CYTOCHROME P450 OXIDASE INHIBITORS AND USES THEREOF

1 . A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein

R 1 is thiazolyl;

L 1 is a bond or C 1 -C 10 alkylene;

A 1 is —O-L A1 - wherein L A1 is a bond;

X is O or S;

A 2 is -L A2 -N(R A2 )—, wherein L A2 is a bond and R A2 is hydrogen;

k is 0;

Z is —C(R 2 R 3 )— wherein R 2 is carbocyclylC 1 -C 6 alkyl, and R 3 is hydrogen;

p is 1, and L 3 represents -L 5 -W-L 5′ -, wherein W is a bond or C 1 -C 10 alkylene, and wherein L 5 and L 5′ are each independently a bond or C 1 -C 10 alkylene, and wherein L 5 and L 5′ are each independently optionally substituted at each occurrence with 1 or 2 substituents selected from the group consisting of hydroxyl, carbocyclyl, and carbocyclylC 1 -C 6 alkyl;

R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, carbocyclylC 1 -C 6 alkyl, -L 6 -C(O)NR 8 R 9 , -L 6 -C(O)-L 6′ -N(R 9 )C(O)NR 8 R 10 , L 6 -C(O)-L 6′ -NR 8 R 9 , -L 6 -S(O) j )R 8 and -L 6 -S(O) j NR 8 R 9 wherein j is independently selected at each occurrence from the group consisting of 0, 1, and 2, wherein L 6 and L 6′ are each independently selected at each occurrence from a bond or C 1 -C 10 alkylene, C 2 -C 10 alkenylene or C 2 -C 10 alkyneylene, wherein R 8 , R 9 and R 10 are each independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 hydroxyalkyl, carbocyclyl, carbocyclylC 1 -C 6 alkyl, and heterocycloC 1 -C 6 alkyl, and wherein L 6′ is substituted with a heterocyclyl;

R 5 is hydrogen; and

wherein each carbocyclyl and heterocyclyl moiety is independently optionally substituted at each occurrence with C 1 -C 6 alkyl and heterocyclyl.

2 . A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

tert-butyl(1S,3S,4S)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,3S,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-4-(acetylamino)-1-benzyl-2-hydroxy-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-[(methylsulfonyl)amino]-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-1-benzyl-4-{[(dimethylamino)carbonyl]amino}-2-hydroxy-5-phenylpentylcarbamate;

methyl (1S,3S,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-1-benzyl-4-{[(dimethylamino)sulfonyl]amino}-2-hydroxy-5-phenylpentylcarbamate;

tert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

isobutyl (1S,3S,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

isopropyl (1S,3S,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

tert-butyl(1S,3R,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-4-ylmethyl(1S,3S,4S)-1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-4-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(2-isopropyl-1,3-thiazol-4-ylacetyl]amino}-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl(1S,2S,4S)-1-benzyl-4-{[(tert-butylamino)carbonyl]amino}-2-hydroxy-5-phenylpentylcarbamate;

tert-butyl benzyla2R,3S)-2-hydroxy-4-phenyl-3-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}butyl)carbamate;

1,3-thiazol-5-ylmethyl(1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl(4-pyridin-2-ylbenzylamino]propylcarbamate;

tert-butyl 3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl 1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl 4-(acetylamino)-1-benzyl-2-hydroxy-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl 4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl 1-benzyl-2-hydroxy-4-[(methylsulfonylamino]-5-phenylpentylcarbamate;

1,3-thiazol-4-ylmethyl 1-benzyl-3-hydroxy-5-phenyl-4-{[(1,3-thiazol-4-ylmethoxy)carbonyl]amino}pentylcarbamate;

1,3-thiazol-5-ylmethyl 1-benzyl-2-hydroxy-4-{[(2-isopropyl-1,3-thiazol-4-ylacetyl]amino}-5-phenylpentylcarbamate;

1,3-thiazol-5-ylmethyl 1-benzyl-4-{[(tert-butylamino)carbonyl]amino}-2-hydroxy-5-phenylpentylcarbamate; and

tert-butyl benzyl(2-hydroxy-4-phenyl-3-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}butyl)carbamate.

