1-8C)alkyl, optionally substituted with one or more halogens or hydroxy groups, (2-8C)alkenyl, (1-8C)alkylidene, (2-8C)alkynyl, (1-8C)alkoxy, (1-8C)acyl, (6-14C)aryl, C(O)OH, C(O)OR6, C(O)NR9R10, wherein R9 and R10 are the same or different being H or (1-8C)alkyl, or SO2R11 and R11 is (1-8C)alkyl optionally substituted by one or more fluorine atoms;
• Y is SO2 or C(O);
• A is CHR12, R12 being H, phenyl, benzyl, (1-8C)alkyl, optionally substituted with OH or COR13 wherein R13 is OH, (1-8C)alkoxy, morpholino, morphodino(1-8C) alkoxy, NH2, NHR14 or NR14R15, R14 and R15 being independently (1-8C)alkyl optionally substituted with C(O)R2 or R14 and R15 are a nonaromatic (4-8)membered ring together with the nitrogen atom to which they are bonded, or R12 together with R3 is —(CH2)s— when R4 is Q, s being 2, 3 or 4, or A is NR2;
• and
• n is 0 or 1;
• which compound has an apparent Caco-2 permeability of 8 nm/s or higher;
• or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A method of treating or preventing thrombosis or thrombosis-related diseases in a subject, said method comprising administering to the subject an effective amount of a compound of the formula (I), wherein formula (I) is

• R1—Y—[NR2—A—C(O)]n—NR3—CHR4—C(O)—R5 (I)
• in which
• R1 is (1-8C)alkyl, (6-14C)aryl-(1-8C)alkenyl, (6-14C)aryl-(1-8C)alkanoyl, (6-14C)aryl, (7-15C)aralkyl, bisaryl, heteroaryl, heteroaralkyl, heterocycloalkyl, cycloalkyl or cycloalkyl substituted alkyl;
• R2 is H or (1-8C)alkyl;
• R3 is Q when R4 is H, or R3is H or (1-8C)alkyl when R4 is Q;
• Q is
• wherein the substructure
• is a structure selected from
• wherein
• X is O or S;
• X′ being independently CH or N;
• and m is 0, 1, 2 or 3;
• wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom;
• R5 is OH or OR6, R6 being (1-8C)alkyl, (3-12C)cycloalkyl or (7-15C)aralkyl, or R5 is NR7R8, wherein R7 and R8 are the same or different being H, (1-8C)alkyl, (3-12C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl, optionally substituted with (1-8C)alkoxy, C(O)OH or C(O)OR6, or R7 and R8 together with the nitrogen atom to which they are bonded are a nonaromatic (4-8) membered ring optionally containing another heteroatom, which ring may be condensed with another optionally aromatic ring and may be substituted with OH, an oxo group, (1-8C)alkyl, optionally substituted with one or more halogens or hydroxy groups, (2-8C)alkenyl, (1-8C)alkylidene, (2-8C)alkynyl, (1-8C)alkoxy, (1-8C)acyl, (6-14C)aryl, C(O)OH, C(O)OR6, C(O)NR9R10, wherein R9 and R10 are the same or different being H or (1-8C)alkyl, or SO2R11 and R11 is (1-8C)alkyl optionally substituted by one or more fluorine atoms;
• Y is SO2 or C(O);
• A is CHR12, R12 being H, phenyl, benzyl, (1-8C)alkyl, optionally substituted with OH or COR13 wherein R13 is OH, (1-8C)alkoxy, morpholino, morpholino(1-8C)alkoxy, NH2, NHR14 or NR14R15, R14 and R15 being independently (1-8C)alkyl optionally substituted with C(O)OR2 or R14 and R15 are a nonaromatic (4-8)membered ring together with the nitrogen atom to which they are bonded, or R12 together with R3 is —(CH2)s— when R4 is Q, s being 2, 3 or 4, or A is NR2;
• and n is 0 or 1;
• which compound has an apparent Caco-2 permeability of 8 nm/s or higher;
• or a pharmaceutically acceptable salt thereof or a prodrug thereof.