Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
The present invention provides compounds of Formula I, pharmaceutical compositions comprising these compounds and methods of using these compounds to prevent or treat FXR-mediated or TGR5-mediated diseases or conditions.
1. A compound represented by Formula I or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:
wherein:
R a is hydrogen or substituted or unsubstituted —C 1 -C 8 alkyl;
R b is selected from the group consisting of:
1) —C(O)NR 10 R 11 ;
2) —C(O)NHSO 2 R 1 ; and
3) —SO 2 R 1 ;
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted aryl;
8) Substituted or unsubstituted arylalkyl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted heteroarylalkyl; and
12) NR 10 ′R 11 ′;
R 2 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 4 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 2 or —NHR 2 ;
Or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 5 and R 6 are independently hydrogen or a hydroxyl protecting group;
R 7 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl; and
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
R 10 and R 11 are each independently selected from hydrogen, C 1 -C 4 -haloalkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; and
R 10 ′ and R 11 ′ are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R 10 ′ and R 11 ′ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.
2. A compound of claim 1 , represented by Formula II or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:
wherein, R a , R b , R 2 , R 3 , R 4 , R 7 and m are as defined in claim 1 .
3. A compound of claim 1 , represented by Formula III or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:
wherein R a , R b , R 2 , R 3 , R 7 and m are as defined in claim 1 .
4. The compound of claim 1 , represented by one of formulas (III-1˜III-18), or a pharmaceutically acceptable salt, ester, solvate or combination thereof, where R 1 , R 7 , R 10 and m are as defined in claim 1 :
5. A compound of claim 1 , represented by Formula IV-A or Formula IV-B or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:
wherein R 1 and m are as defined in claim 1 .
6. A compound according to claim 1 , selected from:
(A) Compounds according to Formula IV-A wherein R 1 and m are delineated for each compound in Table 1:
TABLE 1
Compound
m
R 1
1
0
Methyl
2
0
Ethyl
3
0
Isopropyl
4
0
Butyl
5
0
t-Butyl
6
0
Propyl
7
0
Benzyl
8
0
Vinyl
9
0
Allyl
10
0
CF 3
11
0
12
0
13
0
14
0
15
0
16
0
17
0
NH 2
18
0
19
0
20
0
21
0
22
0
23
0
24
0
25
0
F
26
1
Methyl
27
1
Ethyl
28
1
Isopropyl
29
1
Butyl
30
1
t-Butyl
31
1
Propyl
32
1
Benzyl
33
1
Vinyl
34
1
Allyl
35
1
CF 3
36
1
37
1
38
1
39
1
40
1
41
1
42
1
NH 2
43
1
44
1
45
1
46
1
47
1
48
1
49
1
50
1
F
51
2
Methyl
52
2
Ethyl
53
2
Isopropyl
54
2
Butyl
55
2
t-Butyl
56
2
Propyl
57
2
Benzyl
58
2
Vinyl
59
2
Allyl
60
2
CF 3
61
2
62
2
63
2
64
2
65
2
66
2
67
2
NH 2
68
2
69
2
70
2
71
2
72
2
73
2
74
2
75
2
F
and
(B) Compounds according to Formula IV-B wherein R 1 and m are delineated for each example in Table 2:
TABLE 2
Compound
m
R 1
76
0
Methyl
77
0
Ethyl
78
0
Isopropyl
79
0
Butyl
80
0
t-Butyl
81
0
Propyl
82
0
Benzyl
83
0
Vinyl
84
0
Allyl
85
0
CF 3
86
0
87
0
88
0
89
0
90
