Aryl linked imidazole and triazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Z is selected from

A is selected from: cyclopropyl, phenyl, benxo[d][1,3]dioxol-5-yl, tetrahydro-2H-pyran-2-yl, thiazolyl, pyridyl and pyrazinyl, each of which can be optionally substituted with up to two R 5 groups;

X is a bond or —CH 2 —;

R 1 is

each occurrence of R 2 is independently selected from H and C 1 -C 6 alkyl, or two R 2 groups on the same carbon atom can be joined together to form a cyclopropyl group;

R 3 is selected from H and C 1 -C 6 alkyl, or R 3 and an R 2 group, together with the atoms to which they are attached, can combine to form a C 3 -C 6 heterocyclic ring;

R 4 is H, or R 3 and R 4 can join together to form a linker group selected from —CH 2 — and —CH 2 —CH 2 , thereby forming a fused bicyclic ring with ring B;

each occurrence of R 5 is independently selected from halo, —OR 8 , —N(R 6 ) 2 —, 5 or 6-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to two R 7 groups, which can be the same or different;

each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, and —O—(C 1 -C 6 alkyl);

each occurrence of R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OR 8 , and —NHCHCH(cyclopropyl)OH;

each occurrence of R 8 is independently H or C 1 -C 6 alkyl; and

R 9 is F.

2. The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

Z is

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein

A is thiazol-2-yl or pyridin-3-yl, and

R 5 is selected from —N(H)—C(O)—C 1 -C 4 alkyl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-hydroxypiperidin-1-yl and 7-hydroxyhexadydropyrrolo[1,2-a]pyrazin-2(1H)-yl.

5. The compound of claim 1 , having the formula (Ib):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

Z is

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein

A is thiazol-2-yl or pyridin-3-yl, and

R 5 is selected from —N(H)—C(O)—C 1 -C 4 alkyl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-hydroxypiperidin-1-yl and 7-hydroxyhexadydropyrrolo[1,2-a]pyrazin-2(1H)-yl.

8. The compound of claim 1 , having the formula (Ic):

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

Z is

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:

A is thiazol-2-yl or pyridin-3-yl, and

R 5 is selected from —N(H)—C(O)—C 1 -C 4 alkyl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-hydroxypiperidin-1-yl and 7-hydroxyhexadydropyrrolo[1,2-a]pyrazin-2(1H)-yl.

11. The compound of claim 1 , having the formula (Id):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

Z is

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

A is thiazol-2-yl or pyridin-3-yl, and

R 5 is selected from —N(H)—C(O)—C 1 -C 4 alkyl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-hydroxypiperidin-1-yl and 7-hydroxyhexadydropyrrolo[1,2-a]pyrazin-2(1H)-yl.

14. A compound selected from the following:

N-(5-((6-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)thiazol-2-yl)acetamide;

(R)-5-((7-(1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)thiazol-2-amine;

N-(1-(4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)ethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-sulfonamide;

N-(1-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)ethyl)-N-methyl-2-(4-methylpiperazin-1-yl)thiazole-5-sulfonamide;

N-((2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)(phenyl)methyl)-2-(4-methylpiperazin-1-yl)thiazole-5-sulfonamide;

N—((R)-1-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)ethyl)-2-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)thiazole-5-sulfonamide;

N—((S)-1-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)ethyl)-2-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)thiazole-5-sulfonamide;

N-(5-(N-(2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)propan-2-yl)sulfamoyl)thiazol-2-yl)acetamide;

N-(5-((2-(4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)acetamide;

5-((2-(4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)-2-(4-methylpiperazin-1-yl)thiazole;

(R)—N-(5-(N-(1-(4-(1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)phenyl)cyclopropyl)sulfamoyl)thiazol-2-yl)acetamide;

N-(5-(N-((5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)pyridin-2-yl)methyl)sulfamoyl)thiazol-2-yl)acetamide;

N-(5-(N-(4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)benzyl)sulfamoyl)thiazol-2-yl)acetamide;

N-(5-(N-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)benzyl)sulfamoyl)thiazol-2-yl)acetamide;

N-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenethyl)pyridine-3-sulfonamide;

N-(5-((4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)isoindolin-2-yl)sulfonyl)thiazol-2-yl)acetamide;

5-((4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)isoindolin-2-yl)sulfonyl)-2-(4-methylpiperazin-1-yl)thiazole;

N-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)benzyl)pyridine-3-sulfonamide;