3 . The compound of claim 1 , wherein L 1 is C 1 -C 10 alkylene.

4 . The compound of claim 1 , wherein L 1 is methylene.

5 . The compound of claim 1 , wherein X is O.

6 . The compound of claim 1 , wherein R 2 is benzyl.

7 . The compound of claim 1 , wherein W is a bond.

8 . The compound of claim 1 , wherein L 5 is C 1 -C 10 alkylene.

9 . The compound of claim 1 , wherein L 5 is methylene.

10 . The compound of claim 1 , wherein L 5′ is C 1 -C 10 alkylene.

11 . The compound of claim 1 , wherein L 5′ is ethylene.

12 . The compound of claim 1 , wherein L 5′ is substituted with benzyl.

13 . The compound of claim 1 , wherein R 4 is -L 6 -C(O)NR 8 R 9 .

14 . The compound of claim 1 , wherein R 4 is -L 6 -C(O)-L 6′ -NR 8 R 9 .

15 . The compound of claim 1 , wherein R 4 is -L 6 -C(O)-L 6′ -N(R 9 )C(O)NR 8 R 10 .

16 . The compound of claim 1 , wherein

L is methylene;

X is O; and

R 2 is benzyl.

17 . The compound of claim 1 , wherein

L 1 is methylene;

X is O; and

R 2 is benzyl;

W is a bond;

L 5 is methylene; and

L 5′ is ethylene substituted with benzyl.

18 . The compound of claim 1 , wherein R 8 is C 1 -C 6 alkyl.

19 . The compound of claim 1 , wherein at least one of R 8 and R 9 is methyl.

20 . The compound of claim 1 , wherein R 4 is -L 6 -C(O)-L 6′ -N(R 9 )C(O)NR 8 R 10 , wherein

L 6 is a bond,

L 6′ is C 1 -C 10 alkylene;

R 9 is hydrogen,

R 8 is C 1 -C 6 alkyl, and

R 10 is heterocycloC 1 -C 6 alkyl.

21 . The compound of claim 1 , wherein the heterocyclyl moiety is substituted with C 1 -C 6 alkyl.

22 . A pharmaceutical composition comprising a compound or salt thereof of claim 1 .

23 . The pharmaceutical composition of claim 22 , further comprising a drug which is metabolizable by a CYP enzyme.

24 . The pharmaceutical composition of claim 22 , wherein said CYP enzyme is CYP3A4, CYP2D6 or CYP2C9.

25 . The pharmaceutical composition of claim 22 , wherein said drug is an antiviral drug.

26 . A method for inhibiting a metabolizing activity of a CYP enzyme in a subject of interest, comprising administering said drug and an effective amount of a compound or salt thereof according to claim 1 to a subject in need thereof, thereby improving the pharmacokinetics of said drug in the subject.

27 . The method of claim 26 , wherein said CYP enzyme is CYP3A4, CYP2D6 or CYP2C9.

28 . A method for improving the pharmacokinetics of a drug that is metabolizable by a CYP enzyme, comprising administering said drug and an effective amount of a compound or salt thereof according to claim 1 to a subject in need thereof, thereby increasing the blood or liver level of said drug in the subject.

29 . The compound of claim 1 , wherein

L 1 is methylene;

X is O; R 2 is benzyl;

L 5 is methylene;

L 5′ is methylene substituted with benzyl;

W is methylene;

R 4 is -L 6 -C(O)-L 6′ -N(R 9 )C(O)NR 8 R 10 , wherein L 6 is a bond, L 6′ is C 3 alkylene substituted with morpholino, R 8 is methyl, and R 9 is hydrogen; and

R 10 is isopropylthiazolylmethyl;

and R 5 is hydrogen.