Oxazole derivatives useful as modulators of FAAH
View Patent ↗The present invention is directed to certain Oxazole derivatives which are useful as modulators of Fatty Acid Amide Hydrolase (FAAH) and as FAAH imaging agents. 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:
R 1 is
n is 0, 1 or 2;
X 1 and X 2 are each independently selected from hydrogen, and C 1-4 alkyl optionally mono, di- or tri-substituted with fluoro, or
X 1 and X 2 taken together form an oxo group;
Y is selected from O and —N;
R 4 is a heterocycle with two to four heteroatoms selected from O, S and N:
wherein R 4 is optionally mono or di-substituted with substituents independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) mono, di or tri-halo —C 1-4 alkyl,
(d) OH,
(e) mono, di or tri-halo —OC 1-4 alkyl,
(f) —OC 1-4 alkyl, optionally substituted with hydroxyl, halo or amino,
(g) —C 1-4 alkyl optionally substituted with one or two substituents selected from hydroxyl, CN, —CHF 2 and —CF 3 ,
(h) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy, halo or CN,
(i) —S(O) n C 1-4 alkyl,
(j) —S(O) n NR 6 R 7 ,
(k) —C(O)—NH—NR 8 R 9 ,
(l) —C(O)—OH,
(m) —C(O)—OC 1-4 alkyl, optionally substituted with halo or hydroxy,
(n) —C(O)—NR 10 R 11 ,
(o) —C(O)—C 1-4 alkyl optionally mono, di or tri substituted with halo,
(p) —C(NR 12 )—NR 13 R 14 ,
(q) HET 4 ,
(r) aryl,
(s) —C(O)—NH—NH—C(O)H,
(t) —CH 2 —C(O)—O—C 1-4 alkyl, whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH
(u) —CH 2 —C(O)NR 15 R 16 , whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH,
(v) —NR 17 R 18 , and
(w) mono, di or tri-halo C1-4alkyl-NR 17 R 18 ,
wherein choices (q) and (r) 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, and
(12)=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, wherein said C 1-4 alkyl is optionally substituted with CF 3 ,
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 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 5 is selected from the group consisting of:
(1) hydrogen
(2) mono, di or tri-halo C 1-4 alkyl,
(3) aryl,
(4) HET 1 ,
(5) C 3-6 cycloalkyl,
(6) CH 2 -aryl,
(7) CH 2 -HET 1 ,
(8) CH 2 —C 3-6 cycloalkyl,
(9) —C 1-4 alkyl optionally substituted with one or two substituents selected from hydroxyl, CN, —CHF 2 and —CF 3 , and
(10) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy, halo or CN,
with the proviso that when Y is O, R 5 is not present;
R 2 is selected from phenyl or pyridyl:
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) —NR 21 R 22 , wherein R 21 and R 22 are each independently selected from hydrogen and C 1-4 alkyl,
(e) —C 1-4 alkyl optionally substituted with hydroxy, halo or cyano, or amino
(f) —CF 3 ,
(g) —OC 1-4 alkyl optionally substituted with hydroxyl or halo,
(h) —C(O)O—C 1-3 alkyl,
(i) —C(O)NR 21 R 22 , and
(j) —S-aryl, optionally substituted with halo, C 1-4 alkyl or —OC 1-4 alkyl;
R 3 is phenyl or pyridyl:
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 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
3. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
4. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
5. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
6. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.