US 7,119,094 B1Granted

Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade

AssigneeWarner-Lambert Company

InventorsMichael S. South, John J. Parlow, Darin E. Jones, Brenda Case, Tom Dice, Richard Lindmark, Michael J. Hayes, Melvin L. Rueppel, Rick Fenton, Gary W. Franklin, Horng-Chih Huang, Wei Huang, Carrie Kusturin, Scott A. Long, William L. Neumann, David B. Reitz, John I. Trujillo, Ching-Cheng Wang, Rhonda Wood, Qingping Zeng, Matthew W. Mahoney

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Abstract

The invention relates to substituted polycyclic aryl and heteroaryl pyrazinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

A compound having the formula

or a pharmaceutically acceptable salt thereof, where the substituents are selected to form compounds selected from the group consisting of:
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-cyanophenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-aminophenyl, and Y0 is 4-amidino-3-fluorobenzyl;
B is isopropyl, A is a bond, R1 is hydrogen, R2 is 3-aminophenyl, and Y0 is 4-amidino-3-fluorobenzyl;
B is aminomethyl, A is CH2, R1 is chloro, R2 is phenyl, and Y0 is 4-amidinobenzyl;
B is aminomethyl, A is CH2CH2, R1 is chloro, R2 is phenyl, and Y0 is 4-amidinobenzyl;
B is aminomethyl, A is CH2CH2CH2, R1 is chloro, R2 is phenyl, and Y0 is 4-amidinobenzyl;
B is cyanomethyl, A is CH2, R1 is chloro, R2 is phenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-carbomethoxyphenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 5-amino-2-fluorophenyl, and Y0 is 4-amidino-2-fluorobenzyl;
B is t-butyl, A is a bond, R1 is chloro, R2 is 3-aminophenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-(N-methylamino)phenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 2-methyl-3-aminophenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is hydrogen, R2 is 3-(N-methylamino)phenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-amino-6-(S—CH2—CO2H)phenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-amino-6-(S—CH3)phenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is hydrogen, R2 is 3,5-diaminophenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is hydrogen, R2 is 3-amino-5-(NH—C(O)—CF3)phenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-amino-5-carboxyphenyl, and Y0 is 4-amidinobenzyl;
B is isopropyl, A is a bond, R1 is bromo, R2 is 3-aminophenyl, and Y0 is 4-amidinobenzyl;
and
B is isopropyl, A is a bond, R1 is chloro, R2 is 3-amino-methoxycarbonylphenyl, and Y0 is 4-amidinobenzyl.

19 more elements

Abstract

Claims46