Imidazole derivatives useful as modulators of FAAH and as FAAH imaging agents
View Patent ↗The present invention is directed to certain Inidazole 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, Alzeimer Disease, and Parkinson's Disease.
1. A compound of the formula I:
or a pharmaceutically acceptable salt thereof wherein:
n=0, 1 or 2
R 1 is phenyl
wherein the phenyl is substituted with
wherein R 5 is selected from the group consisting of:
(a) halo,
(b) —CN,
(c) halo C 1-4 alkyl,
(d) —OC 1-4 alkyl, optionally substituted with hydroxy, 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)—OH,
(j) —C(O)—OC 1-4 alkyl, optionally substituted with halo or hydroxy,
(k) —C(O)—NR 10 R 11 ,
(l) —C(O)—C 1-4 alkyl optionally mono, di or tri substituted with halo,
(m) HET 2 ,
(n) aryl,
(o) —CH 2 —C(O)—O—C 1-4 alkyl, whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH
(p) —CH 2 —C(O)NR 15 R 16 , whereas the CH 2 may be optionally substituted with C 1-4 alkyl or OH, and
(q) —NR 17 R 18 ,
wherein choices (m) and (n) 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)—NR 19 R 20 ,
(9) —NH 2 ,
(10) Oxo,
(11) ═S,
wherein R 6 ,R 7 , R 10 , R 11 , 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 C 1-4 -alkyl is optionally mono-, di-, or tri-substituted with halo, or
R 6 and R 7 or R 10 and R 11 or R 15 and R 16 or R 17 and R 18 or R 19 and R 20 are joined together so that together 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) hydrogen,
(2) aryl,
(3) HET 3 ,
(4) —CH 2 -aryl,
(5) —CH 2 —HET 3 ,
(6) —C 1-6 alkyl, and
(7) —C 3-6 cycloalkyl,
wherein choice (2), (3), (4), (5), (6) and (7) 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 ;
R 3 is selected from the group consisting of:
(1) aryl,
(2) HET 4 , and
(3) C 3-6 cycloalkyl,
wherein choice (1), (2) and (3) are each 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; and
R 4 is selected from the group consisting of:
(1) —C 1-4 -alkyl,
(2) -haloC 1-4 alkyl,
(3) H; and
HET 2 , HET 3 and HET 4 are each independently a 5- to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, containing 1-4 heteroatoms selected from 0, S and N, and optionally substituted with 1-2 oxo groups.
2. A compound of claim 1 wherein:
R 1 is phenyl,
wherein the phenyl is substituted with
and wherein R 5 , is selected from the group consisting of
(a) —CN,
(b) halo C 1-4 alkyl,
(c) —O—C 1-4 alkyl, optionally substituted with hydroxyl, halo or amino
(d) —C 1-4 alkyl optionally substituted with hydroxyl or CN,
(e) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy,
(f) —S(O) n C 1-4 alkyl wherein n is 1 or 2,
(g) —S(O) 2 NR 6 R 7 ,
(h) —C(O)—NR 10 R 11 ,
(i) HET 2 ,
(j) aryl, and
wherein choices (i) and (j) 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, wherein the C 1-4 -alkyl is optionally momo-, di-, or tri-substituted with halo.
3. A compound of claim 2
wherein:
R 1 is phenyl,
wherein the phenyl is substituted with
and R 5 is selected from the group consisting of
(a) —C 1-4 alkyl optionally substituted with hydroxy,
(b) —S(O) 2 C 1-4 alkyl,
(c) —C(O)—NR 10 R 11 ,
(d) HET 2 , and
(e) halo,
wherein choice (d) 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 14alkyl 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, wherein C 1-4 -alkyl is optionally mono-, di-, or tri-substituted with halo.
