Tetracyclic inhibitors of fatty acid amide hydrolase

1. A compound of Formula (I):

wherein

R 1 is H;

R 2 is pyridyl optionally substituted with R x ;

or R 1 and R 2 taken together with the oxazole to which they are attached form oxazolo[4,5-b]pyridin-2-yl;

where R x is —C 1-6 alkyl; —C 3-6 cycloalkyl; —CF 3 ; —CN; —C(O)C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents; —CO 2 C 1-4 alkyl; —CO 2 H; —C(O)N(R a )R b ; —OH; —OC 1-6 alkyl; halo; —NO 2 ; —NR a R b ; —N(R a )C(O)R b ; —N(R a )SO 2 R b ; —SO 2 N(R a )R b ; —S(O) 0-2 R f ; or tetrazolyl;

where R a and R b are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl; and

R f is —C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents;

R 3 is —H; —C 1-6 alkyl; C 3-6 cycloalkyl; —CF 3 ; —CN; —C(O)C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents; —CO 2 C 1-4 alkyl; —CO 2 H; —C(O)N(R c )R d ; —OH; —OC 1-6 alkyl; -halo; —NO 2 ; —NR c R d ; —N(R c )C(O)R d ; —N(R c )SO 2 R d ; —SO 2 N(R c )R d ; —S(O) 0-2 R f ; or —CH 2 N(R g )R h ;

where R c and R d are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl;

R f is —C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents; and

R g and R h are each independently H or C 1-4 alkyl; or R g and R h taken together with the nitrogen to which they are attached form a monocyclic saturated heterocycloalkyl group;

X is —CH 2 —, —O—, or —CH(OH)—; and

Y is absent or is —CH 2 —, —O—, —NR i —, —CH 2 O—, or —OCH 2 —;

wherein R i is —H or —C 1-6 alkyl; and provided that when Y is absent, a single bond is present between the two phenyl rings of formula I or;

a pharmaceutically acceptable salt of a compound of Formula (I).

2. A compound according to claim 1 wherein R 2 is unsubstituted 2-pyridyl.

3. A compound according to claim 1 wherein R 2 is 2-pyridyl substituted with —CN, —CO 2 Me, —CO 2 Et, —CO 2 H, or —CONH 2 .

4. A compound according to claim 1 selected from the group consisting of compounds of Formula (I) wherein R 3 is —H.

5. A compound according to claim 1 wherein R 3 is —CH 2 N(R g )R h .

6. A compound according to claim 5 wherein R g and R h are both methyl.

7. A compound according to claim 5 wherein R g and R h are taken together with the nitrogen to which they are attached to form piperidine, morpholine, thiomorpholine, pyrrolidine, or N-methylpiperazine.

8. A compound according to claim 1 wherein X is —CH 2 — or —O—.

9. A compound according to claim 1 wherein X is —O—.

10. A compound according to claim 8 wherein X is —CH 2 —.

11. A compound according to claim 1 wherein Y is absent or is selected from the group consisting of —CH 2 —, —O—, or —CH 2 O—.

12. A compound of claim 1 selected from the group consisting of:

1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(4-(benzyloxy)phenyl)propane;

2-(4-(Benzyloxy)phenoxy)-1-(5-(pyridin-2-yl)oxazol-2-yl)ethanone;

1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(3-(benzyloxy)phenyl)-propane;

2-(3-(Benzyloxy)phenoxy)-1-(5-(pyridin-2-yl)oxazol-2-yl)ethanone;

3-(4-(Phenoxymethyl)phenyl)-1-(5-(pyridin-2-yl)oxazol-2-yl)propan-1-one;

1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(4-phenoxyphenyl)propane;

1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(4-(phenylamino)phenyl)propane;

1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(4-benzylphenyl)propane;

1-Oxo-1-[5-(2-pyridyl)oxazol-2-yl]-3-(4-biphenyl)propane;

3-(4-(Benzyloxy)phenyl)-1-(oxazolo[4,5-b]pyridin-2-yl)propan-1-one;

6-{2-[3-(4-Phenoxy-phenyl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4-Phenoxy-phenyl)-propionyl]-oxazol-5-yl}-nicotinic acid methyl ester;

6-{2-[3-(4-Phenoxy-phenyl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-{2-[3-(4-Phenoxy-phenyl)-propionyl]-oxazol-5-yl}-nicotinic acid;

6-{2-[3-(4-Phenoxymethyl-phenyl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4-Phenoxymethyl-phenyl)-propionyl]-oxazol-5-yl}-nicotinic acid methyl ester;

6-{2-[3-(4-Phenoxymethyl-phenyl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-{2-[3-(4-Phenoxymethyl-phenyl)-propionyl]-oxazol-5-yl}-nicotinic acid;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carbonitrile;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid methyl ester;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid ethyl ester;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-nicotinic acid methyl ester;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-nicotinic acid;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid amide;

