Substituted amino acids as erythropoietin mimetics

A method for treating a disease or condition mediated by EPO receptor comprising administering an effective amount a compound of Formula I

• wherein:
• R1 is the side chain of a natural or unnatural α-amino acids, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C1-5alkyl, C1-5alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC1-5alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C1-5alkoxycarbonyl);
• R2 and R3
• may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl;
• R4 and R5
• may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl;
• W is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
• Q is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
• X is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, and (CH2)m—C(O)— where m is 2-5;
• Y is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, and (CH2)m—C(O)— where m is 2-5;
• n is 1, 2, or 3;
• Z is selected from the group consisting of hydroxy, C1-5 alkoxy, phenoxy, phenylC1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, phenylamino, phenylC1-5alkylamino, piperidin-1-yl
• substituted piperidin-1-yl (where the substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, halo, aminocarbonyl, C1-5alkoxycarbonyl, and oxo;
• substituted phenylC1-5alkylamino (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, phenylC5alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• —OCH2CH2(OCH2CH2)sOCH2CH2O—, —NHCH2CH2(OCH2CH2)sOCH2CH2NH—, —NH(CH2)pO(CH2)qO(CH2)pNH—, —NH(CH2)qNCH3(CH2)sNH—, —NH(CH2)sNH—, and (NH(CH2)s)3N,
• where s, p, and q are independently selected from 1-7 with the proviso that if n is 2, Z is not hydroxy, C1-5 alkoxy, amino,
• C1-5alkylamino, diC1-5alkylamino, phenylamino, or phenylC1-5alkylamino, piperidin-1-yl
• with the further proviso that if n is 3, Z is (NH(CH2)s)3N,
• and salts thereof.

A method for modulating EPO receptor, comprising contacting the EPO receptor with an EPO receptor modulating amount of a compound of Formula I

• wherein:
• R1 is the side chain of a natural or unnatural α-amino acids, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C1-5alkyl, C1-5alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC1-5alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C1-5alkoxycarbonyl);
• R2 and R3
• may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl;
• R4 and R5
• may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl;
• W is selected from the group consisting of—CH═CH—, —S—, and —CH═N—;
• Q is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
• X is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, and (CH2)m—C(O)— where m is 2-5;
• Y is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, and (CH2)m—C(O)— where m is 2-5;
• n is 1, 2, or 3;
• Z is selected from the group consisting of hydroxy, C1-5 alkoxy, phenoxy, phenylC1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, phenylamino, phenylC1-5alkylamino, piperidin-1-yl
• substituted piperidin-1-yl (where the substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, halo, aminocarbonyl, C1-5alkoxycarbonyl, and oxo;
• substituted phenylC1-5alkylamino (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, phenylC1-5alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• —OCH2CH2(OCH2CH2)sOCH2CH2O—, —NHCH2CH2(OCH2CH2)sOCH2CH2NH—, —NH(CH2)pO(CH2)qO(CH2)pNH—, —NH(CH2)qNCH3(CH2)sNH—, —NH(CH2)sNH—, and (NH(CH2)s)3N,
• where s, p, and q are independently selected from 1-7 with the proviso that if n is 2, Z is not hydroxy, C1-5 alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, phenylamino, or phenylC1-5alkylamino, piperidin-1-yl
• with the further proviso that if n is 3, Z is (NH(CH2)s)3N,
• and salts thereof.

A method for treating a disease or condition mediated by EPO receptor comprising administering an effective amount of a compound of Formula I

• wherein:
• R1 is the side chain of a natural or unnatural α-amino acids, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C1-5alkyl, C1-5alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC1-5alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C1-5alkoxycarbonyl);
• R2 and R3
• may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl;
• R4 and R5
• may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl;
• W is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
• Q is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
• X is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, and (CH2)m—C(O)— where m is 2-5;
• Y is selected from the group consisting of carbon, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, and (CH2)m—C(O)— where m is 2-5;
• n is 1, 2, or 3;
• Z is selected from the group consisting of hydroxy, C1-5 alkoxy, phenoxy, phenylC1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, phenylamino, phenylC1-5alkylamino, piperidin-1-yl
• substituted piperidin-1-yl (where the substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, halo, aminocarbonyl, C1-5alkoxycarbonyl, and oxo;
• substituted phenylC1-5alkylamino (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, phenylC1-5alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• substituted phenoxy (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• substituted phenylC1-5alkoxy (where the aromatic substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),
• —OCH2CH2(OCH2CH2)sOCH2CH2O—, —NHCH2CH2(OCH2CH2)sOCH2CH2NH—, —NH(CH2)pO(CH2)qO(CH2)pNH—, —NH(CH2)qNCH3(CH2)sNH—, —NH(CH2)sNH—, and (NH(CH2)s)3N,
• where s, p, and q are independently selected from 1-7 with the proviso that if n is 2, Z is not hydroxy, C1-5 alkoxy, amino,
• C1-5alkylamino, diC,5alkylamino, phenylamino, or phenylC1-5alkylamino, piperidin-1-yl
• with the further proviso that if n is 3, Z is (NH(CH2)s)3N,
• and salts thereof.