Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use
View Patent ↗Substituted aryl and heteroaryl derivatives are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from the group consisting of: phenyl, naphthyl, dihydroindenyl, tetrahydronaphthyl, indolyl, isoindolyl and pyridyl;
one to two R 1 groups are selected from:
a 6-10 membered aryl, aryloxy or arylthio group, or a 5-10 membered heteroaryl, heteroaryloxy or heteroarylthio group containing 1-2 nitrogen and 0-1 O or S atoms, said aryl and heteroaryl group, and the aryl and heteroaryl portions of aryloxy, arylthio, heteroaryloxy and heteroarylthio being optionally substituted with 1-3 groups selected from halo, OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 , NR 6 R 7 , C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl, the alkyl portions of C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and (2) 1-2 groups selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 and NR 6 R 7 ,
said R 1 group being further optionally substituted with a member selected from the group consisting of pyrazole, imidazole, tetrazole, pyrrole, triazole, thiazole, furan, thiophene, thiadiazole and oxazole, optionally substituted with 1-2 groups selected from halo, OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 , NR 6 R 7 , C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl, the alkyl portions of C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and (2) 1-2 groups selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 and NR 6 R 7 ;
each R 2 is H, halo, OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 , NR 6 R 7 , C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl, the alkyl portions of C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and (2) 1-2 groups selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 and NR 6 R 7 ;
X is selected from the group consisting of: —O—, —S—, —(C(R 3 ) 2 ) 1-2 —, —OC(R 3 ) 2 —, —C(R 3 ) 2 O—;
R 3 is H, C 1-10 alkyl, C 2-4 alkenyl, Aryl or heteroaryl, said Aryl and heteroaryl being optionally substituted with 1-2 of halo, OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 , NR 6 R 7 , C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl, the alkyl portions of C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and (2) 1-2 groups selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 and NR 6 R 7 , with no more than one R 3 group being other than H and C 1-10 alkyl,
R 4 is H or C 1-6 alkyl, and
R 5 represents a member selected from the group consisting of: Aryl or Ar—C 1-10 alkyl;
R 6 and R 7 each independently represent H or C 1-3 alkyl;
p is 0, 1 or 2;
R a represents CH 2 CH 2 CO 2 R 4 , CH 2 CH(OH)CO 2 R 4 or 5-tetrazolyl; and
R b is H, halo, OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 , NR 6 R 7 , C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl, the alkyl portions of C 1-6 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and (2) 1-2 groups selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 and NR 6 R 7 .
2. A compound in accordance with claim 1 wherein ring A is selected from the group consisting of phenyl, naphthyl, pyridyl and tetrahydronaphthyl.
3. A compound in accordance with claim 2 wherein ring A is selected from the group consisting of phenyl, naphthyl and pyridyl.
4. A compound in accordance with claim 1 wherein 1-2 R 1 groups are selected from the group consisting of: phenyl, naphthyl, indolyl, imidazolyl, pyrazolyl, pyrimidinyl and O-phenyl, optionally substituted with 1-3 groups selected from: halo, CN, OC 1-6 alkyl, OhaloC 1-6 alkyl, CO 2 C 1-6 alkyl, CO 2 H, C(O)C 1-6 alkyl, SO 2 C 1-6 alkyl, NO 2 , C(O)NR 6 R 7 and pyrazolyl.
5. A compound in accordance with claim 1 wherein each R 2 is selected from the group consisting of: H, halo, C 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 alkyl and OhaloC 1-6 alkyl.
6. A compound in accordance with claim 5 wherein each R 2 is selected from the group consisting of: H, Cl, F, OMe, OEt, O-n-propyl, O-i-propyl, O-n-butyl, O-t-butyl, CF 3 and OCF 3 .
7. A compound in accordance with claim 1 wherein X represents —(C(R 3 ) 2 ) 1-2 —, —O(C(R 3 ) 2 —, or —C(R 3 ) 2 O—, wherein R 3 is independently selected from H, C 1-10 alkyl, Aryl and heteroaryl, said Aryl and heteroaryl being optionally substituted with 1-2 halo, CN, C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl and OhaloC 1-6 alkyl groups.
