Benzoimidazoles as prolyl hydroxylase inhibitors

摘要

The present invention is directed to benzoimidazole compounds of the formula:;
and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. Compounds of the present invention are useful in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions modulated by prolyl hydroxylase activity.

主权项

1. A method for the therapeutic treatment of anemia, comprising the step of administering to a patient in need thereof a therapeutically effective amount of compound having PHD inhibitor activity of formula (I):wherein:n is 2-4
each Rl is independently selected from H, halo, —C1-4alkyl, —C3-8cycloalkyl —C1-4perhaloalkyl, trifluoroC1-4alkoxy, —OH, —NO2, —CN, CO2H, —OC1-4alkyl, —SC1-4alkyl, —S(C1-4alkyl)-Rc, —S(O)2(C1-4alkyl)-Rc, —S(O)—C1-4alkyl, —SO2—C1-4alkyl, —S—Rc, —S(O )—Rc, —SO2—Rc, —SO2—NH—Rc, —O—Rc, —CH2—O—Rc, —C(O)NH—Rc, —NRaRb, benzyloxy optionally substituted with Rd, phenyl or monocyclic heteroaryl optionally substituted with Rd, —C3-8cycloalkyl optionally containing O, S or N wherein said —C3-8cycloalkyl is optionally substituted with Rd, and two adjacent R1 groups may be joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N; Ra and Rb are each independently H, C1-4alkyl, —C(O)C1-4alkyl, —C(O)—Rc, —C(O)CH2—Re, C1-4alkyl-Re, —SO2—Rc, —SO2—C1-4alkyl, phenyl optionally substituted with Rd, benzyl optionally substituted with Rd or monocyclic heteroaryl ring optionally substituted with Rd; or Ra and Rb can be taken together with the nitrogen to which they are attached to form an optionally substituted monocyclic heterocycloalkyl ring optionally containing one or more heteroatoms; Rc is —C3-8cycloalkyl, phenyl optionally substituted with Rd, benzyl optionally substituted with Rd, or a monocyclic heteroaryl ring optionally substituted with Rd; Rd is independently —H, halo, —OH, —C1-4alkyl or —C1-4perhaloalkyl, trifluoroC1-4alkoxy, —OC1-4alkyl, —O-phenyl, or —O-benzyl; Re is —C3-8heterocycloalkyl optionally containing one or more O, S or N; R2 and R3 are both H, —CF3, or C1-3alkyl; each Z is C or N, provided that no more than two Z′s can simultaneously be N; and further provided that when all Z groups are C, two adjacent R1 groups are joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N; and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof.