Derivatives of pyridoxine for inhibiting HIV integrase

1. A method of treating an HIV infection in a mammal, said method comprising administering to said mammal a compound in an amount effective for the treatment of said HIV infection,

wherein said compound is selected from the group consisting of:

(i) a compound of formula I,

wherein:

X is H or OH;

Y is H or OH;

R 1 is H or halogen (F, Cl, Br, I);

R 2 is H or halogen (F, Cl, Br, I);

R 3 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, or benzyl;

R 4 is H, C 1-6 alkyl, or benzyl; and

R 5 is H or C 1-6 alkyl; or pharmaceutically acceptable salts or solvates thereof;

(ii) a compound of formula Ic,

wherein:

X is O or N—OH;

Y is H or OH;

R 1 is H or halogen (F, Cl, Br, I);

R 2 is H or halogen (F, Cl, Br, I);

R 3 is H, C 1-6 alkyl or benzyl;

R 4 is H, C 1-6 alkyl or benzyl; and

R 5 is H or C 1-6 alkyl; or

pharmaceutically acceptable salts thereof; and

(iii) a compound selected from the group consisting of:

(R)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N-hydroxy-N,2,2-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)-N-methylpicolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-3-hydroxy-4-(hydroxymethyl)-N-methoxypicolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-methylpicolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-methylpicolinamide;

5-(4-fluorobenzoyl)-N,3-dihydroxy-4-methylpicolinamide;

(E)-5-((4-fluorophenyl)(hydroxyimino)methyl)-N,3-dihydroxy-4-methylpicolinamide; and

(S)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or

pharmaceutically acceptable salts thereof.

2. A method of treating AIDS or AIDS-related complex in a mammal, said method comprising administering to said mammal a compound in an amount effective for the treatment of said AIDS or AIDS-related complex,

wherein said compound is selected from the group consisting of:

(i) a compound of formula I,

wherein:

X is H or OH;

Y is H or OH;

R 1 is H or halogen (F, Cl, Br, I);

R 2 is H or halogen (F, Cl, Br, I);

R 3 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, or benzyl;

R 4 is H, C 1-6 alkyl, or benzyl; and

R 5 is H or C 1-6 alkyl; or pharmaceutically acceptable salts thereof;

(ii) a compound of formula Ic,

wherein:

X is O or N—OH;

Y is H or OH;

R 1 is H or halogen (F, Cl, Br, I);

R 2 is H or halogen (F, Cl, Br, I);

R 3 is H, C 1-6 alkyl or benzyl;

R 4 is H, C 1-6 alkyl or benzyl; and

R 5 is H or C 1-6 alkyl; or

pharmaceutically acceptable salts thereof; and

(iii) a compound selected from the group consisting of:

(R)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N-hydroxy-N,2,2-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)-N-methylpicolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-3-hydroxy-4-(hydroxymethyl)-N-methoxypicolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-methylpicolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-methylpicolinamide;

5-(4-fluorobenzoyl)-N,3-dihydroxy-4-methylpicolinamide;

(E)-5-((4-fluorophenyl)(hydroxyimino)methyl)-N,3-dihydroxy-4-methylpicolinamide; and

(S)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or

pharmaceutically acceptable salts or solvates thereof.

3. A method of inhibiting HIV replication in a mammal, said method comprising administering to said mammal a compound in an amount effective to inhibit HIV replication in a mammal,

wherein said compound is selected from the group consisting of:

(i) a compound of formula I,

wherein:

X is H or OH;

Y is H or OH;

R 1 is H or halogen (F, Cl, Br, I);

R 2 is H or halogen (F, Cl, Br, I);

R 3 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, or benzyl;

R 4 is H, C 1-6 alkyl, or benzyl; and

R 5 is H or C 1-6 alkyl; or pharmaceutically acceptable salts or solvates thereof;

(ii) a compound of formula Ic,

wherein:

X is O or N—OH;

Y is H or OH;

R 1 is H or halogen (F, Cl, Br, I);

R 2 is H or halogen (F, Cl, Br, I);

R 3 is H, C 1-6 alkyl or benzyl;

R 4 is H, C 1-6 alkyl or benzyl; and

R 5 is H or C 1-6 alkyl; or

pharmaceutically acceptable salts or solvates thereof; and

(iii) a compound selected from the group consisting of:

(R)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N-hydroxy-N,2,2-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)-N-methylpicolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-3-hydroxy-4-(hydroxymethyl)-N-methoxypicolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-methylpicolinamide;

5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-methylpicolinamide;

5-(4-fluorobenzoyl)-N,3-dihydroxy-4-methylpicolinamide;

(E)-5-((4-fluorophenyl)(hydroxyimino)methyl)-N,3-dihydroxy-4-methylpicolinamide; and

(S)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or

pharmaceutically acceptable salts thereof.

4. The method of claim 3 , wherein said HIV is resistant to at least one HIV inhibiting agent.

5. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of:

(i) a compound of formula Ia,

wherein X is OH; and R 3 is H, C 1-6 alkyl or benzyl; or pharmaceutically acceptable salts thereof;

(ii) a compound of formula Ib,

wherein X is OH; and R 3 is H, C 1-6 alkyl or benzyl; or pharmaceutically acceptable salts thereof; and

(iii) a compound selected from the group consisting of:

(R)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; and

(S)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or

pharmaceutically acceptable salts thereof.

6. The method of claim 2 , wherein the compound of formula I is selected from the group consisting of:

(I) a compound of formula Ia,

wherein X is OH; and R 3 is H, C 1-6 alkyl or benzyl; or pharmaceutically acceptable salts thereof;

(ii) a compound of formula Ib,

wherein X is OH; and R 3 is H, C 1-6 alkyl or benzyl; or pharmaceutically acceptable salts thereof; and

(iii) a compound selected from the group consisting of:

(R)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; and

(S)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or

pharmaceutically acceptable salts thereof.

7. The method of claim 3 , wherein the compound of formula I is selected from the group consisting of:

(i) a compound of formula Ia,

wherein X is OH; and R 3 is H, C 1-6 alkyl or benzyl; or pharmaceutically acceptable salts thereof;

(ii) a compound of formula Ib,

wherein X is OH; and R 3 is H, C 1-6 alkyl or benzyl; or pharmaceutically acceptable salts thereof; and

(iii) a compound selected from the group consisting of:

(R)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;

5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; and

(S)-5-((3-chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or

pharmaceutically acceptable salts thereof.