PYRAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH
The present invention is directed to certain imidazole 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;
Y is selected from the group consisting of:
(1) halo,
(2) —C 1-4 alkyl,
(3) -haloC 1-4 alkyl,
(4) —CN,
(5) hydroxyl, and
(6) H;
n is 0, 1 or 2;
R 1 is selected from the group consisting of
(1) aryl, and
(2) HET 1 ,
wherein choice (1) and (2), 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) —OC 1-4 alkyl, optionally substituted with hydroxy, halo or amino,
(e) —C 1-4 alkyl optionally substituted with hydroxy or CN,
(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)—NE-NR 8 R 9 ,
(j) —C(O)—N(OH)—NH 2 ,
(k) —C(O)—OH,
(l) —C(O)—OC 1-4 alkyl, optionally substituted with halo or hydroxy,
(m) —C(O)—NR 10 R 11 ,
(n) —C(O)—C 1-4 alkyl,
(o) —C(NR 12 )_NR 13 R 14 ,
(p) HET 4 , and
(q) aryl,
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,
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 15 R 16 ,
wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , 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 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)nC 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 choice (1), (2), (3), (4), (5) and (6) 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, and
(g) —C(O)O—C 1-3 alkyl;
R 3 is selected from the group consisting of:
(1) aryl,
(2) HET 5 , 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.
2 . A compound of claim 1
wherein:
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridinyl,
(3) pyridazinyl,
(4) pyrimidinyl,
(5) pyrazinyl,
(6) thiazolyl,
(7) thiophenyl,
(8) pyrrolyl,
(9) oxazolyl, and
(10) a bicyclic ring selected from the group consisting of:
Wherein choice of (1), (2), (3), (4), (5), (6), (7), (8) and (9) are each 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) Ti C 1-4 alkyl wherein n is 0, 1 or 2,
(i) —S(O) n NR 6 R 7 ,
(j) —C(O)—N(OH)—NH 2 ,
(k) —C(O)—NR 10 R 11 ,
(l) HET 4 , and
(m) aryl,
wherein choices (1) and (m) 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, and
(9) —C(O)—NR 15 R 16 ,
wherein R 6 , R 7 , R 10 , R 11 , R 15 , and R 16 , are each independently selected from H and C 1-4 alkyl, or
R 6 and R 7 or R 10 and R 11 or R 15 and R 16 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, C 1-4 alkyl, —C(O)—C 1-4 alkyl and —S(O)nC 1-4 alkyl.
3 . A compound of claim 2
wherein:
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridinyl,
(3) pyrimidinyl,
(4) pyrazinyl, and
(5) pyridazinyl,
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 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,
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 15 R 16 ,
wherein R 10 , R 11 , R 15 and R 16 are each independently selected from H and C 1-4 alkyl, or
R 10 and R 11 or R 15 and R 16 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, C 1-4 alkyl, —C(O)—C 1-4 alkyl and —S(O)nC 1 — 4alkyl.
4 . A compound of claim 1
wherein:
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 (1), (2), (3), and (4) 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, —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 choice (1) and (2) 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 5
wherein:
R 2 is selected from the group consisting of:
(1) phenyl,
(2) pyridinyl,
(3) pyridazinyl,
(4) pyrimidinyl,
(5) pyrizinyl,
(5) thiazolyl,
(6) oxazolyl, and
(7) pyrazolyl
wherein choice (1), (2), (3), (4), (5), (6) and (7) are each optionally mono or di-substituted with halo, OC 1-4 alkyl optically 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) —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.
8 . A compound of claim 7
wherein
R 3 is selected from the group consisting of:
(1) phenyl,
(2) pyrimidinyl, and
(3) pyridinyl,
wherein choices (1), (2) and (3) are each optionally mono or di-substituted with halo, haloC 1-4 alkyl, or —OC 1-4 alkyl optionally substituted with halo.
9 . A compound according to claim 1 wherein X is S and Y is H.
