OXAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH
The present invention is directed to certain oxazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer Disease, and Parkinson's Disease.
1 . A compound of the formula I:
or a pharmaceutically acceptable salt thereof wherein:
X is S or SO;
n is 0, 1 or 2;
R 1 is selected from the group consisting of:
(1) aryl, and
(2) HET 1 ,
wherein R 1 is optionally mono or di-substituted with substituents R 4 and R 5 ; and wherein R 4 and R 5 are independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) mono, di or tri-halo C 1-4 alkyl,
(d) mono, di or tri-halo OC 1-4 alkyl,
(d) —OC 1-4 alkyl, optionally substituted with hydroxyl, halo or amino,
(e) —C 1-4 alkyl optionally substituted with one or two substituents selected from hydroxyl, CN, —CHF 2 and —CF 3 ,
(f) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy, halo or CN,
(g) —S(O) n C 1-4 alkyl,
(h) —S(O) n NR 6 R 7 ,
(i) —C(O)—NH—NR 8 R 9 ,
(j) —C(O)—OH,
(k) —C(O)—OC 1-4 alkyl, optionally substituted with halo or hydroxy,
(l) —C(O)—NR 10 R 11 ,
(m) —C(O)—C 1-4 alkyl optionally mono, di or tri substituted with halo,
(o) —C(NR 12 )—NR 13 R 14 ,
(p) HET 4 ,
(q) aryl,
(r) —C(O)—NH—NH—C(O)H,
(s) —CH 2 —C(O)—O—C 1-4 alkyl, whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH
(t) —CH 2 —C(O)NR 15 R 16 whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH, and
(u) —NR 17 R 18 ,
wherein choices (p) and (q) are each optionally mono or di-substituted with substituents selected from
(1) halo,
(2) —CN,
(3) —OH,
(4) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(5) —CF 3 ,
(6) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(7) —C(O)OH, and
(8) —C(O)O—C 1-3 alkyl;
(9) —C(O)—NR 19 R 20 ,
(10) —NH 2 ,
(11) Oxo,
(12)=8,
with the proviso that the substituent on choice (q) is other than oxo or ═S,
wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 , are each independently selected from H and C 1-4 alkyl,
or
R 6 and R 7 or R 8 and R 9 or R 10 and R 11 or R 13 and R 14 or R 15 and R 16 or R 17 and R 18 or R 19 and R 20 are joined together to form a ring with the atoms to which they are attached there is formed a 5-membered heterocyclic ring of 4 to 7 atoms, said ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, said ring being optionally mono or di-substituted with substituents independently selected from halo, hydroxyl, oxo, C 1-4 alkyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, —C(O)—C 1-4 alkyl and —S(O) n C 1-4 alkyl;
R 2 is selected from the group consisting of
(1) aryl,
(2) HET 3 ,
(3) —CH 2 -aryl,
(4) —CH 2 —HET 3 ,
(5) —C 1-6 alkyl, and
(6) —C 3-6 cycloalkyl,
wherein R 2 is optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) halo,
(b) —CN,
(c) —OH,
(d) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(e) —CF 3 ,
(f) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(g) —C(O)O—C 1-3 alkyl and
(h) —S-aryl, optionally substituted with halo, C 1-4 alkyl or —OC 1-4 alkyl;
R 3 is selected from the group consisting of:
(1) aryl,
(2) HET 5 , and
(3) C 3-6 cycloalkyl,
wherein R 3 is optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) hydroxy,
(b) halo,
(c) —C 3-6 cycloalkyl,
(d) —OC 3-5 cycloalkyl,
(e) C 1-4 alkyl,
(f) —OC 1-4 alkyl,
(g) —C(O)CH 3
(h) mono, di or tri-halo C 1-4 alkyl,
(i) mono, di or tri-halo-OC 1-4 alkyl, and
(j) —S(O) n —C 1-4 alkyl;
wherein aryl is as a mono- or bi-cyclic aromatic ring system; and HET 1 , HET 2 , HET 3 , HET 4 and HET 5 are each independently a 5 to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, or N-oxide thereof, said containing 1 to 4 heteroatoms selected from O, S and N, and optionally substituted with 1 to 2 oxo groups.
