Substituted 2H-1,3-benzoxazin-4(3H)-ones

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is a member selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, benzyl, and substituted benzyl;
• R2 is a member selected from the group consisting of H, and C1-6 alkyl;
• R3 is a member selected from the group consisting of H, C1-6 alky C2-6 alkenyl, C2-6 alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, halogen, cyano and —C(O)R3a, wherein R3a is a member selected from the group consisting of H, hydroxy, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino and di-C1-6 alkylamino;
• R4 is a member selected from the group consisting of H and C1-6 alkyl;
• R5 is a member selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, benzyl, aryl, C1-6 alkyl-N—(R5a)2;
• C1-6 alkyl-O—(R5a);
• wherein each R5a is a member independently selected from the group consisting of H, C1-6 alkyl, and optionally, two R5a groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring;
• Ar is an aromatic ring selected from the group consisting of benzene, pyridine, pyrazine and pyrimidine, each of which is optionally substituted with from 1-2 R6 substituents,
• wherein each R6 is independently selected from the group consisting of halogen, cyano, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-5 cycloalkyl-alkoxy, amino, C1-6 alkylamino, di-C1-6 alkylamino, —C(═NR6a)—N(R6b)2, —C(O)R6a, —O(CH2)mOR6b, —(CH2)mOR6b, —O(CH2)mN(R6b)2 and —(CH2)mN(R6b)2,
• wherein each subscript m is independently an integer of from 1 to 3, each R6a is a member independently selected from the group consisting of H, hydroxy, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino and di-C1-6 alkylamino, and each R6b is a member independently selected from the group consisting of H, C1-4 alkyl and C1-4 alkanoyl, and optionally, two R6b groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring;
• L is a linking group selected from the group consisting of a bond and —NH—;
• R7 is a member selected from the group consisting of H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy and C1-6 haloalkyl;
• and pharmaceutically acceptable salts thereof.

A method of treating thrombosis in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of a compound having the formula:

• wherein
• R1 is a member selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, benzyl, and substituted benzyl;
• R2 is a member selected from the group consisting of H, and C1-6 alkyl;
• R3 is a member selected from the group consisting of H, C1-6 alky C2-6 alkenyl, C2-6 alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, halogen, cyano and —C(O)R3a, wherein R3a is a member selected from the group consisting of H, hydroxy, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino and di-C1-6 alkylamino;
• R4 is a member selected from the group consisting of H and C1-6 alkyl;
• R5 is a member selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, benzyl, aryl, C1-6 alkyl-N—(R5a)2;
• C1-6 alkyl-O—(R5a);
• wherein each R5a is a member independently selected from the group consisting of H, C1-6 alkyl, and optionally, two R5a groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring;
• Ar is an aromatic ring selected from the group consisting of benzene, pyridine, pyrazine and pyrimidine, each of which is optionally substituted with from 1-2 R6 substituents,
• wherein each R6 is independently selected from the group consisting of halogen, cyano, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-5 cycloalkyl-alkoxy, amino, C1-6 alkylamino, di-C1-6 alkylamino, —C(═NR6a)—N(R6b)2, —C(O)R6a, —O(CH2)mOR6b, —(CH2)nOR6b —O(CH2)mN(R6b)2 and —(CH2)mN(R6b)2,
• wherein each subscript m is independently an integer of from 1 to 3, each R6a is a member independently selected from the group consisting of H, hydroxy, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino and di-C1-6 alkylamino, and each R6b is a member independently selected from the group consisting of H, C1-4 alkyl and C1-4 alkanoyl, and optionally, two R6b groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring;
• L is a linking group selected from the group consisting of a bond and —NH—;
• and
• R7 is a member selected from the group consisting of H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy and C1-6 haloalkyl;
• or a pharmaceutically acceptable salt thereof.