0
91
0
92
0
NH 2
93
0
94
0
95
0
96
0
97
0
98
0
99
0
100
0
F
101
1
Methyl
102
1
Ethyl
103
1
Isopropyl
104
1
Butyl
105
1
t-Butyl
106
1
Propyl
107
1
Benzyl
108
1
Vinyl
109
1
Allyl
110
1
CF 3
111
1
112
1
113
1
114
1
115
1
116
1
117
1
NH 2
118
1
119
1
120
1
121
1
122
1
123
1
124
1
125
1
F
126
2
Methyl
127
2
Ethyl
128
2
Isopropyl
129
2
Butyl
130
2
t-Butyl
131
2
Propyl
132
2
Benzyl
133
2
Vinyl
134
2
Allyl
135
2
CF 3
136
2
137
2
138
2
139
2
140
2
141
2
142
2
NH 2
143
2
144
2
145
2
146
2
147
2
148
2
149
2
150
2
F
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
7. A compound according to claim 1 selected from:
(A) Compounds according to Formula V-A wherein R 1 and m are delineated for each compound in Table 3:
TABLE 3
Compound
m
R 1
151
0
Methyl
152
0
Ethyl
153
0
Isopropyl
154
0
Butyl
155
0
t-Butyl
156
0
Propyl
157
0
Benzyl
158
0
Vinyl
159
0
Allyl
160
0
CF 3
161
0
162
0
163
0
164
0
165
0
166
0
167
0
NH 2
168
0
169
0
170
0
171
0
172
0
173
0
174
0
175
0
F
176
1
Methyl
177
1
Ethyl
178
1
Isopropyl
179
1
Butyl
180
1
t-Butyl
181
1
Propyl
182
1
Benzyl
183
1
Vinyl
184
1
Allyl
185
1
CF 3
186
1
187
1
188
1
189
1
190
1
191
1
192
1
NH 2
193
1
194
1
195
1
196
1
197
1
198
1
199
1
200
1
F
201
2
Methyl
202
2
Ethyl
203
2
Isopropyl
204
2
Butyl
205
2
t-Butyl
206
2
Propyl
207
2
Benzyl
208
2
Vinyl
209
2
Allyl
210
2
CF 3
211
2
212
2
213
2
214
2
215
2
216
2
217
2
NH 2
218
2
219
2
220
2
221
2
222
2
223
2
224
2
225
2
F
and
(B) Compounds according to Formula V-B wherein R 1 and m are delineated for each compound in Table 4:
TABLE 4
Compound
m
R 1
226
0
Methyl
227
0
Ethyl
228
0
Isopropyl
229
0
Butyl
230
0
t-Butyl
231
0
Propyl
232
0
Benzyl
233
0
Vinyl
234
0
Allyl
235
0
CF 3
236
0
237
0
238
0
239
0
240
0
241
0
242
0
NH 2
243
0
244
0
245
0
246
0
247
0
248
0
249
0
250
0
F
251
1
Methyl
252
1
Ethyl
253
1
Isopropyl
254
1
Butyl
255
1
t-Butyl
256
1
Propyl
257
1
Benzyl
258
1
Vinyl
259
1
Allyl
260
1
CF 3
261
1
262
1
263
1
264
1
265
1
266
1
267
1
NH 2
268
1
269
1
270
1
271
1
272
1
273
1
274
1
275
1
F
276
2
Methyl
277
2
Ethyl
278
2
Isopropyl
279
2
Butyl
280
2
t-Butyl
281
2
Propyl
282
2
Benzyl
283
2
Vinyl
284
2
Allyl
285
2
CF 3
286
2
287
2
288
2
289
2
290
2
291
2
292
2
NH 2
293
2
294
2
295
2
296
2
297
2
298
2
299
2
300
2
F
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
8. A compound selected from:
(A) Compounds according to Formula VI-A wherein, R 10 and m are delineated for each compound in Table 5:
TABLE 5
Compound
m
R 10
301
0
Methyl
302
0
Ethyl
303
0
Isopropyl
304
0
Butyl
305
0
t-Butyl
306
0
Propyl
307
0
Benzyl
308
0
Vinyl
309
0
Allyl
310
0
CF 3
311
0
312
0
313
0
314
0
315
0
316
0
317
0
H
318
0
319
0
320
0
321
0
322
0
323
0
324
0
325
0
326
1
Methyl
327
1
Ethyl
328
1
Isopropyl
329
1
Butyl
330
1
t-Butyl
331
1
Propyl
332
1
Benzyl
333
1
Vinyl
334
1
Allyl
335
1
CF 3
336
1
337
1
338
1
339
1
340
1
341
1
342
1
H
343
1
344
1
345
1
346
1
347
1
348
1
349
1
350
1
351
2
Methyl
352
2
Ethyl
353
2
Isopropyl
354
2
Butyl
355
2
t-Butyl
356
2
Propyl
357
2
Benzyl
358
2
Vinyl
359
2
Allyl
360
2
CF 3
361
2
362
2
363
2
364
2
365
2
366
2
367
2
H
368
2
369
2
370
2
371
2
372
2
373
2
374
2
375
2
and
(B) Compounds according to Formula VI-B wherein R 10 and m are delineated for each compound in Table 6:
TABLE 6
Compound
m
R 10
376
0
Methyl
377
0
Ethyl
378
0
Isopropyl
379
0
Butyl
380
0
t-Butyl
381
0
Propyl
382
0
Benzyl
383
0
Vinyl
384
0
Allyl
385
0
CF 3
386
0
387
0
388
0
389
0
390
0
391
0
392
0
H
393
0
394
0
395
0
396
0
397
0
398
0
399
0
400
0
401
1
Methyl
402
1
Ethyl
403
1
Isopropyl
404
1
Butyl
405
1
t-Butyl
406
1
Propyl
407
1
Benzyl
408
1
Vinyl
409
1
Allyl
410
1
CF 3
411
1
412
1
413
1
414
1
415
1
416
1
417
1
H
418
1
419
1
420
1
421
1
422
1
423
1
424
1
425
1
426
2
Methyl
427
2
Ethyl
428
2
Isopropyl
429
2
Butyl
430
2
t-Butyl
431
2
Propyl
432
2
Benzyl
433
2
Vinyl
434
2
Allyl
435
2
CF 3
436
2
437
2
438
2
439
2
440
2
441
2
442
2
H
443
2
444
2
445
2
446
2
447
2
448
2
449
2
450
2
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
9. The compound of claim 1 , wherein R b is —C(O)NHSO 2 R 1 .
10. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
11. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
12. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
13. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
14. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
15. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
16. A compound represented by Formula I or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:
wherein:
R a is hydrogen or substituted or unsubstituted —C 1 -C 8 alkyl;
R b is —C(O)NR 10 R 11 ;
R 2 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 4 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 2 or —NHR 2 ;
Or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 5 and R 6 are independently hydrogen or a hydroxyl protecting group;
R 7 is ethyl; and
R 10 and R 11 are each independently selected from hydrogen, substituted or unsubstituted C 1 -C 8 -alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.
17. A compound selected from the compounds set forth below, or a pharmaceutically acceptable salt, ester, solvate or combination thereof:
18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, ester, solvate, or combination thereof
and a pharmaceutically acceptable excipient or carrier.
19. A pharmaceutical composition comprising the compound of claim 10 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof, and a pharmaceutically acceptable excipient or carrier.
20. A pharmaceutical composition comprising the compound of claim 11 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof, and a pharmaceutically acceptable excipient or carrier.
21. A pharmaceutical composition comprising the compound of claim 12 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof, and a pharmaceutically acceptable excipient or carrier.
22. A pharmaceutical composition comprising the compound of claim 13 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof, and a pharmaceutically acceptable excipient or carrier.
23. A pharmaceutical composition comprising the compound of claim 14 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof, and a pharmaceutically acceptable excipient or carrier.
24. A pharmaceutical composition comprising the compound of claim 15 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof, and a pharmaceutically acceptable excipient or carrier.
25. A method for ameliorating a disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula I or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:
wherein:
R a is hydrogen or substituted or unsubstituted —C 1 -C 8 alkyl;
R b is selected from the group consisting of:
1) —C(O)NR 10 R 11 ;
2) —C(O)NHSO 2 R 1 ; and
3) —SO 2 R 1 ;
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted aryl;
8) Substituted or unsubstituted arylalkyl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted heteroarylalkyl; and
12) —NR 10 R 11 ;
R 2 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 4 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 2 or —NHR 2 ;
Or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 5 and R 6 are independently hydrogen or a hydroxyl protecting group;
R 7 is selected from the group consisting of:
7) Hydrogen;
8) Halogen;
9) Substituted or unsubstituted —C 1 -C 8 alkyl;
10) Substituted or unsubstituted —C 2 -C 8 alkenyl;
11) Substituted or unsubstituted —C 2 -C 8 alkynyl; and
12) Substituted or unsubstituted —C 3 -C 8 cycloalkyl; and
R 10 and R 11 are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.
26. The method of claim 25 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
27. The method of claim 25 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
28. The method of claim 25 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
29. The method of claim 25 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
30. The method of claim 25 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
31. The method of claim 25 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
32. The method of claim 25 wherein the disease or condition is primary biliary cirrhosis.
33. The method of claim 32 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
34. The method of claim 32 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
35. The method of claim 32 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
36. The method of claim 32 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
37. The method of claim 32 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
38. The method of claim 32 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
39. The method of claim 25 wherein the disease or condition is nonalcoholic steatohepatitis.
40. The method of claim 39 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
41. The method of claim 39 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
42. The method of claim 39 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
43. The method of claim 39 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
44. The method of claim 39 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
45. The method of claim 39 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
46. The method of claim 25 wherein the disease or condition is nonalcoholic fatty liver disease.
47. The method of claim 46 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
48. The method of claim 46 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
49. The method of claim 46 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
50. The method of claim 46 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
51. The method of claim 46 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
52. The method of claim 46 , wherein the compound has the structure
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
53. A method of producing a compound of Formula (1-5),
wherein:
m is 0, 1, 2 or 3;
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted aryl;
8) Substituted or unsubstituted arylalkyl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted heteroarylalkyl; and
12) —NR 10 R 11 ;
R 7 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl; and
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl; and
R 10 and R 11 are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring;
comprising the steps of:
(a) protecting the hydroxyl groups of a compound of Formula (1-1),
thereby producing a compound of Formula (1-2),
wherein P 1 and P 2 are the same or different and are each a hydroxyl protecting group;
(b) reacting the compound of Formula (1-2) with diphenylphosphoryl azide, thereby forming a compound of Formula (1-3),
(c) reacting the compound of Formula (1-3) with R 1 SO 2 NH 2 , thereby producing a compound of Formula (1-4),
and
(d) deprotecting the compound of Formula (1-4), thereby producing the compound of Formula (1-5).