2 . A compound of claim 1
wherein:
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyridazinyl,
(4) pyrimidyl,
(5) pyrazinyl,
(6) thiazolyl,
(7) thienyl,
(8) pyrrolyl,
(9) oxazolyl, and
(10) oxadiazole;
wherein R 1 is optionally mono or di-substituted with substituents R 4 and R 5 , wherein R 4 and R 5 are independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) mono, di or tri-halo C 1-4 alkyl,
(d) —O—C 1-4 alkyl, optionally substituted with hydroxyl, halo or amino
(e) —C 1-4 alkyl optionally substituted with hydroxyl or CN,
(f) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy,
(h) —S(O) n C 1-4 alkyl wherein n is 0, 1 or 2,
(i) —S(O) n NR 6 R 7 ,
(j) —C(O)—NR 10 R 11 ,
(k) HET 4 ,
(l) aryl, and
wherein choices (k) and (l) are each optionally mono or di-substituted with substituents selected from
(1) halo,
(2) —CN,
(3) —OH,
(4) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(5) —CF 3 ,
(6) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(7) —C(O)OH,
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 19 R 20 ,
wherein R 6 , R 7 , R 10 , R 11 , R 19 and R 20 are each independently selected from H and C 1-4 alkyl.
3 . A compound of claim 2
wherein:
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) pyrazinyl,
(5) pyridazinyl,
(6) 1,2,4-oxadiazolyl, and
(7) 1,3,4-oxadiazolyl,
optionally mono or di-substituted with substituents R 4 and R 5 , which are independently selected from the group consisting of
(a) —C 1-4 alkyl optionally substituted with hydroxy,
(b) —S(O) n C 1-4 alkyl,
(c) —C(O)—NR 10 R 11 ,
(d) HET 4 , and
(e) halo,
wherein HET 4 is optionally mono or di-substituted with substituents selected from:
(1) halo,
(2) —CN,
(3) —OH,
(4) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(5) —CF 3 ,
(6) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(7) —C(O)OH, and
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 19 R 20 ,
wherein R 10 , R 11 , R 19 and R 20 are each independently selected from H and C 1-4 alkyl.
4 . A compound of claim 1
wherein:
R 2 is selected from the group consisting of
(1) aryl,
(2) HET 3 ,
(3) —CH 2 aryl, and
(4) —CH 2 HET 3 ,
wherein R 2 is optionally mono or di-substituted with substituents independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) —OH,
(d) -Hydroxy C 1-4 alkyl,
(e) —C 1-4 alkyl,
(f) —C 1-4 haloalkyl, and
(g) —OC 1-4 alkyl, optionally substituted with halo or hydroxyl.
5 . A compound of claim 4
wherein:
R 2 is selected from the group consisting of:
(1) aryl, and
(2) HET 3 ,
wherein R 2 is optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) halo,
(b) —CN,
(c) —OH,
(d) -hydroxy
(e) —CH 3 ,
(f) —CF 3 , and
(g) —OCH 3 .
6 . A compound of claim 5
wherein:
R 2 is selected from the group consisting of
(1) phenyl,
(2) pyridyl,
(3) pyridazinyl,
(4) pyrimidyl,
(5) pyrazinyl,
(6) thiazolyl,
(7) oxazolyl,
(8) pyrazolyl,
(9) 1,2,4-oxadiazolyl, and
(10) 1,3,4-oxadiazolyl,
wherein R 2 is optionally mono or di-substituted with halo, OC 1-4 alkyl optimally substituted with halogen, —C 1-4 haloalkyl, hydroxyl and CN.
7 . A compound of claim 1
wherein:
R 3 is selected from the group consisting of:
(1) aryl, and
(2) HET 5 ,
wherein choice (1) and (2) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
(a) halo,
(b) —C 3-6 cycloalkyl,
(c) —OC 1-4 alkyl,
(d) mono, di or tri-halo C 1-4 alkyl, and
(e) mono, di or tri-halo —OC 1-4 alkyl.
8 . A compound of claim 7
wherein
R 3 is selected from the group consisting of:
(1) phenyl,
(2) pyrimidinyl,
(3) pyridyl,
wherein R 3 is optionally mono or di-substituted with halo, haloC 1-4 alkyl, or —OC 1-4 alkyl optionally substituted with halo.
9 . A compound of claim 1 wherein X is S.
