Heterocyclic GLP-1R agonists
Disclosed herein are heterocyclic compounds that activate GLP-1R pathways. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the GLP-1R agonists are disclosed, alone or in combination with other therapeutic agents, for the treatment of diabetes, obesity, and other diseases or conditions dependent on GLP-1R pathways.
1 . A compound selected from the group consisting of:
TABLE 1′
Com-
pound
ID
Structure
32
C49H48F2N10O5
36
C49H48F2N10O5
114
C48H46F2N10O5
115
C45H42F2N10O6
116
C49H48F2N10O6
117
C47H45F2N9O6
118
C47H46F2N12O3
119
C48H45FN10O5
121
C49H48F2N10O6
122
C46H42F2N10O6
123
C48H46F2N10O5
124
C48H45FN10O5
125
C47H45F2N9O6
126
C49H46F2N10O5
127
C49H47FN10O5
128
C48H48F2N12O3
129
C47H44F2N10O5S
131
C54H57F2N11O6
132
C54H57F2N11O6
134
C49H48F2N10O5
135
C49H47F2N11O5
136
C48H44F2N10O6
137
C48H47F2N9O3
138
C48H49F2N9O4
139
C46H45F2N11O5S
140
C48H48F2N10O5
201
C49H51F2N9O6S
203
C52H59FN9O6P
204
C51H53F2N9O6S
205
C50H54F2N10O6S
206
C46H45F2N11O5S
208
C47H44F2N10O5
209
C48H47F2N11O5
210
C48H47F2N11O5
211
C48H47F2N11O5
212
C48H47F2N11O5
213
C49H46F2N10O5
214
C49H46F2N10O5
215
C49H46F2N10O5
216
C50H55FN9O6P
217
C48H47F2N11O5
218
C48H47F2N11O5
219
C50H45F2N11O4
220
C49H46F2N10O6
221
C47H44F2N10O6
222
C49H48ClFN10O6
223
C48H49FN806
224
C49H47F3N10O6
225
C48H47F2N11O6
226
C49H46F2N10O6
227
C49H46F2N10O6
228
C50H51FN10O6
229
C48H47F2N11O5
230
C49H46ClFN10O6
231
C48H47F2N11O6
232
C48H47F2N11O6
233
C49H48F2N10O6
235
C49H47F3N10O5
236
C48H46F3N11O5
237
Isomer 1
C48H44F2N10O5
238
C48H47F2N11O6
239
C48H47F2N11O6
240
C50H53F2N9O4
241
C50H53F2N9O5
242
C49H45F3N10O6
243
C50H53F2N9O4
244
C49H51F2N9O4
246
C51H53F2N9O4
302
C49H49FN10O5
305
C50H51FN10O5
306
C46H45F2N11O5S
307
C46H45F2N11O5S
308
C49H48ClFN10O5
309
C49H46F4N10O5
310
C49H46F4N10O5
311
C48H47F2N11O5
312
C48H47F2N11O5
313
C48H47F2N11O5
318
Isomer 1a
C50H48F2N10O5
319
Isomer 1b
C50H48F2N10O5
323
C49H47FN10O5
324
C48H47F2N11O6
406
C48H46F2N10O5
410
C49H46F2N10O5
412
C48H47F2N9O6
413
C48H46F2N10O5
415
C50H48F2N10O5
416
C48H48F2N10O5
417
C49H50F2N10O4
418
C48H46F2N10O5
419
C48H46F2N10O5
420
C48H46F2N10O5
421
C48H48F2N10O5
422
C48H47F2N9O6
423
C48H46F2N10O5
424
C50H48F2N10O5
425
C48H46F2N10O5
426
C50H48F2N10O5
427
C50H50F2N10O5
428
C49H51F2N9O6S
429
C49H48F2N10O6
431
C49H48F2N10O6
432
C48H50F2N10O4
433
C50H50F2N10O5
434
C50H50F2N10O5
435
C50H50F2N10O5
436
C48H44F2N10O5
437
C49H44F2N10O5
501
C51H59FN9O6P
502
C46H44F2N10O5
503
C48H48F2N10O6S
504
C48H48F2N10O6S
505
C47H46F2N10O5
506
C49H55FN9O6P
507
C49H47F3N10O5
508
C47H48F2N10O6S
509
C50H48F2N10O5
510
C49H45F2N11O5
511
C49H47F3N10O5
512
C49H47F3N10O5
515
C49H47F3N10O5
516
C49H46F2N10O5
518
C49H50F2N10O5
519
C49H46F2N10O5
521
C48H46F2N10O5
522
C50H50F2N10O5
523
C50H50F2N10O5
525
C48H48F2N10O6S
526
C46H44F2N10O7S
527
C49H50F2N10O6S
528
C49H46F2N10O5
529
C49H46F2N10O5
532
C50H50F2N10O5
533
C47H46F2N10O6S
534
C47H46F2N10O6S
535
C48H47F2N11O6S
536
C48H48F2N10O7S
537
C51H52F2N10O5
542
C49H46F2N10O5
545
C53H54FN9O6
602
C50H49F2N9O6S
604
C49H48F2N10O6S
605
C50H49F2N906S
606
C49H48F2N10O5
607
C47H46F2N10O5
608
C49H48F2N10O6S