8. A compound in accordance with claim 1 wherein R a represents —CH 2 CH 2 CO 2 R 4 .
9. A compound in accordance with claim 8 wherein R a represents —CH 2 CH 2 CO 2 R 4 and R 4 represents H.
10. A compound in accordance with claim 1 wherein R b represents H.
11. A compound in accordance with claim 1 wherein:
ring A is selected from the group consisting of: phenyl, naphthyl, dihydroindenyl, tetrahydronaphthyl, indolyl, isoindolyl and pyridyl;
1-2 R 1 groups are selected from the group consisting of: phenyl, naphthyl, indolyl, imidazolyl, pyrazolyl, pyrimidinyl and O-phenyl, optionally substituted with 1-3 groups selected from: halo, CN, OC 1-6 alkyl, OhaloC 1-6 alkyl, CO 2 C 1-6 alkyl, CO 2 H, C(O)C 1-6 alkyl, SO 2 C 1-6 alkyl, NO 2 , C(O)NR 6 R 7 and pyrazolyl;
each R 2 is selected from the group consisting of: H, halo, C 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 alkyl and OhaloC 1-6 alkyl;
X represents —(C(R 3 ) 2 ) 1-2 —, —O(C(R 3 ) 2 —, or —C(R 3 ) 2 O—, wherein R 3 is independently selected from H, C 1-10 alkyl, Aryl and heteroaryl, said Aryl and heteroaryl being optionally substituted with 1-2 halo, CN, C 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 alkyl and OhaloC 1-6 alkyl groups;
R a represents —CH 2 CH 2 CO 2 R 4 and R 4 represents H, and
R b represents H.
12. A compound in accordance with claim 1 selected from one of the following compounds:
COMPOUND
R 1
R 21
47
3,5-ClPh
3,5-ClPh
48
3-FPh
3-FPh
49
4-FPh
4-FPh
50
4-n-BuOPh
4-n-BuOPh
51
Ph
4-CF 3 OPh
52
4-tBuPh
4-CF 3 OPh
53
4-iPrOPh
4-CF 3 OPh
54
4-nBuOPh
4-CF 3 OPh
55
2-EtOPh
4-CF 3 OPh
56
2-iPrOPh
4-CF 3 OPh
57
4-FPh
4-CF 3 OPh
58
2-FPh
4-CF 3 OPh
59
3-ClPh
4-CF 3 OPh
60
2-ClPh
4-CF 3 OPh
61
4-CNPh
4-CF 3 OPh
62
2-CNPh
4-CF 3 OPh
63
2-CF 3 OPh
4-CF 3 OPh
64
2-CF 3 Ph
4-CF 3 OPh
65
4-(C 2 H 5 O 2 C)Ph
4-CF 3 OPh
66
4-AcetylPh
4-CF 3 OPh
67
4-MeSO 2 Ph
4-CF 3 OPh
68
2-MeOPh
4-CF 3 OPh
69
4-MeOPh
4-CF 3 OPh
70
4-HOPh
4-CF 3 OPh
71
4-CF 3 Ph
4-CF 3 OPh
72
3-NO 2 Ph
4-CF 3 OPh
73
4-NO 2 Ph
4-CF 3 OPh
74
4-CO 2 HPh
4-CF 3 OPh
75
4-(N,N-dimethyl)Ph
4-CF 3 OPh
76
4-(NMe 2 CH 2 )Ph
4-CF 3 OPh
77
4-(NH 2 CO)Ph
4-CF 3 OPh
78
4-(NHMeCO)Ph
4-CF 3 OPh
79
4-(NMe 2 CO)Ph
4-CF 3 OPh
80
2,4-ClPh
4-CF 3 OPh
81
2-EtO, 4-ClPh
4-CF 3 OPh
82
3-Cl, 4-nPrOPh
4-CF 3 OPh
83
3-Cl, 4-EtOPh
4-CF 3 OPh
84
3-F, 4-EtOPh
4-CF 3 OPh
85
3-Cl, 4-MeOPh
4-CF 3 OPh
86
3-F, 4-MeOPh
4-CF 3 OPh
87
3,4-ClPh
4-CF 3 OPh
88
3-Cl, 4-FPh
4-CF 3 OPh
89
3,5-ClPh
4-CF 3 OPh
90
2,3,5-FPh
4-CF 3 OPh
91
3-CN, 4-F Ph
4-CF 3 OPh
92
3-F, 4-CN Ph
4-CF 3 OPh
93
2-F, 5-CF 3 Ph
4-CF 3 OPh
94
2-F, 5-CN Ph
4-CF 3 OPh
95
2-MeO, 5-NO 2 Ph
4-CF 3 OPh
96
2-MeO, 5-CN Ph
4-CF 3 OPh
97
4-Pyridyl
