Benzoimidazoles as prolyl hydroxylase inhibitors

1. A compound having PHD inhibitor activity of the formula (I):

wherein:

n is 2-4;

each R 1 is independently selected from H, halo, —C 1-4 -alkyl, —C 3-8 cycloalkyl, —C 1-4 perhaloalkyl, trifluoroC 1-4 -alkoxy, —OH, —NO 2 , —CN, CO 2 H, —OC 1-4 alkyl, —SC 1-4 -alkyl, —S(C 1-4 -alkyl)-R c , —S(O) 2 (C 1-4 alkyl)-R c , —S(O)—C 1-4 -alkyl, —SO 2 —C 1-4 alkyl, —S—R c , —S(O)—R c , —SO 2 —R c , —SO 2 —NH—R c , —O—R c , —CH 2 —O—R c , —C(O)NH—R c , —NR a R b , benzyloxy optionally substituted with R d , phenyl optionally substituted with R d , —C 3-8 cycloalkyl optionally containing one or more O, S or N wherein said —C 3-8 cycloalkyl is optionally substituted with R d , and two adjacent R 1 groups may be joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N;

R a and R b are each independently H, C 1-4 -alkyl, —C(O)C 1-4 alkyl, —C(O)—R c , —C(O)CH 2 —R e , C 1-4 alkyl-R e , —SO 2 —R c , —SO 2 —C 1-4 -alkyl, phenyl optionally substituted with R d , benzyl optionally substituted with R d or monocyclic heteroaryl ring optionally substituted with R d ; or R a and R b 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;

R c is —C 3-8 cycloalkyl, phenyl optionally substituted with R d , benzyl optionally substituted with R d , or a monocyclic heteroaryl ring optionally substituted with R d ;

R d is independently —H, halo, —OH, —C 1-4 alkyl or —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, —OC 1-4 alkyl, —O-phenyl, or —O-benzyl;

R e is —C 3-8 heterocycloalkyl optionally containing one or more O, S or N;

R 2 and R 3 are both H, —CF 3 , or C 1-3 alkyl;

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's are C, two adjacent R 1 groups are joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N;

or an enantiomer, a diastereomer, a racemate, or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , where R 2 and R 3 are each —H.

3. A compound of claim 1 wherein each R 1 is independently selected from the group consisting of H, halo, —CF 3 , —OCF 3 , phenyl (optionally substituted or unsubstituted with up to three —CF 3 , halo, —OH, C 1-4 -alkyl, C 1-4 alkoxy, and —OCF 3 ), phenoxy (optionally substituted or unsubstituted with up to three halo, C 1-4 -alklyl, C 1-4 alkoxy, and —OCF 3 ), benzyloxy-phenyl (optionally substituted or unsubstituted with up to three halo), benzyloxy, benzyloxymethyl, phenylsulfanyl (optionally substituted or unsubstituted with up to three —C 1-4 -alkyl, halo, —CF 3 , —OCF 3 , and —C 1-4 -alkoxy), benzylsulfanyl (optionally substituted or unsubstituted with up to three halo, C 1-4 -alkyl, C 3-8 cycloalkylmethyl, —CF 3 , and —OCF 3 ), phenethylsulfanyl, benzenesulfonyl (optionally substituted or unsubstituted with up to three C 1-4 -alkyl, C 1-4 -alkoxy, halo, —CF 3 , and —OCF 3 ), phenylmethanesulfonyl (optionally substituted or unsubstituted with up to three C 1-4 -alkyl, C 1-4 alkoxy, halo, C 3-8 cycloalkylmethyl, —CF 3 , and —OCF 3 ), phenyl-ethanesulfonyl, benzenesulfinyl, cyano-biphenyl-4-ylmethylsulfanyl, cyano-biphenyl-4-ylmethanesulfonyl, phenylcarbamoyl, benzylcarbamoyl, benzylamino, phenylsulfamoyl, phenylamino, benzoylamino, and benzenesulfonylamino.

4. A compound of claim 1 , where two adjacent R 1 groups are joined to form an optionally substituted 3-8 membered ring containing one or more O, S or N.