609
C49H48F2N10O6S
610
C51H47F2N9O5
611
C51H53F2N9O6
612
C53H55ClFN9O6
613
C50H50F2N10O5
614
C51H47F2N9O5
615
C50H49F3N10O5
616
C49H49F2N11O4
617
C51H50F2N10O6
618
C49H47F3N10O5
619
C49H47F3N10O6
701
C50H49F3N10O5
702
C49H50F2N10O5
703
C49H50F2N10O5
704
C53H54FN9O6
705
C49H47F3N10O6
706
C49H47F3N10O6
707
C50H49F3N10O5
708
C49H47F3N10O5
709
C49H47F3N10O5
710
C51H50FN9O7
711
C49H47F3N10O5
712
C49H47F3N10O5
713
C49H47F3N10O5
714
C53H54FN9O6
715
C49H46F2N10O6
and
716
C49H47F3N10O5;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , selected from the group consisting of the compounds with ID numbers 36, 121, 128, 208, 209, 213, 214, 220, 225, 226, 302, 311, 313, 323, 406, 410, 417, 427, 428, 429, 433, 436, 437, 611-619, 703, 705-708, 710-715 and 716, or a pharmaceutically acceptable salt thereof.
3 . The pharmaceutically acceptable salt of the compound of claim 1 .
4 . The pharmaceutically acceptable salt of claim 3 , selected from L-arginine, hemi-calcium, mono-potassium, mono-sodium, L-lysine, and betaine salt forms.
5 . The pharmaceutically acceptable salt of claim 3 , wherein the salt is compound 214 monosodium salt or compound 36 monosodium salt.
6 . The pharmaceutically acceptable salt of claim 5 , wherein the salt is amorphous.
7 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
8 . A method of treating a GLP-1 related disorder in a subject in need thereof comprising administering a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
9 . The compound according to claim 1 , wherein the compound is selected from the group consisting of compounds with ID numbers 36, 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, 617, 705-708, 710-715 and 716, or a pharmaceutically acceptable salt thereof.
10 . The compound according to claim 1 , wherein the compound is selected from the group consisting of compounds with ID numbers 36, 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, and 617, or a pharmaceutically acceptable salt thereof.
11 . The compound according to claim 1 , with the ID number 36:
or a pharmaceutically acceptable salt thereof.
12 . The compound according to claim 1 , with the ID number 214:
or a pharmaceutically acceptable salt thereof.
13 . The compound according to claim 1 , with the ID number 707:
or a pharmaceutically acceptable salt thereof.
14 . The compound according to claim 1 , with the ID number 710:
or a pharmaceutically acceptable salt thereof.
15 . The compound according to claim 1 , with the ID number 711:
or a pharmaceutically acceptable salt thereof.
16 . The compound according to claim 1 , with the ID number 713:
or a pharmaceutically acceptable salt thereof.
17 . The compound according to claim 1 , with the ID number 714:
or a pharmaceutically acceptable salt thereof.
18 . The compound according to claim 1 , with the ID number 225:
19 . The compound according to claim 1 , with the ID number 226:
or a pharmaceutically acceptable salt thereof.
20 . The pharmaceutically acceptable salt of claim 3 , wherein the pharmaceutically acceptable salt is compound ID number 214 monosodium salt.