4-CF 3 OPh
98
3-Pyridyl
4-CF 3 OPh
99
6-EtO, 2-Naphthyl
4-CF 3 OPh
100
5-CN, 2-Indole
4-CF 3 OPh
101
4-(1-pyrazole)phenyl
4-CF 3 OPh
102
2-F, 4-pyridyl
4-CF 3 OPh
103
2-Cl, 4-pyridyl
4-CF 3 OPh
104
1-imidazole
4-CF 3 OPh
105
5-pyrazole
4-CF 3 OPh
106
3-(1-pyrazole) Ph
4-CF 3 OPh
107
2,6-Pyrimidine
4-CF 3 OPh
108
3,5-Pyrimidine
4-CF 3 OPh
109
2-MeO, 5-Pyridyl
4-CF 3 OPh
110
3-Indole
4-CF 3 OPh
111
5-CF 3 O, 3-Indole
4-CF 3 OPh
112
5-CF 3 , 3-Indole
4-CF 3 OPh
113
4,6-Cl, 3-Indole
4-CF 3 OPh
116
cyclopropyl
4-CF 3 OPh
118
4-CF 3 OPh
4-F Ph
119
4-CF 3 OPh
4-tBu Ph
119
4-CF 3 OPh
3-Cl, 4-F Ph
120
4-CF 3 OPh
3-Cl, 4-nPrO Ph
121
4-CF 3 OPh
3-Cl, 4-EtO Ph
122
4-CF 3 OPh
3-Cl, 4-MeO Ph
123
4-CF 3 OPh
3,5-Cl Ph
124
4-CF 3 OPh
2,4-Cl Ph
125
4-CF 3 OPh
2-EtO, 4-Cl Ph
126
4-CF 3 OPh
3-F, 4-EtO Ph
127
4-CF 3 OPh
2-CF 3 Ph
128
4-CF 3 OPh
2,3,5-F Ph
129
4-CF 3 OPh
2-EtO Ph
130
4-CF 3 OPh
2-Cl Ph
131
4-CF 3 OPh
3-Cl Ph
132
4-CF 3 OPh
3-F, 4-MeO Ph
133
4-CF 3 OPh
3,4-Cl Ph
136
OPh
4-CF 3 OPh
137
OPh
3,4-Cl Ph
138
O-(4-MeO Ph)
3,4-Cl Ph
139
O-(3-CN Ph)
3,4-Cl Ph
140
O-(3-F, 4-MeO Ph)
3,4-Cl Ph
141
O-(3-MeO Ph)
3,4-Cl Ph
142
O-(4 CF 3 O Ph)
3,4-Cl Ph
143
O-(4-F Ph)
3,4-Cl Ph
144
O-(4-CN Ph)
3,4-Cl Ph
145
O-(4-F Ph)
4-CF 3 OPh
COMPOUND
R
Isomer
148
4-CF 3 OPh
Enantiomer A
(Faster Eluting)
149
4-CF 3 OPh
Enantiomer B
(Slower Eluting)
150
4-F Ph
Racemic
152
4-CF 3 OPh
4-CF 3 OPh
153
4-nBuO Ph
4-CF 3 OPh
COMPOUND
R 1
R 21
R 3
161
3-CN Ph
4-CF 3 OPh
Me
Enantiomer A
162
3-CN Ph
4-CF 3 OPh
Me
Enantiomer B
163
2-CF 3 Ph
4-CF 3 OPh
Me
Racemic
164
2-CF 3 Ph
4-CF 3 Ph
Me
Racemic
165
2-CF 3 Ph
3,4-Cl Ph
Me
Racemic
166
2-CF 3 Ph
2-Naphthyl
Me
Racemic
167
2-CF 3 Ph
6 MeO, 2-
Me
Naphthyl
Racemic
168
2-CF 3 Ph
3-Quinoline
Me
Racemic
169
3-Cl Ph
3,4-Cl Ph
Me
Racemic
COMPOUND
R 1
R 21
Isomer
178
4-CN Ph
4-CN Ph
Racemic
179
O-(4-F Ph)
4-CF 3 OPh
Racemic
COMPOUND
R 1
R 21
R 3
184
4-nBuO Ph
4-nBuO Ph
H
185
4-CF 3 OPh
4-CF 3 O Ph
Et
Enantiomer A
186
4-CF 3 OPh
4-CF 3 OPh
Et
Enantiomer B
187
3-CNPh
4-CF 3 OPh
Me
Enantiomer A
188
3-CNPh
4-CF 3 OPh
Me
Enantiomer B
189
3-CNPh
4-CF 3 OPh
H
190
Ph
4-CF 3 OPh
H
191
6-MeO, 2-
4-CF 3 OPh
H
Naphthyl
192
O(4-F Ph)
4-CF 3 OPh
Me
Racemic
COMPOUND
R 1
R 21
X
199
4-Cl Ph
4-CF 3 OPh
O
200
3,4-F Ph
4-CF 3 OPh
O
201
3-CN Ph
4-CF 3 OPh
O
202
2-CF 3 Ph
4-CF 3 OPh
O
203
3,5-Cl Ph
4-CF 3 OPh
O
204
6-MeO, 2-
3,5-Cl Ph
O
Naphthyl
205
4-CF 3 OPh
4-CF 3 OPh
S
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
14. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat said type 2 diabetes mellitus.
15. A method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim 1 in an amount effective to treat atherosclerosis.