5. A compound of claim 1 wherein said optionally substituted 3-8 membered ring is aromatic.

6. A compound of claim 1 , wherein each R 1 is independently selected from H, halo, —C 1-4 -alkyl, —CF 3 , —C 3-8 cycloalkyl, —OCF 3 , —C 1-4 -alkylsulfonyl, —C 1-4 alkylsulfinyl, —C 1-4 -alkylsulfanyl, —NO 2 , —NH 2 , —NH—C 1-4 -alkyl, —NH—SO 2 —C 3-8 cycloalkyl, —NH—SO 2 —C 1-4 -alkyl, —NH—C(O)—C 1-4 -alkyl, —CN, —CO 2 H, —OC 1-4 alkyl, —NH—(CH 2 ) 2 -morpholine, —NH(CO)CH 2 -morpholine, —NHC(O)—CH 2 -piperidine, —NHC(O)—CH 2 —(N-methylpiperazine), —NH—C 1-4 -alkyl-morpholine, —S—(CH 2 ) 2 -morpholine, —C(O)—NH-morpholine, pyrrolidine, piperidine, and morpholine.

7. A compound selected from the group consisting of:

1-(1H-Naphtho[2,3-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(3H-Naphtho[1,2-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(8H-Imidazo[4′,5′:3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylic acid;

1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(6,7-Dichloro-1H-imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(1H-Imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(6-Chloro-9H-purin-8-yl)-1H-pyrazole-4-carboxylic acid;

and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of compound having PHD inhibitor activity of formula (I):

wherein:

n is 2-4;

each R 1 is independently selected from H, halo, —C 1-4 -alkyl, —C 3-8 cycloalkyl, —C 1-4 -perhaloalkyl, trifluoroC 1-4 alkoxy, —OH, —NO 2 , —CN, CO 2 H, —OC 1-4 alkyl, —SC 1-4 alkyl, —S(C 1-4 alkyl)-R c , —S(O) 2 (C 1-4 -alkyl)-R c , —S(O)—C 1-4 -alkyl, —SO 2 —C 1-4 -alkyl, —S—R c , —S(O)—R c , —SO 2 —R c , —SO 2 —NH—R c , —O—R c , —CH 2 —O—R c , —C(O)NH—R c , —NR a R b , benzyloxy optionally substituted with R d , phenyl optionally substituted with R d , —C 3-8 cycloalkyl optionally containing O, S or N wherein said —C 3-8 cycloalkyl is optionally substituted with R d , and two adjacent R 1 groups may be joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N;

R a and R b are each independently H, C 1-4 -alkyl, —C(O)C 1-4 alkyl, —C(O)—R c , —C(O)CH 2 —R e , C 1-4 alkyl-R e , —SO 2 —R c , —SO 2 —C 1-4 -alkyl, phenyl optionally substituted with R d , benzyl optionally substituted with R d or monocyclic heteroaryl ring optionally substituted with R d ; or R a and R b 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;

R c is —C 3-8 cycloalkyl, phenyl optionally substituted with R d , benzyl optionally substituted with R d , or a monocyclic heteroaryl ring optionally substituted with R d ;

R d is independently —H, halo, —OH, —C 1-4 alkyl or —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, —OC 1-4 alkyl, —O-phenyl, or —O-benzyl;

R e is —C 3-8 heterocycloalkyl optionally containing one or more O, S or N;

R 2 and R 3 are both H, —CF 3 , or C 1-3 alkyl;

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's are C, two adjacent R 1 groups are joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N;

or an enantiomer, a diastereomer, a racemate, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising one or more compounds selected from the group consisting of:

1-(5-Bromo-7-methyl-1H-imidazo[4,5-f]quinolin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(1H-Naphtho[2,3-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(3H-Naphtho[1,2-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(8H-Imidazo[4′,5′:3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylic acid;

1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(6,7-Dichloro-1H-imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(1H-Imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid;

1-(6-Chloro-9H-purin-8-yl)-1H-pyrazole-4-carboxylic acid;

and pharmaceutically acceptable salts thereof.