10 . A compound of formula II
Wherein
R 1 is selected from the group consisting of:
(1) phenyl,
(2) pyridinyl,
(3) pyrimidinyl,
(4) pyrazinyl, and
(5) pyridazinyl,
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 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,
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 15 R 16 ,
wherein R 10 , R 11 , R 15 and R 16 are each independently selected from H and C 1-4 alkyl, or R 10 and R 11 or R 15 and R 16 are joined together so that together with the atoms to which they are attached there is fowled 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, C 1-4 alkyl, —C(O)—C 1-4 alkyl and —S(O)nC 1-4 -alkyl;
R 2 is selected from the group consisting of:
(1) aryl, and
(2) HET 3 ,
wherein choice (1) and (2) are each 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 hydroxyl, halo, CN
(e) —CH 3 ,
(f) —CF 3 , and
(g) —O C 1-4 alkyl, optionally substituted with halo; and
R 3 is selected from the group consisting of
(1) aryl,
(2) HET 5 , and
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, optionally substituted with hydroxyl, halo or CN, and
(d) —OC 1-4 alkyl, optionally substituted with halo.
11 . A compound according to claim 10 wherein
R 2 is selected from the group consisting of:
(1) phenyl,
(2) pyridinyl,
(3) pyridazinyl,
(4) pyrimidinyl,
(5) pyrizinyl,
(6) thiazolyl,
(7) pyrazolyl and
(8) oxazolyl,
wherein choice (1), (2), (3), (4), (5), (6), (7) and (8) are each optionally mono or di-substituted with halo, haloC 1-4 alkyl, hydroxyl, CN and di or tri-halo —OC 1-4 alkyl.
R 3 is selected from the group consisting of:
(1) phenyl,
(2) pyrimidinyl,
(3) pyridinyl,
wherein choices (1), (2) and (3) are each optionally mono or di-substituted with halo, haloC 1-4 alkyl, or —OC 1-4 alkyl optionally substituted with halo.
12 . A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
13 . A compound of the structure formula
wherein
Example
R
2.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Example
R
22
23
or structural formula
Example
R
26
27
28
29
or structural formula
Example
R
31
32
33
34
or structural formula
or structural formula
Example
R 1
R 2
37
38
39
or structural formula
Example
R
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
or structural formula
Example
R 1
R 2
58
59
60
61
62
63
64
65
or structural formula
Example
R
66
67
or structural formula
Example
R
69
70
71
72
73
74
75
76
77*
78
79
80
or structural formula
Example
R 1
R 2
81
82
83
84
or structural formula
or structural formula
Example
R 1
R 2
90
91
92
or structural formula
Example
R 1
R 2
97
98
99
100
101
or structural formula
Example
R 1
R 2
104
105
106
107
108
or structural formula
Example
R 1
R 2
111
112
113
114
115
116
117
118
119
120
or structural formula
Example
R
Example
R
125
H
126
CH 3
or structural formula
or structural formula
Example
R
Example
R
132
133
134
or structural formula
Example
R
136
or structural formula
Example
R
Example
R
138
139
140
141
142
143
144
145
146
147
148
149
or structural formula
Example
R
Example
R
150
151
152
or structural formula
or structural formula
TABLE 24
Example
R
Example
R
157
158
or structural formula
Example
R 1
R 2
160
161
162
163
164
165
166
167
168
169
170
or structural formula
Example
R 1
R 2
Enantiomer
174
E1
175
E2
176
E1
177
E2
or structural formula
Example
R 1
R 2
179
180
or structural formula
Example
R 1
R 2
182
or structural formula
Example
R 1
R 2
R 3
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
or structural formula
or structural formula
230
231
232
233
14 . A compound according to claim 1 selected from
4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole,
4-[(4-Chlorophenyl)thio]-1-ethyl-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole,
4-[(4-Chlorophenyl)thio]-3-(2,3-dihydro-1,4-benzodioxin-6-yl-1-phenyl)-1H-pyrazole,
4-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole,
4-[(4-chlorophenyl)thio]-1-(4-fluoro-2-pyridyl)-3-[4-(methylsulfinyl)phenyl]-1H-pyrazole,
