Methods for increasing the stabilization of hypoxia inducible factor-1 alpha

1. A method for inhibiting hypoxia-inducible factor-1alpha (HIF-1α) 4-prolyl hydroxylase activity in a subject, comprising administering to a subject a HIF-1α prolyl hydroxylase inhibitor having the formula:

wherein L is chosen from CH 2 or SO 2 ;

Z has the formula:

R represents from 0 to 5 substitutions for hydrogen;

the index n is an integer from 0 to 5;

R 1 and R 2 are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 10 linear, C 3 -C 10 branched, or C 3 -C 10 cyclic alkyl;

iii) substituted or unsubstituted C 2 -C 10 linear, C 3 -C 10 branched, or C 3 -C 10 cyclic alkenyl;

iv) substituted or unsubstituted C 2 -C 10 linear or C 3 -C 10 branched alkynyl;

v) substituted or unsubstituted C 6 or C 10 aryl;

vi) substituted or unsubstituted C 1 -C 9 heterocyclic;

vii) substituted or unsubstituted C 1 -C 9 heteroaryl; or

viii) R 1 and R 2 can be taken together to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring having from form 2 to 20 carbon atoms and from 1 to 7 heteroatoms; or

a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein L is CH 2 .

3. The method according to claim 1 , wherein L is SO 2 .

4. The method according to claim 1 , wherein each R is a substitution for hydrogen independently chosen from:

i) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

ii) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkenyl;

iii) substituted or unsubstituted C 2 -C 12 linear or C 3 -C 12 branched alkynyl;

iv) C 6 or C 10 substituted or unsubstituted aryl;

v) C 1 -C 9 substituted or unsubstituted heterocyclic;

vi) C 1 -C 11 substituted or unsubstituted heteroaryl;

vii) halogen;

viii) —[C(R 23a )(R 23b )] x OR 10 ;

R 10 is chosen from:

a) —H;

b) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

c) C 6 or C 10 substituted or unsubstituted aryl or alkylenearyl;

d) C 1 -C 9 substituted or unsubstituted heterocyclic;

e) C 1 -C 11 substituted or unsubstituted heteroaryl;

ix) —[C(R 23a )(R 23b )] x N(R 11a )(R 11b );

R 11a and R 11b are each independently chosen from:

a) —H;

b) —OR 12 ;

R 12 is hydrogen or C 1 -C 4 linear alkyl;

c) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

d) C 6 or C 10 substituted or unsubstituted aryl;

e) C 1 -C 9 substituted or unsubstituted heterocyclic;

f) C 1 -C 11 substituted or unsubstituted heteroaryl; or

g) R 11a and R 11b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

x) —[C(R 23a )(R 23b )] x C(O)R 13 ;

R 13 is:

a) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

b) —OR 14 ;

R 14 is hydrogen, substituted or unsubstituted C 1 -C 4 linear alkyl, C 6 or C 10 substituted or unsubstituted aryl, C 1 -C 9 substituted or unsubstituted heterocyclic, C 1 -C 11 substituted or unsubstituted heteroaryl;

c) —N(R 15a )(R 15b );

R 15a and R 15b are each independently hydrogen, substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl; C 6 or C 10 substituted or unsubstituted aryl; C 1 -C 6 substituted or unsubstituted heterocyclic; C 1 -C 11 substituted or unsubstituted heteroaryl; or R 15a and R 15b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

xi) —[C(R 23a )(R 23b )] x OC(O)R 16 ;

R 16 is:

a) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

b) —N(R 17a )(R 17b );

R 17a and R 17b are each independently hydrogen, substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl; C 6 or C 10 substituted or unsubstituted aryl; C 1 -C 6 substituted or unsubstituted heterocyclic; C 1 -C 11 substituted or unsubstituted heteroaryl; or R 17a and R 17b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

xii) —[C(R 23a )(R 23b )] x NR 18 C(O)R 19 ;

R 18 is:

a) —H; or

b) substituted or unsubstituted C 1 -C 4 linear, C 3 -C 4 branched, or C 3 -C 4 cyclic alkyl;

R 19 is:

a) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

b) N(R 20a )(R 20b );

R 20a and R 20b are each independently hydrogen, substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl; C 6 or C 10 substituted or unsubstituted aryl; C 1 -C 9 substituted or unsubstituted heterocyclic; C 1 -C 11 substituted or unsubstituted heteroaryl; or R 20a and R 20b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

xiii) —[C(R 23a )(R 23b )] x CN;

xiv) —[C(R 23a )(R 23b )] x NO 2 ;

xv) —[C(R 23a )(R 23b )] x R 21 ;

