Antimicrobial compounds and methods
The invention is directed to compounds that are active as antibacterial agents. The invention compounds are active against gram-positive and gram-negative bacteria and can be used to treat infections caused by gram-positive and gram-negative bacteria. Also disclosed are processes and intermediates for making the compounds.
1 . A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Z is (C═O);
ring A is selected from the group consisting of
J is absent or is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —,
wherein each R 3 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, and C 1 -C 6 haloalkyl, wherein m is 0, 1 or 2;
Y is a linear C 1 -C 8 alkylene optionally substituted with OH, NH 2 , CN, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COO(C 1 -C 6 alkyl), COOH, CONH 2 , or C 1 -C 6 alkoxy, and wherein up to two methylene units of the C 1 -C 8 alkylene are optionally and independently replaced by O, NH, N—(C 1 -C 6 alkyl), N—(C 1 -C 6 hydroxyalkyl), N—(C 1 -C 6 haloalkyl), N—(C 1-6 alkylene-C 3-8 cycloalkyl), NH(C═O), N—(C 1-6 alkyl)(C═O), or (C═O);
ring B is a 5 to 12 membered fused, spiro, or bridged bicyclic heterocycloalkylene containing up to 3 nitrogen atoms, wherein the fused, spiro, or bridged bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, OH, and C 1 -C 6 hydroxyalkyl; or
ring B is a 5 to 12 membered fused, spiro, or bridged bicyclic cycloalkylene optionally substituted with up to two substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, OH, and C 1 -C 6 hydroxyalkyl;
L is absent, or is a linear or branched C 1 -C 6 alkylene optionally substituted with C 1 -C 6 alkoxy, halo, CN, OH, NH 2 , COO(C 1 -C 6 alkyl), or CONH 2 , wherein one methylene unit of the C 1 -C 6 alkylene may be replaced with O, NH, (C═O), or N—(C 1-6 alkyl);
R 1 is H, NH 2 , NH(C 1 -C 6 alkyl), NHCO(C 1 -C 6 alkyl), or NH(C 1 -C 6 alkyl-SO 3 − );
R 1 ′ is H, NH 2 , NH(C 1 -C 6 alkyl), NHCO(C 1 -C 6 alkyl), or NH(C 1 -C 6 alkyl-SO 3 − ); and
R 2 is independently selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, O(C 1 -C 6 haloalkyl), and C 1 -C 6 alkoxy, and n is 0, 1, or 2.
2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of
and/or
Y is selected from the group consisting of CH 2 , CH(CH 3 ), CH(COOEt) CH(COOH),
and/or
ring B is selected from the group consisting of
3 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
is selected from the group consisting of
and/or
is selected from the group consisting of
4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof which is a compound of formula IIA or IIB:
wherein:
L is absent, or is a linear or branched C 1 -C 6 alkylene, wherein one methylene unit of the C 1 -C 6 alkylene may be independently replaced with O, NH, (C═O), or N—(C 1-6 alkyl);
is selected from the group consisting of
R i and R ii are each independently H, OH, NH 2 , CN, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COO(C 1 -C 6 alkyl), COOH, CONH 2 , or C 1 -C 6 alkoxy;
R 1 and R 4 are each independently H, NH 2 or NH(C 1 -C 6 alkyl); and
NR x R y is NH 2 or NH(C 1 -C 6 alkyl).
5 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of
and/or CR i R ii is selected from the group consisting of CH 2 , CH(C 1 -C 6 alkyl), C(C 1 -C 6 alkyl) 2 , CH—COO(C 1 -C 6 alkyl) and CHCOOH; and/or
ring B is selected from the group consisting of
6 . The compound of claim 1 or a pharmaceutically acceptable salt thereof which is a compound of formula IIIA or IIIB:
wherein:
L is absent, or is a linear or branched C 1 -C 6 alkylene, wherein one methylene unit of the C 1 -C 6 alkylene may be independently replaced with O, NH, (C═O), or N—(C 1-6 alkyl);
Y 2 is ethylene optionally substituted with OH, NH 2 , halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and wherein one methylene unit of the ethylene may be replaced by O, NH, N—(C 1 -C 6 alkyl), N—(C 1 -C 6 hydroxyalkyl), N—(C 1 -C 6 haloalkyl), N—(C 1-6 alkylene-cycloalkyl), NH(C═O), N—(C 1-6 alkyl) (C═O), or (C═O);
is selected from the group consisting of
R 1 and R 4 ′ are each independently H, NH 2 or NH(C 1 -C 6 alkyl); and
NR x R y is NH 2 or NH(C 1 -C 6 alkyl).
7 . The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of
and/or
Y 2 is selected from the group consisting of
and/or
ring B is selected from the group consisting of
8 . The compound of claim 1 , selected from the compounds listed in Table 7, Table 8, Table 9, Table 10, or Table 11 or pharmaceutically acceptable salts thereof:
TABLE 7
No.
Salt Structure
Free Base 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
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
TABLE 8
No.
Salt Structure
Free Base Structure
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
TABLE 9
No.
Salt Structure
Free Base Structure
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
TABLE 10
No.
Structure
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
TABLE 11
Structure
9 . The compound of claim 1 , wherein:
ring A is selected from the group consisting of
J is
Y is CH 2 ;
ring B is selected from the group consisting of
10 . The compound of claim 9 which is:
or a pharmaceutically acceptable salt thereof.
11 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
12 . A method of treating a bacterial infection in a patient in need of such treatment, comprising administering to the patient a compound as recited in claim 1 .
13 . The method of claim 12 , wherein the bacterial infection is caused by a bacterium including gram positive and gram negative bacteria, selected from Francisella tularensis, Burkholderia mallei, Burkholderia pseudomallei, Bacillus anthracis, Yersinia pestis, Salmonella, Clostridium difficile, Citrobacter, Enterobacter, Burkholderia genus, cepacia, Mycobacterium, Proteus, Streptococcus, Serratia, Enterobacteriaceae, Escherichia, Klebsiella, Pseudomonas , and Acinitobacter.