10 . A compound of claim 1 of the Formula
wherein
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyridazinyl,
(4) pyrimidyl,
(5) pyrazinyl,
(6) thiazolyl,
(7) thienyl,
(8) pyrrolyl,
(9) oxazolyl, and
(10) oxadiazole;
wherein R 1 is optionally mono or di-substituted with substituents R 4 and R 5 , which are independently selected from the group consisting of
(a) halo,
(b) —CN,
(c) mono, di or tri-halo C 1-4 alkyl,
(d) —O—C 1-4 alkyl, optionally substituted with hydroxyl, halo or amino
(e) —C 1-4 alkyl optionally substituted with hydroxyl or CN,
(f) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy,
(h) —S(O) n C 1-4 alkyl wherein n is 0, 1 or 2,
(i) —S(O) n NR 6 R 7 ,
(j) —C(O)—NR 10 R 11 ,
(k) HET 4 ,
(l) aryl, and
wherein choices (k) and (l) are each optionally mono or di-substituted with substituents selected from
(1) halo,
(2) —CN,
(3) —OH,
(4) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(5) —CF 3 ,
(6) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(7) —C(O)OH,
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 19 R 20 ,
wherein R 6 , R 7 , R 10 , R 11 , R 19 and R 20 , are each independently selected from H and C 1-4 alkyl;
R 2 is selected from the group consisting of:
(1) aryl,
(2) HET 3 ,
(3) —C 1-6 alkyl, and
(4) —C 3-6 cycloalkyl,
wherein choice R 2 is optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) halo,
(b) —CN,
(c) —OH,
(d) -hydroxy C 1-4 alkyl,
(e) —C 1-4 alkyl,
(f) —C 1-4 haloalkyl, and
(g) —OC 1-4 alkyl, optionally substituted with halo or hydroxyl; and
R 3 is selected from the group consisting of:
(1) aryl, and
(2) HET 5 ,
wherein choice (1) and (2) are each optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) halo,
(b) —C 3-6 cycloalkyl,
(c) —C 1-4 alkyl,
(d) —OC 1-4 alkyl,
(e) mono, di or tri-halo C 1-4 alkyl, and
(f) mono, di or tri-halo —OC 1-4 alkyl.
11 . A compound of claim 10 wherein
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) pyrazinyl,
(5) pyridazinyl,
(6) 1,2,4-oxadiazolyl, and
(7) 1,3,4-oxadiazolyl,
optionally mono or di-substituted with substituents R 4 and R 5 , which are independently selected from the group consisting of
(a) —C 1-4 alkyl optionally substituted with hydroxy,
(b) —S(O) n C 1-4 alkyl,
(e) —C(O)—NR 10 R 11 ,
(d) HET 4 , and
(e) halo,
wherein HET 4 is optionally mono or di-substituted with substituents selected from:
(1) halo,
(2) —CN,
(3) —OH,
(4) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(5) —CF 3 ,
(6) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(7) —C(O)OH, and
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 19 R 20 ,
wherein R 10 , R 11 , R 19 and R 20 are each independently selected from H and C 1-4 alkyl,
R 2 is selected from the group consisting of
(1) phenyl,
(2) pyridyl,
(3) pyridazinyl,
(4) pyrimidyl,
(5) pyrazinyl,
(6) thiazolyl,
(7) oxazolyl,
(8) pyrazolyl,
(9) 1,2,4-oxadiazolyl, and
(10) 1,3,4-oxadiazolyl,
wherein R 2 is optionally mono or di-substituted with halo, OC 1-4 alkyl optimally substituted with halogen, —C 1-4 haloalkyl, hydroxyl and CN; and
R 3 is selected from the group consisting of:
(1) phenyl,
(2) pyrimidyl,
(3) pyridyl,
wherein R 3 is optionally mono or di-substituted with halo, haloC 1-4 alkyl, or —OC 1-4 alkyl optionally substituted with halo.