4. A compound of claim 1
wherein:
R 2 is selected from the group consisting of:
(1) hydrogen,
(2) aryl,
(3) HET 3 ,
(4) —C 1-6 alkyl, and
(5) —C 3-6 cycloalkyl,
wherein choice (2), (3), (4) and (5) 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) —O C 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) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,
wherein choice (2) and (3) are each 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) —CH 3 ,
(f) —CF 3 , and
(g) —OCH 3 .
6. A compound of claim 1
wherein
R 3 is selected from the group consisting of:
(1) phenyl, and
(2) HET 4 ,
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.
7. A compound of claim 6
wherein
R 3 is selected from the group consisting of:
(1) phenyl,
(2) pyrimidinyl,
(3) pyridinyl,
(4) pyridazinyl,
(5) pyrazinyl,
wherein choices (1), (2), (3), (4) and (5) are each optionally mono or di-substituted with halo, haloC 1-4 -alkyl, or —OC 1-4 alkyl optionally substituted with halo.
8. A compound of the Formula
or a pharmaceutically acceptable salt thereof wherein:
R 1 is phenyl,
wherein the phenyl is substituted with
and R 5 is selected from the group consisting of
(a) —CN,
(b) halo C 1-4 alkyl,
(c) —O—C 1-4 alkyl, optionally substituted with hydroxyl, halo or amino
(d) —C 1-4 allyl optionally substituted with hydroxyl or CN,
(e) —C 1-2 alkyl-C 3-6 cycloalkyl optionally substituted with hydroxy,
(g) —S(O) n C 1-4 alkyl wherein n is 1 or 2,
(h) —S(O) 2 NR 6 R 7 ,
(i) —C(O)—NR 10 R 11 ,
(j) HET 2 ,
(k) aryl, and
wherein choices (j) and (k) 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,
wherein C 1-4 alkyl is optionally tritiated or mono-, di-, or tri-substituted with halo, or
R 2 is selected from the group consisting of:
(1) hydrogen,
(2) aryl,
(3) HET 3 ,
(4) —C 1-6 alkyl, and
(5) —C 3-6 cycloalkyl,
wherein choice (2), (3), (4) and (5) 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) phenyl, and
(2) HET 4 ,
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;
R 4 is selected from the group consisting of:
(1) —C 1-4 alkyl, optionally tritiated, and
(2) H.
9. A compound of claim 8 wherein
R 1 is phenyl,
wherein the phenyl is substituted with
and R 5 is selected from the group consisting of
(a) —C 1-4 alkyl optionally substituted with hydroxy,
(b) —S(O) 2 C 1-4 alkyl,
(c) —C(O)—NR 10 R 11 , and
(d) HET 2 ,
wherein choice (d) 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, wherein C 1-4 alkyl is optionally tritiated or mono-, di-, or tri-substituted with halo, or R 2 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,
wherein choice (2) and (3) are each 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) —CH 3 ,
(f) —CF 3 , and
(g) —OCH 3 ;
R 3 is selected from the group consisting of:
(1) phenyl,
(2) pyrimidinyl,
(3) pyridinyl,
(4) pyrazinyl, and
(5) pyridazinyl,
wherein choices (1), (2), (3), (4) and (5) are each optionally mono or di-substituted with halo, haloC 1-4 alkyl, or —OC 1-4 -alkyl optionally substituted with halo.
10. A compound according to claim 1 selected from the group consisting of:
Example
Compound structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
12. A method of treating a FAAH mediated disease in a patient in need of such treatment in order to slow or reverse the progression of the disease comprising: administration to a patient in need of such treatment of a therapeutically effective amount of a compound of formula I, according to claim 1 and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherapeutic neuralgia, pain, fibromyalgia, pain, migraine, and sleep disorder.
13. A compound which is
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound according to claim 13 in combination with a pharmaceutically acceptable carrier.
15. A method of treating a FAAH mediated disease in a patient in need of such treatment in order to slow or reverse the progression of the disease comprising: administration to a patient in need of such treatment of a therapeutically effective amount of a compound of claim 13 and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherapeutic neuralgia, pain, fibromyalgia, pain, migraine, and sleep disorder.