Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof
Amino, amido, and heterocyclic compounds are disclosed. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diabetes complications, inflammation, and neurodegeneration, obesity, cancer, ischemia/reperfusion injury, cardiovascular disease and other diseases related to RAGE activity.
1. A method for treating or ameliorating in a mammal a disease or condition that is causally related to RAGE activity in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula A-Ia or A-Ib:
wherein
L 1 is —NH—, —CH 2 —NH—, —CH 2 —CH 2 —NH—, —CO—NH— or —CO—NH-L 2 -CO—NH—; and Cy is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or
L 1 is a bond and Cy is
R 1 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or halo;
each R 2 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, substituted sulfinyl, substituted sulfanyl, unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol; or two adjacent R 1 and R 2 groups may join together to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
R 3 is H, or substituted or unsubstituted C 1 -C 6 alkyl;
the subscript n is 0, 1, 2, or 3;
L 2 is C 1 -C 3 alkylene;
X is CH or N; Y is O or NR 5 ;
R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is H or substituted or unsubstituted alkyl; and * represents an attachment point; or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof;
and wherein the disease or condition is diabetes.
2. The method according to claim 1 , wherein the compound is according to formula A-II, A-III, A-IV, A-V, A-VI, A-VII:
wherein Cy, X, Y, R 1 , R 2 , R 3 , R 4 , and n are as in claim 1 .
3. The method according to claim 1 , wherein the compound is according to formula A-XIVa, A-XIVb, or A-XIVd:
4. The method according to claim 1 , wherein the compound is according to A-XV:
5. The method according to claim 1 , wherein the compound is according to formula A-XVIa or A-XVIb:
6. The method according to claim 1 , wherein the compound is according to formula A-XXa or A-XXb:
7. The method according to claim 1 , wherein the compound is according to formula A-XIVa, A-XIVb, A-XIVd, A-XV, A-XVIb, or A-XXa:
8. The method according to claim 1 , wherein the compound is any one of the compounds listed in Table 1, or Table 2 below:
TABLE 1
Compd #
Structure
CB-1
CB-6
CB-7
CB-8
CB-13
CB-14
CD-1
CD-21
TABLE 2
ID
STRUCTURE
201
202
203
204
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
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
.
9. The method according to claim 1 , wherein R 1 is independently selected from H, halo, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted C 1 -C 6 alkoxy; and each R 2 is independently selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, methylthio, and substituted or unsubstituted C 1 -C 6 alkoxy.
10. The method according to claim 2 , wherein R 1 is independently selected from H, halo, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted C 1 -C 6 alkoxy; and each R 2 is independently selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, methylthio, and substituted or unsubstituted C 1 -C 6 alkoxy.
11. The method according to claim 1 , wherein Cy is:
a) phenyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, carboxy, carbalkoxy, and substituted or unsubstituted C 1 -C 6 alkoxy;
b) pyridyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, and substituted or unsubstituted C 1 -C 6 alkoxy;
c) substituted or unsubstituted pyrrolyl, imidazolyl, triazolyl, thienyl, furanyl, thiazolyl, or oxazolyl; or
d) substituted or unsubstituted thiazolyl.
12. The method according to claim 1 , wherein Cy is thiazolyl, substituted with difluorophenyl.
13. The method according to claim 1 , wherein the compound is according to formula A-VIIIa, A-VIIIb, A-VIIId, A-IX, A-Xa, or A-Xb :
wherein Cy, and R 1 are as in claim 1 .
14. The method according to claim 13 , wherein Cy is:
a) phenyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, carboxy, carbalkoxy, and substituted or unsubstituted C 1 -C 6 alkoxy;
b) pyridyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, and substituted or unsubstituted C 1 -C 6 alkoxy;
c) substituted or unsubstituted pyrrolyl, imidazolyl, triazolyl, thienyl, furanyl, thiazolyl, or oxazolyl; or
d) substituted or unsubstituted thiazolyl.
15. The method according to claim 13 , wherein Cy is thiazolyl, substituted with difluorophenyl.
16. The method according to claim 13 , wherein R 1 is independently selected from H, halo, amino, substituted amino, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, and substituted or unsubstituted C 1 -C 6 alkoxy.
17. The method according to claim 1 , wherein the compound is according to formula A-XIa, A-XIb, A-XId, A-XII, A-XIIa, or A-XIIIb:
wherein Cy is as in claim 1 .
18. The method according to claim 17 , wherein Cy is:
a) phenyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, carboxy, carbalkoxy, and substituted or unsubstituted C 1 -C 6 alkoxy;
b) pyridyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, and substituted or unsubstituted C 1 -C 6 alkoxy;
c) substituted or unsubstituted pyrrolyl, imidazolyl, triazolyl, thienyl, furanyl, thiazolyl, or oxazolyl; or
d) substituted or unsubstituted thiazolyl.
19. The method according to claim 17 , wherein Cy is thiazolyl, substituted with difluorophenyl.
20. The method according to claim 1 , wherein the compound is according to formula A-XVIIIa or A-XVIIIb:
wherein R 1 is halo, amino, substituted amino, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, or substituted or unsubstituted C 1 -C 6 alkoxy; R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Y is O, NH, or N—Me.
21. A method for treating or ameliorating in a mammal a disease or condition that is causally related to RAGE activity in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula A-Ia:
wherein
L 1 is —NH—, —CH 2 —NH—, —CH 2 —CH 2 —NH—, —CO—NH— or —CO—NH-L 2 -CO—NH—; and Cy is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or
L 1 is a bond and Cy is
R 1 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or halo;
each R 2 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, substituted sulfinyl, substituted sulfanyl, unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol; or two adjacent R 1 and R 2 groups may join together to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
the subscript n is 0, 1, 2, or 3;
L 2 is C 1 -C 3 alkylene;
X is CH or N; Y is O or NR 5 ;
R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is H or substituted or unsubstituted alkyl; and * represents an attachment point; or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof;
and wherein the disease or condition is diabetes.
22. The method according to claim 21 , wherein the compound is according to formula A-VI:
wherein Cy, R 1 , R 2 , and n are as in claim 21 .
23. The method according to claim 22 , wherein R 1 is independently selected from H, halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, and substituted or unsubstituted C 1 -C 6 alkoxy; and each R 2 is independently selected from halo, amino, substituted amino, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, methylthio, and substituted or unsubstituted C 1 -C 6 alkoxy.
24. The method according to claim 22 , wherein Cy is:
a) phenyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, carboxy, carbalkoxy, and substituted or unsubstituted C 1 -C 6 alkoxy;
b) pyridyl substituted with one or more groups selected from halo, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, —NHAc, Cl, —SMe, and substituted or unsubstituted C 1 -C 6 alkoxy;
c) substituted or unsubstituted pyrrolyl, imidazolyl, triazolyl, thienyl, furanyl, thiazolyl, or oxazolyl; or
d) substituted or unsubstituted thiazolyl.
25. The method according to claim 22 , wherein Cy is thiazolyl, substituted with difluorophenyl.