12 . A compound of claim 10 of the Formula
wherein:
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyridazinyl,
(4) pyrimidyl,
(5) pyrazinyl,
wherein R 1 is optionally mono or di-substituted with substituents R 4 and R 5 , which are independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) mono, di or tri-halo C 1-4 alkyl,
(d) —O—C 1-4 alkyl, optionally substituted with hydroxyl, halo or amino
(e) —C(CH 3 ) 2 —OH;
R 2 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyridazinyl,
(4) pyrimidyl,
(5) pyrazinyl,
(6) pyrazolyl,
wherein R 2 is optionally mono or di-substituted with halo, OC 1-4 alkyl optimally substituted with halogen, —C 1-4 -haloalkyl, hydroxyl and CN; and
R 3 is selected from the group consisting of
(1) phenyl,
(2) pyrimidyl,
(3) pyridyl,
wherein R 3 is optionally mono or di-substituted with halo, haloC 1-4 alkyl, or OC 1-4 alkyl optionally substituted with halo.
13 . A compound of claim 12 wherein:
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrazinyl,
wherein R 1 is optionally mono or di-substituted with substituents R 4 and R 5 , which are independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) mono, di or tri-halo C 1-4 alkyl,
(d) —O—C 1-4 alkyl, optionally substituted with hydroxyl, halo or amino
(e) —C(CH 3 ) 2 —OH;
R 2 is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
wherein R 2 is optionally mono or di-substituted with halo, OC 1-4 alkyl optimally substituted with halogen, —C 1-4 haloalkyl, hydroxyl and CN; and
R 3 is selected from the group consisting of
(1) phenyl,
(2) pyrimidyl,
(3) pyridyl,
wherein R 3 is optionally mono or di-substituted with halo, haloC 1-4 alkyl, or —OC 1-4 alkyl optionally substituted with halo.
14 . A compound of the formula I:
or a pharmaceutically acceptable salt thereof wherein:
X is S or SO;
n is 0, 1 or 2;
R 1 is selected from the group consisting of:
(1) aryl, and
(2) HET 1 ,
wherein R 1 is optionally mono or di-substituted with substituents R 4 and R 5 ; and wherein R 4 and R 5 are independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) mono, di or tri-halo C 1-4 alkyl,
(d) mono, di or tri-halo OC 1-4 alkyl,
(d) —OC 1-4 alkyl, optionally substituted with hydroxyl, halo or amino,
(e) —C 1-4 alkyl optionally substituted with one or two substituents selected from hydroxyl, CN, —CHF 2 and —CF 3 ,
(f) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy, halo or CN,
(g) —S(O) n C 1-4 alkyl,
(h) —S(O) n NR 6 R 7 ,
(i) —C(O)—NH—NR 8 R 9 ,
(j) —C(O)—OH,
(k) —C(O)—OC 1-4 alkyl, optionally substituted with halo or hydroxy,
(l) —C(O)—NR 10 R 11 ,
(m) —C(O)—C 1-4 alkyl optionally mono, di or tri substituted with halo,
(o) —C(NR 12 )—NR 13 R 14 ,
(p) HET 4 ,
(q) aryl,
(r) —C(O)—NH—NH—C(O)H,
(s) —CH 2 —C(O)—O—C 1-4 alkyl, whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH
(t) —CH 2 —C(O)NR 15 R 16 , whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH, and
(u) —NR 17 R 18 ,
wherein choices (p) and (q) are each optionally mono or di-substituted with substituents selected from
(1) halo,
(2) —CN,
(3) —OH,
(4) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(5) —CF 3 ,
(6) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(7) —C(O)OH, and
(8) —C(O)O—C 1-3 alkyl;
(9) —C(O)—NR 19 R 20 ,
(10) —NH 2 ,
(11) Oxo,
(12) ═S,
with the proviso that the substituent on choice (q) is other than oxo or ═S,
wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 , are each independently selected from H and C 1-4 alkyl,
or
R 6 and R 7 or R 8 and R 9 or R 10 and R 11 or R 13 and R 14 or R 15 and R 16 or R 17 and R 18 or R 19 and R 20 are joined together to form a ring with the atoms to which they are attached there is formed a 5-membered heterocyclic ring of 4 to 7 atoms, said ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, said ring being optionally mono or di-substituted with substituents independently selected from halo, hydroxyl, oxo, C 1-4 alkyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, —C(O)—C 1-4 alkyl and —S(O) n C 1-4 alkyl;
R 2 is selected from the group consisting of:
(1) aryl,
(2) HET 3 ,
(3) —CH 2 -aryl,
(4) —CH 2 —HET 3 ,
(5) —C 1-6 alkyl, and
(6) —C 3-6 cycloalkyl,
wherein R 2 is optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) halo,
(b) —CN,
(c) —OH,
(d) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano,
(e) —CF 3 ,
(f) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(g) —C(O)O—C 1-3 alkyl and
(h) —S-aryl, optionally substituted with halo, C 1-4 alkyl or —OC 1-4 alkyl;
R 3 is selected from the group consisting of:
(1) aryl,
(2) HET 5 , and
(3) C 3-6 cycloalkyl,
wherein R 3 is optionally mono or di-substituted with substituents independently selected from the group consisting of
(a) hydroxy,
(b) halo,
(c) —C 3-6 cycloalkyl,
(d) —OC 3-5 cycloalkyl,
(e) —C 1-4 alkyl,
(f) —OC 1-4 alkyl,
(g) —C(O)CH 3
(h) mono, di or tri-halo C 1-4 alkyl,
(i) mono, di or tri-halo-OC 1-4 alkyl, and
(j) —S(O) n —C 1-4 alkyl;
wherein aryl is as a mono- or bi-cyclic aromatic ring system; and HET 1 , HET 2 , HET 3 , HET 4 and HET 5 are each independently a 5 to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, or N-oxide thereof, said containing 1 to 4 heteroatoms selected from O, S and N, and optionally substituted with 1 to 2 oxo groups.