4-[(4-Chloro-2-pyridyl)thio]-1-phenyl-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole,
4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-5-iodo-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole,
4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-3[4 -cyanophenyl]-1H-pyrazole,
2-{4-[(4-Chlorophenyl)thio]-3-[4-(1,2,4-oxadiazol-3-yl)phenyl]-1H-pyrazol-1-yl}-5-methoxypyridine,
2-{4-[(4-Chlorophenyl)thio]-3-[4-(1,2,4-oxadiazol-3-yl)phenyl]-1H-pyrazol-1-yl}-5-hydroxypyridine,
3-{4-[(4-Chlorophenyl)sulfonyl]-3 [4-(1,2,4-oxadiazol-3-yl)phenyl]-1H-pyrazol-1-yl}pyridine,
4-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-1H-1,2,3-triazole,
Methyl 4-{4-[(4-chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}benzoate,
5-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-2-methyl-2H-tetrazole,
5-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-1-methyl-1H-tetrazole,
2-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-1,3,4-oxadiazole,
3-(4-(4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl)phenyl)-4H-1,2,4-triazole,
5-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-1,3,4-oxadiazol-2(3H)-one,
4-{4-[(4-Chlorophenyl)thio]-1-pyridin-3-yl-1H-pyrazol-3-yl}benzamide,
3-{4-[(4-Chlorophenyl)thio]-3-[4-(4H-1,2,4-triazol-3-yl)phenyl]-1H-pyrazol-1-yl}pyridine,
4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-N-ethylbenzamide,
N-(2-Chloroethyl)-4-{4-[(4-chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}benzamide,
2-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-4,5-dihydro-1,3-oxazole,
2-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)-1,3-oxazole,
1-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)propan-1-ol,
1-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)propan-1-one,
4-[(4-Chlorophenyl)thio]-3-[4-(1-chloropropyl)phenyl]-1-phenyl-1H-pyrazole,
2-(4-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}phenyl)propan-2-ol,
3-{4-[(4-Chlorophenyl)thio]-3-[4-(1H-pyrazol-1-yl)phenyl]-1H-pyrazol-1-yl}pyridine,
2-{4-[(4-Chlorophenyl)thio]-3-[4-(1H-imidazol-1-yl)phenyl]-1H-pyrazol-1-yl}pyridine,
3-{4-[(4-Methoxyphenyl)thio]-3-[4-(1,2,4-oxadiazol-3-yl)phenyl]-1H-pyrazol-1-yl}pyridine
Methyl 3-{-4-[4-[(4-chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]phenyl}-1,2,4-oxadiazole-5-carboxylate,
3-{4-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]phenyl}-N-ethyl-1,2,4-oxadiazole-5-carboxamide,
2-(3-{4-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]phenyl}-1,2,4-oxadiazol-5-yl)pyridine,
Methyl-5-[4-[(4-chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-pyrazinecarboxylate,
2-{5-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-pyrazinyl}-2-propanol,
2-{5-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-pyrazinyl}-ethanone,
2-{5-[4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl]-2-pyrazinyl}-ethanone,
2-{5-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-pyrazinyl}-ethanol,
2-{5-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-5-methyl-2-pyrazine,
2-[(4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-5-(1,3,4-oxadiazol-2-yl)pyrazine,
2-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-5-(1H-1,2,4-triazol-1-yl)pyrazine,
5-[4-[(4-Chlorophenyl)thio]-1-(3-fluorophenyl)-1H-pyrazol-3-yl]-2-(1H-1,2,4-triazol-1-34)pyridine,
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-2-pyrazinecarbohydrazide,
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-methyl-2-pyrazinecarboxamide,
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-N-cyclopropyl-2-pyrazinecarboxamide,
2-{6-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-pyridinyl}-2-propanol,
6-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}nicotinonitrile,
2-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-5-(1,2,4-oxadiazol-3-yl)pyridine,
Methyl 6-{4-[(4-chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}nicotinate,
2-{5-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-pyridinyl}-2-propanol
