Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof

A compound selected from:

• (A) Compounds according to Formula VI-A wherein, R10 and m are delineated for each compound in Table 5:
• TABLE 5
• Compound
• m
• R10
• 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
• CF3
• 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
• CF3
• 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
• CF3
• 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 R10 and m are delineated for each compound in Table 6:
• TABLE 6
• Compound
• m
• R10
• 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
• CF3
• 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
• CF3
• 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
• CF3
• 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.

A compound represented by Formula I or a pharmaceutically acceptable salt, ester, solvate, or combination thereof:

• wherein:
• Ra is hydrogen or substituted or unsubstituted —C1-C8 alkyl;
• Rb is —C(O)NR10R11;
• R2 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Substituted or unsubstituted —C1-C8 alkyl;
• 3) Substituted or unsubstituted —C2-C8 alkenyl;
• 4) Substituted or unsubstituted —C2-C8 alkynyl;
• 5) Substituted or unsubstituted arylalkyl;
• and
• 6) Substituted or unsubstituted aryl;
• m is selected from 0, 1, 2 and 3;
• R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2 or —OPO32−;
• R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2, —OPO32−, —SR2 or —NHR2;
• Or R3 and R4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
• R5 and R6 are independently hydrogen or a hydroxyl protecting group;
• R7 is ethyl;
• and
• R10 and R11 are each independently selected from hydrogen, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted —C2-C8 alkenyl, substituted or unsubstituted —C2-C8 alkynyl, substituted or unsubstituted —C3-C8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R10 and R11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.

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:
• Ra is hydrogen or substituted or unsubstituted —C1-C8 alkyl;
• Rb is selected from the group consisting of:
• 1) —C(O)NR10R11;
• 2) —C(O)NHSO2R1;
• and
• 3) —SO2R1;
• R1 is selected from the group consisting of:
• 1) Halogen;
• 2) Hydroxyl;
• 3) Substituted or unsubstituted —C1-C8 alkyl;
• 4) Substituted or unsubstituted —C2-C8 alkenyl;
• 5) Substituted or unsubstituted —C2-C8 alkynyl;
• 6) Substituted or unsubstituted —C3-C8 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) —NR10R11;
• R2 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Substituted or unsubstituted —C1-C8 alkyl;
• 3) Substituted or unsubstituted —C2-C8 alkenyl;
• 4) Substituted or unsubstituted —C2-C8 alkynyl;
• 5) Substituted or unsubstituted arylalkyl;
• and
• 6) Substituted or unsubstituted aryl;
• m is selected from 0, 1, 2 and 3;
• R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2 or —OPO32−;
• R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2, —OPO32−, —SR2 or —NHR2;
• Or R3 and R4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
• R5 and R6 are independently hydrogen or a hydroxyl protecting group;
• R7 is selected from the group consisting of:
• 7) Hydrogen;
• 8) Halogen;
• 9) Substituted or unsubstituted —C1-C8 alkyl;
• 10) Substituted or unsubstituted —C2-C8 alkenyl;
• 11) Substituted or unsubstituted —C2-C8 alkynyl;
• and
• 12) Substituted or unsubstituted —C3-C8 cycloalkyl;
• and
• R10 and R11 are each independently selected from hydrogen, substituted or unsubstituted —C1-C8 alkyl, substituted or unsubstituted —C2-C8 alkenyl, substituted or unsubstituted —C2-C8 alkynyl, substituted or unsubstituted —C3-C8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R10 and R11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.

A method of producing a compound of Formula (1-5),

• wherein:
• m is 0, 1, 2 or 3;
• R1 is selected from the group consisting of:
• 1) Halogen;
• 2) Hydroxyl;
• 3) Substituted or unsubstituted —C1-C8 alkyl;
• 4) Substituted or unsubstituted —C2-C8 alkenyl;
• 5) Substituted or unsubstituted —C2-C8 alkynyl;
• 6) Substituted or unsubstituted —C3-C8 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) —NR10R11;
• R7 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Halogen;
• 3) Substituted or unsubstituted —C1-C8 alkyl;
• 4) Substituted or unsubstituted —C2-C8 alkenyl;
• 5) Substituted or unsubstituted —C2-C8 alkynyl;
• and
• 6) Substituted or unsubstituted —C3-C8 cycloalkyl;
• and
• R10 and R11 are each independently selected from hydrogen, substituted or unsubstituted —C1-C8 alkyl, substituted or unsubstituted —C2-C8 alkenyl, substituted or unsubstituted —C2-C8 alkynyl, substituted or unsubstituted —C3-C8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R10 and R11 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 P1 and P2 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 R1SO2NH2, 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).