15 . A compound according to claim 1 selected from the group consisting of:
(1) Methyl-5-[5-[(5-chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate,
(2) Methyl 5-[5-[(5-chloropyridin-2-yl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate,
(3) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,
(4) 2-{5-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,
(5) 2-(5-{2-(4-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyrazin-2-yl)propan-2-ol,
(6) 2-{5-[5-[(4-Chlorophenyl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,
(7) 2-(5-{2-(3-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyrazin-2-yl)propan-2-ol,
(8) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,
(9) 2-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-5-methylpyrazine,
(10) 2-{2-(3-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}-5-methylpyrazine,
(11) 2-[5-[(4-Chlorophenyl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]-5-methylpyrazine,
(12) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,
(13) 2-{5-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(14) 2-(5-{2-(4-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(15) 2-{5-[5-[(2,4-Difluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(16) 2-{5-[5-[(4-Chloro-2-fluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(17) 2-{5-[5-[(3,4-Difluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(18) 2-{5-[5-[(3-Fluoro-4-methoxyphenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(19) 2-(5-{2-(4-Fluorophenyl)-5-[(5-fluoropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(20) 2-{5-[5-[(5-Chloropyrimidin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(21) 2-(5-{2-(4-Fluorophenyl)-5-[(6-methoxypyridin-3-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(22) 2-(5-{2-(4-Fluorophenyl)-5-[(5-fluoropyrimidin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(23) 245-{2-(4-Fluorophenyl)-5-[(5-methoxypyrimidin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(24) 2-(5-{2-(4-Fluorophenyl)-5-[(2-methoxypyrimidin-5-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(25) 2-(5-{2-(4-Fluorophenyl)-5-[(5-methylpyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(26) 2-{5-[5-[(5-Cyclopropylpyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(27) 2-(5-{2-(4-Fluorophenyl)-5-[(2,4,5-trifluorophenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(28) 2-{5-[5-[(4-Chloro-3-fluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-01,
(29) 2-{5-[5-[(4-Chlorophenyl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(30) 2-(5-{2-(3-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(31) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(32) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3,5-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(33) 2-(5-{2-(3,4-Difluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(34) 2-{5-[5-[(4-Chlorophenyl)thio]-2-(3,4-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(35) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3,4-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(36) 2-{5-[5-[(5-Chloropyrimidin-2-yl)thio]-2-(3,4-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(37) 2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluoro-2-methylphenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,
(38) 2-(5-{2-(4-Chlorophenyl)-5-[(5-chloropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(39) 2-(5-{2-(4-Chlorophenyl)-5-[(5-fluoropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(40) 2-(5-{2-(4-Chlorophenyl)-5-[(5-chloropyrimidin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(41) 2-(5-{2-(4-chloro-3-fluorophenyl)-5-[(4-chlorophenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(42) 2-(5-{2-(4-chloro-3-fluorophenyl)-5-[(5-chloropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(43) 2-(5-{2-(3-chloro-4-fluorophenyl)-5-[(4-chlorophenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(44) 2-(5-{2-(3-chloro-4-fluorophenyl)-5-[(5-chloropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-31,
(45) 2-{6-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-3-yl}propan-2-ol,
(46) 2-{6-[5-[(4-chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-3-yl}propan-2-ol,
(47) 4-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]benzonitrile,
(48) 3-{4-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]phenyl}-1,2,4-oxadiazole,
(49) 4-{5-[(5-Chloropyridin-2-yl)thio]-4-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1,3-oxazol-2-yl}benzonitrile,
(50) 2-(5-{5-[(4-chlorophenyl)thio]-2-pyridin-2-yl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(51) 2-(5-{5-[(5-chloropyridin-2-yl)thio]-2-pyridin-2-yl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(52) 3-(4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,2,4oxadiazole,
(53) 2-(4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,3,4oxadiazole,
(54) 5-[(4-chlorophenyl)thio]-4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole, and
(55) 2-{5-[(4-chlorophenyl)thio]-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine,
or a pharmaceutically acceptable salt thereof.