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-2-pyridinecarbonitrile,
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-2-pyridinecarboxamide,
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-2-(1,2,4-oxadiazol-3-yl)pyridine,
6-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]nicotinonitrile,
N-(5-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-2-pyridinyl)acetamide,
1-(6-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-3-pyridinyl)ethanone,
2-[4-[(4-Chlorophenyl)thio]-1-(2-pyridinyl)-1H-pyrazol-3-yl]-5-(1,2,4-oxadiazol-3-yl)pyridine,
2-(3-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-1,2,4-oxadiazol-5-yl)-2-propanol,
Ethyl-5-{4-[(4-chlorophenyl)thio]-1H-pyrazol-3-yl}isoxazole-3-carboxylate,
Ethyl-5-{4-[(4-chlorophenyl)thio]-1-phenyl-1H-pyrazol-5-yl}isoxazole-3-carboxylate,
5-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-2-(methylthio)pyrimidine,
5-[4-[(4-Chlorophenyl)thio]-1-(3-fluorophenyl)-1H-pyrazol-3-yl]pyrimidine-2-carbonitrile,
1-{5-[4-[(4-Chlorophenyl)thio]-1-(3-fluorophenyl)-1H-pyrazol-3-yl]pyrimidin-2-yl}ethanone,
Methyl 2-{4-[(4-chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}-1,3-thiazole-4-carboxylate,
5-{4-[(4-Chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}pyrimidin-2-amine,
5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]pyrimidine-2-carbonitrile,
1-{6-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridazin-3-yl}ethanone,
2-{-4′-[(4-Chlorophenyl)thio]-1′-phenyl-1H,1′H-3,3′-bipyrazol-1-yl}ethanol,
Methyl 2-{4-[(4-chlorophenyl)thio]-1-phenyl-1H-pyrazol-3-yl}pyrimidine-5-carboxylate,
Methyl 5-[4-[(4-chlorophenyl)thio]-1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl]pyrazine-2-carboxylate,
2-{5-[4-[(4-Chlorophenyl)thio]-1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl]pyrazin-2-yl}propan-2-ol,
6-[4-[(4-Chlorophenyl)thio]-1-(2-pyridinyl)-1H-pyrazol-3-yl]nicotinonitrile, and
5-[4-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-methoxypyridine.
15 . A compound of the formula I:
or a pharmaceutically acceptable salt thereof wherein:
n is 0, 1 or 2;
R 1 is selected from the group consisting of:
(1) aryl, and
(2) HET 1 ,
(3) C 1-4 alkyl, optionally mono or di-substituted with Fluoro,
(4) C 3-6 cycloalkyl,
wherein choice (1) and (2), 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) —OC 1-4 alkyl, optionally substituted with hydroxy, halo or amino,
(e) —C 1-4 -alkyl optionally substituted with hydroxyl, CN, OCH 3 , —NHC(O)CH 3 , HET 6 ,
(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)—N(OH)—NH 2 ,
(k) —C(O)—OH,
(l) —C(O)—OC 1-4 alkyl, optionally substituted with halo or hydroxy,
(m) —C(O)—NR 10 R 11 ,
(n) —C(O)—C 1-4 alkyl,
(o) —C(NR 12 )—NR 13 R 14 ,
(p) HET 4 , and
(q) aryl,
(r) —C 3-6 cycloalkyl optionally substituted with CN, C 1-3 alkyl, optionally substituted with hydroxyl, —S(O) 2 CH 3 , pyridine, oxadiazole, COOH, —C(O)OC 1-4 alkyl, —C(O)NR 16 R 17 , wherein R 16 is H or methyl and R 17 is selected from H, C 1-2 alkyl, optionally substituted with hydroxyl, halo, CF 3 , OCH 3 , or R 16 and R 17 are joined together to form a pyrroline or piperazine ring,
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,
(8) —C(O)O—C 1-3 alkyl, and
(9) —C(O)—NR 15 R 16 ,
wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , 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,
(5) —CH 2 C 3-6 cycloalkyl,
(6) H,
wherein choice (1), (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) —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, and
(g) —C(O)O—C 1-3 alkyl;
R 3 is selected from the group consisting of:
(1) aryl,
(2) HET 5 , 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.
16 . A method of treating a FAAH mediated disease comprising administering a therapeutically effective amount of a compound of claim 1 .
17 . A method according to claim 17 , 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.
18 . 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.