R 21 is C 1 -C 10 linear, branched, or cyclic alkyl substituted by from 1 to 21 halogen atoms chosen from —F, —Cl, —Br, or —I;

xvi) —[C(R 23a )(R 23b )] x SO 2 R 22 ;

R 22 is hydrogen, hydroxyl, substituted or unsubstituted C 1 -C 4 linear or C 3 -C 4 branched alkyl; substituted or unsubstituted C 6 , C 10 , or C 1-4 aryl; C 7 -C 15 alkylenearyl; C 1 -C 9 substituted or unsubstituted heterocyclic; or C 1 -C 11 substituted or unsubstituted heteroaryl;

R 23a and R 23b are each independently hydrogen or C 1 -C 4 alkyl; and

the index x is an integer from 0 to 5.

5. The method according to claim 1 , wherein Z is 4-chlorophenyl.

6. The method according to claim 1 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

7. The method according to claim 1 , wherein the HIF-1α prolyl hydroxylase inhibitor is chosen from:

1-Benzyl-3-hydroxy-4-(piperidin-1-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(morpholin-4-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(thiomorpholin-4-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(thiazolidin-3-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(4-benzylpiperidin-1-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(4-benzylpiperazin-1-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(1,4-dioxa-8-azaspiro[4,5]dec-8-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-azepan-1-ylmethylpyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(azocan-1-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-(1,4′-bipiperidinyl-1′-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(3,4-dihydroquinolin-1(2H)-yl)methyl]pyridin-2(1H)-one;

Methyl 1-[(1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl]pyrrolidine-2-carboxylate;

1-Benzyl-3-hydroxy-4-{[2-(methoxymethyl)pyrrolidin-1-yl]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-{[2-(pyrdin-2-yl)pyrrolidin-1-yl]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]pyridin-2(1H)-one;

1-(3-Methoxybenzyl)-3-hydroxy-4-(piperidin-1-ylmethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-{[3-(1-H-imidazol-1-yl)propylamino]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(benzylaminomethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-{[(2-(pyridin-2-yl)ethylamino]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(2-methoxyethylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(1-hydroxy-2-methylpropan-2-ylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(pyridin-4-ylmethylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy 4-{[(furan-2-ylmethyl)amino]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-{[2-(methylthio)ethylamino]methyl}pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(4-methoxybenzylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(1-phenylethylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-(cycloheptylaminomethyl)pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(4-methylcyclohexylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[(1-benzylpiperidin-4-ylamino)methyl]pyridin-2(1H)-one;

3-[(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methylamino]azepan-2-one;

1-Benzyl-3-hydroxy-4-[(1-benzylpyrrolidin-3-ylamino)methyl]pyridin-2(1H)-one;

(R)-1-Benzyl-3-hydroxy-4-[(1-phenylethylamino)methyl]pyridin-2(1H)-one;

1-Benzyl-3-hydroxy-4-[([1,3]dioxolan-2-ylmethylmethylamino)methyl]pyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-thiazolidin-3-ylmethylpyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-azocan-1ylmethylpyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(4-phenylpiperazin-1-ylmethyl)-pyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[1,4′]bipiperidinyl-1′-ylmethylpyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]pyridin-2(1H)-one;

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(benzylaminomethyl)pyridin-2(1H)-one; or

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[(2-methoxyethylamino)methyl]-pyridin-2(1H)-one.

8. The method according to claim 1 , wherein the wherein the HIF-1α prolyl hydroxylase inhibitor has the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl;

or a pharmaceutically acceptable salt thereof.

9. The method according to claim 8 , wherein R 4 is tert-butyl.

10. The method according to claim 8 , wherein Z is 4-chlorophenyl.

11. The method according to claim 8 , wherein the one or more compounds is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.

12. The method according to claim 1 , wherein the subject has an inflammatory disease.

13. The method according to claim 1 , wherein the subject has a medical condition causing a decreased cellular immunity.

14. The method according to claim 13 , wherein the medical condition is cancer.

15. A method for increasing the cellular immune response of a subject having an inflammatory disease, comprising administering to a subject an effective amount of a HIF-1α prolyl hydroxylase inhibitor having the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl;

or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15 , wherein the compound is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures.

17. A method of controlling the immune response in a subject having an inflammatory disease, comprising administering to the subject a HIF-1α prolyl hydroxylase inhibitor having the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or

a pharmaceutically acceptable salt thereof.

18. The method according to claim 17 , wherein R 4 is tert-butyl.

19. The method according to claim 17 , wherein Z is 4-chlorophenyl.

20. The method according to claim 17 , wherein the one or more compounds is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.