16 . A compound according to claim 14 selected from the group consisting of
(1) 5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(1,2,4-oxadiazol-3-yl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(2) 5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidine-2-carbonitrile,
(3) 1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone,
(4) 2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)propan-2-ol,
(5) 5-Chloro-2-({2-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(6) Methyl-4-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}benzoate,
(7) 2-(4-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}phenyl)propan-2-ol,
(8) 4-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1-(methylsulfonyl)piperidinium trifluoroacetate,
(9) Methyl 2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2-methylpropanoate,
(10) 3-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2,3-dimethylbutan-2-ol
(11) 2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2-methylpropan-1-ol,
(12) Methyl 5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridine-2-carboxylate,
(13) 1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanone,
(14) 2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(15) 2-(6-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridazin-3-yl)propan-2-ol,
(16) Ethyl 5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}isoxazole-3-carboxylate,
(17) 2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}isoxazol-3-yl)propan-2-ol,
(18) Methyl 2-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1,3-thiazole-4-carboxylate,
(18) 2-(2-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1,3-thiazol-4-yl)propan-2-ol,
(19) 5-Chloro-2-({2-cyclopropyl-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(20) 5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(21) 5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyrimidine,
(22) (R)-5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(23) (S)-5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(24) (R)-5-Fluoro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(25) (S)-5-Fluoro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(26) Methyl 5-(5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridine-2-carboxylate,
(27) 2-(5-{5-[(4-chlorophenyl) sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridin-2-yl}propan-2-ol,
(28) Methyl 5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridine-2-carboxylate,
(29) 2-(5-{5-[(5-chloropyridin-2-yl) sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl}pyridin-2-yl}propan-2-ol,
(30) 5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfanyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,
(31) Methyl 5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridine-2-carboxylate,
(32) 2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(33) 1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanone,
(34) (R)-1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanol,
(35) (5)-1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanol,
(36) Methyl 5-{2-(5-chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridine-2-carboxylate,
(37) 2-(5-{2-(5-Chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(38) 1-(5-{2-(5-Chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridin-2-yl)ethanone,
(39) (5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)acetonitrile,
(40) 1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-3-hydroxycyclobutanecarbonitrile,
(41) 2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorobenzyl)-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,
(42) Methyl 2-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidine-5-carboxylate,
(43) 6-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-3,4-dihydroisoquinolin-1(2H)-one,
(44) 7-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-3-(difluoromethyl)quinoline,
(45) 6-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-2-(difluoromethyl)quinoline,
(46) 6-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-N,N-dimethylquinoline-2-carboxamide,
(47) 3-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-6-(methylsulfonyl)pyridazine, and
(48) (1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-2-cyclopropyl-1,3-oxazol-4-yl}phenyl)-N,N-dimethylcyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.
17 . A compound of claim 14 , of the formula
R 2
R 3
or
R 1
R 3
or
R 1
R 3
or
R 1
R 2
or
R 3
or a pharmaceutically acceptable salt thereof.
18 . A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
19 . A method according to claim 1 , wherein the disease is selected from osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer Disease, and Parkinson's Disease.
20 . Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of FAAH in a mammal.