6-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-nicotinamide;

4-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid methyl ester;

4-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid;

3-Biphenyl-4-yl-1-(5-pyridin-4-yl-oxazol-2-yl)-propan-1-one;

3-Biphenyl-4-yl-1-(5-pyridin-3-yl-oxazol-2-yl)-propan-1-one;

5-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid methyl ester;

5-[2-(3-Biphenyl-4-yl-propionyl)-oxazol-5-yl]-pyridine-2-carboxylic acid;

6-{2-[3-(4′-Piperidin-1-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4′-Morpholin-4-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4′-Thiomorpholin-4-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4′-Pyrrolidin-1-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4′-Dimethylaminomethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid methyl ester;

6-(2-{3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-propionyl}-oxazol-5-yl)-pyridine-2-carboxylic acid methyl ester;

6-{2-[3-(4′-Piperidin-1-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-{2-[3-(4′-Morpholin-4-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-{2-[3-(4′-Thiomorpholin-4-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-{2-[3-(4′-Pyrrolidin-1-ylmethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-{2-[3-(4′-Dimethylaminomethyl-biphenyl-4-yl)-propionyl]-oxazol-5-yl}-pyridine-2-carboxylic acid;

6-(2-{3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-propionyl}-oxazol-5-yl)-pyridine-2-carboxylic acid;

3-Biphenyl-4-yl-1-{5-[6-(1H-tetrazol-5-yl)-pyridin-2-yl]-oxazol-2-yl}-propan-1-one;

3-(4-Phenoxymethyl-phenyl)-1-{5-[6-(1H-tetrazol-5-yl)-pyridin-2-yl]-oxazol-2-yl}-propan-1-one; and

6-{2-[3-(4-phenoxymethylphenyl)-propionyl]-oxazol-5-yl}-pyridine-2-carbonitrile; or

a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition for arresting the development, relieving or diminishing the symptoms of a disease, disorder, or medical condition mediated by FAAH activity, comprising:

(a) an effective amount of at least one compound of Formula (I) of claim 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or an pharmaceutically active metabolite thereof, or any combination thereof; and

(b) a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising an effective amount of a compound according to claim 12 , and pharmaceutically acceptable excipient.

15. A pharmaceutical composition according to claim 13 , further comprising: an analgesic selected from the group consisting of opioids and non-steroidal anti-inflammatory drugs.

16. A pharmaceutical composition according to claim 13 , further comprising: an active ingredient selected from the group consisting of aspirin, acetaminophen, opioids, ibuprofen, naproxen, COX-2 inhibitors, gabapentin, pregabalin, and tramadol.

17. A compound of Formula (I):

wherein

R 1 is H;

R 2 is pyridyl optionally substituted with R x ;

where R x is —C 1-6 alkyl; —C 3-6 cycloalkyl; —CF 3 ; —CN; —C(O)C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents; —CO 2 C 1-4 alkyl; —CO 2 H; —C(O)N(R a )R b ; —OH; —OC 1-6 alkyl; halo; —NO 2 ; —NR a R b ; —N(R a )C(O)R b ; —N(R a )SO 2 R b ; —SO 2 N(R a )R b ; —S(O) 0-2 R f ; or tetrazolyl;

where R a and R b are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl; and

R f is —C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents;

R 3 is —H; —C 1-6 alkyl; C 3-6 cycloalkyl; —CF 3 ; —CN; —C(O)C 1-4 alkyl optionally substituted with one, two, or three fluoro substituents; —CO 2 C 1-4 alkyl; —CO 2 H; —C(O)N(R c )R d ; —OH; —OC 1-6 alkyl; —halo; —NO 2 ; NR c ; R d ; —N(R C )C(O)R d ; —N(R c )SO 2 R d ; —SO 2 N(R c )R d ; —S(O) 0-2 R f ; or —CH 2 N(R g )R h ;

where R c and R d are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl;

R f is —C 1-4 optionally substituted with one, two, or three fluoro substituents; and

R g and R h are each independently H or C 1-4 alkyl; or R g and R h taken together with the nitrogen to which they are attached form a monocyclic saturated heterocycloalkyl group;

X is —CH 2 —, —O—, —S—, —S(O) 2 —, —N(R i )—, or —CH(OH)—; and

Y is absent or is —CH 2 —, —O—, —S—, —S(O) 2 —, —S(O) 2 —, —NR i —, —CH 2 O—, or -OCH 2 —;

wherein R i is —H or —C 1-6 alkyl; and provided that when Y is absent, a single bond is present between the two phenyl rings of formula I; or a pharmaceutically acceptable salt thereof.