N-(5-(N-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)benzyl)sulfamoyl)thiazol-2-yl)acetamide;

N-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)benzyl)-2-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)thiazole-5-sulfonamide;

N-(5-((2-(2-(1-(2-methoxyethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)acetamide;

N-(5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)acetamide;

(7R,8aS)-2-(5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;

1-(4-fluorophenethyl)-5-(2-(1-(methylsulfonyl)pyrrolidin-2-yl)phenyl)-1H-imidazole;

(7R,8aS)-2-(5-((2-(2-(1-methyl-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;

3-bromo-2-chloro-5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)pyridine;

5-(2-(1-(benzo[d][1,3]dioxol-5-ylsulfonyl) pyrrolidin-2-yl)phenyl)-1-(4-fluorophenethyl)-1H-imidazole;

5-(2-(1-((2,5-dimethoxyphenyl)sulfonyl)pyrrolidin-2-yl)phenyl)-1-(4-fluorophenethyl)-1H-imidazole;

5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)-N,N-dimethylpyridin-2-amine;

4-(5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)pyridin-2-yl)morpholine;

N-(5-((2-(2-(1-methyl-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)acetamide;

N-(5-((2-(2-(1-cyclopropyl-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiazol-2-yl)acetamide;

1-(5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)pyridin-2-yl)piperidin-4-ol;

1-cyclopropyl-2-((5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl) sulfonyl)pyridin-2-yl)amino)ethanol;

2-(4-(5-((2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)pyridin-2-yl)piperazin-1-yl)ethanol;

4-chlorophenyl 2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidine-1-carboxylate

tert-butyl 2-(2-(1-cyclopropyl-1H-imidazol-5-yl)phenyl)pyrrolidine-1-carboxylate;

tert-butyl 2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidine-1-carboxylate;

isopropyl 2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidine-1-carboxylate;

1-(4-fluorophenethyl)-5-(2-(pyrrolidin-2-yl)phenyl)-1H-imidazole;

(2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;

(2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)(pyridin-3-yl)methanone;

(2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)(6-morpholinopyridin-3-yl)methanone;

cyclopropyl(2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)methanone;

1-(4-fluorophenethyl)-5-(2-(1-methylpyrrolidin-2-yl)phenyl)-1H-imidazole;

2-(2-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)-N-isopropylpyrrolidine-1-carboxamide;

cyclopropyl(2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)methanone;

(2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)(pyridin-3-yl)methanone;

(2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;

2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)-N-isopropylpyrrolidine-1-carboxamide;

1-(4-fluorophenethyl)-5-(3-(1-(methylsulfonyl)pyrrolidin-2-yl)phenyl)-1H-imidazole;

(2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)(6-morpholinopyridin-3-yl)methanone;

5-(3-(1-((2,5-dimethoxyphenyl)sulfonyl)pyrrolidin-2-yl)phenyl)-1-(4-fluorophenethyl)-1H-imidazole;

3-Bromo-2-chloro-5-((2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)pyridine;

N-((5-((2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)thiophen-2-yl)methyl)benzamide;

Isopropyl 2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidine-1-carboxylate;

1-(5-((2-(3-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)phenyl)pyrrolidin-1-yl)sulfonyl)pyridin-2-yl)piperidin-4-ol;

5-((5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-2-(4-methylpiperazin-1-yl)thiazole;

5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline;

4-(5-((5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)pyridin-2-yl)morpholine;

5-((5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N,N-dimethylpyridin-2-amine;

5-((5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-(2-methoxyethyl)-N-methylpyridin-2-amine;

(7R,8aS)-2-(5-((5-(1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)thiazol-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;

(7R,8aS)-2-(5-((5-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)thiazol-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;

(7R,8aS)-2-(5-((8-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)thiazol-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;

5-((4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-5,6-dihydro-1,7-naphthyridin-7(8H)-yl)sulfonyl)-2-(4-methylpiperazin-1-yl)thiazole; and

5-((4-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)sulfonyl)-2-(4-methylpiperazin-1-yl)thiazole;

or a pharmaceutically acceptable salt of any of the foregoing compounds.

15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 , further comprising an anti-HIV drug.

17. A method for improving the pharmacokinetics of a therapeutic compound that is metabolized by a CYP3A enzyme in subject, said method comprising administering to said subject in need of such treatment a combination of: (a) said therapeutic compound that is metabolized by a CYP3A enzyme and (b) a compound of claim 1 , or a pharmaceutically acceptable salt thereof.