Modulators of ATP-binding cassette transporters

1. A method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound having formula IIIB:

wherein:

X 9 is CH 2 , CF 2 , CH 2 —CH 2 , or CF 2 —CF 2 ;

m is 0 to 4;

Ht 1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH;

x, q, and z is independently 0-5;

Q-R Q , X—R X and Z—R Z each is independently R′;

L is a bond, O, S, SO, SO 2 , C(O), NR′, C 1-4 aliphatic, or CHR L ;

R L is —OR′, —SR′, —SOR′, —SO 2 R′, or —N(R′) 2 ; or

wherein ring A′ is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A′ is optionally substituted with q occurrences of -QR Q ;

Ar is phenyl or a six-membered heteroaromatic ring;

R′ is independently selected from hydrogen or an optionally substituted group selected from a C 1 -C 8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

R′ is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;

R 1 is oxo, R 6 or ((C1-C4)aliphatic) n -Y; or two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy, 1,2-difluoromethylenedioxy, 1,2-ethylenedioxy, or 1,2-tetrafluoroethylenedioxy;

n is 0 or 1;

Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ;

R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;

R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;

R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 ,NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 N(R 6 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;

R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;

R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;

R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2 -C 6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z′;

Z′ is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and

R 8 is an amino protecting group.

2. The method of claim 1 , wherein the ABC transporter is CFTR.

3. A method of treating a condition, disease, or disorder in a patient implicated by CFTR transporter activity wherein the condition, disease, or disorder is cystic fibrosis, comprising the step of administering to said patient a compound having formula IIIB:

wherein:

X 9 is CH 2 , CF 2 , CH 2 —CH 2 , or CF 2 —CF 2 ;

m is 0 to 4;

Ht 1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH;

x, q, and z is independently 0-5;

Q-R Q , X—R x and Z—R Z each is independently R′;

L is a bond, O, S, SO, SO 2 , C(O), NR′, C 1-4 aliphatic, or CHR L ;

R L is —OR′, —SR′, —SOR′, —SO 2 R′, or —N(R′) 2 ; or

L is

wherein ring A′ is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A′ is optionally substituted with q occurrences of -QR Q ;

Ar is phenyl or a six-membered heteroaromatic ring;

R′ is independently selected from hydrogen or an optionally substituted group selected from a C 1 -C 8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

R′ is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;

R 1 is oxo, R 6 or ((C1-C4)aliphatic) n -Y; or two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy, 1,2-difluoromethylenedioxy, 1,2-ethylenedioxy, or 1,2-tetrafluoroethylenedioxy;

n is 0 or 1;

Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ;

R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;

R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;

R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 N(R 6 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;

R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;

R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;

R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2 -C 6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z′;

Z′ is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and

R 8 is an amino protecting group.

4. The method of claim 3 , wherein two R′ in N(R′) 2 taken together with the nitrogen atom, form an optionally substituted 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S.

5. The method of claim 3 , wherein m is 0.

6. The method of claim 3 , wherein Ht 1 is a thiazolyl ring, wherein Ht is optionally substituted with up to three substituents.

7. The method of claim 3 , wherein X 9 is CH 2 .

8. The method of claim 3 , wherein X 9 is CF 2 .

9. The method of claim 3 , wherein L is —CH 2 —.

10. The method of claim 3 , wherein L is —CH—R L , wherein R L is —OH, —NHR D , or NR AA R BB ; wherein

each of R AA , R BB , and R D is independently hydrogen, C1-C6 aliphatic, C3-C7 cycloalkyl, (C3-C7-cycloalkyl)-C1-C6 aliphatic, (C3-C7-cycloalkenyl)-C1-C6-aliphatic, 3-7-membered heterocyclyl, (3-7-membered heterocyclyl)-C1-C6-aliphatic, 3-6 membered heteroaryl, (3-6-membered heteroaryl)-C1-C6 aliphatic, wherein said aliphatic, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted with up to three substituents selected from OH, —O(C 1-4 -aliphatic), or (C1-C4 aliphatic) p -Y; wherein

p is 0 or 1;

Y is OR or NHC(O)R;

R is hydrogen or C 1-4 aliphatic; or

R AA and R BB , taken together with the nitrogen atom, is a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from 0, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C1-C4 aliphatic) p —Y; and

wherein up to two methylene groups in any said aliphatic above are optionally and independently replaced with O, C(O), or NH.

11. The method of claim 10 , wherein R D is hydrogen.

12. The method of claim 10 , wherein R D is optionally substituted C 1 -C 6 aliphatic.

13. The compound according to claim 10 , wherein R D is selected from C1-C6 alkyl, optionally substituted with up two substituents selected from OH, —O(C1-C4 alkyl), acetamido, NH 2 , NH(C1-C4 alkyl), or N(C1-C4 alkyl) 2 .

14. The method of claim 10 , wherein R D is selected from an optionally substituted C3-C6 cycloalkyl, or (C3-C6 cycloalkyl or cycloalkenyl ring)-C1-C6 aliphatic.

15. The method of claim 10 , wherein R D is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenylethyl or cyclohexylmethyl.

16. The method of claim 10 , wherein R D is selected from optionally substituted 3-7 membered heterocyclyl or (3-7 membered heterocyclyl)-C1-C6 aliphatic, wherein said heterocyclyl contains up to 2 heteroatoms selected from O, S, or N.

17. The method of claim 10 , wherein R D is selected from (N-methyl-pyrrolidin-2-yl)-ethyl, pyrrolidin-1-yl-ethyl, tetrahydrofuran-2-yl-methyl, morpholin-4-yl-ethyl, or morpholin-4-yl-propyl.

18. The method of claim 10 , wherein R D is selected from optionally substituted 5-6 membered heteroaryl or (5-6-membered heteroaryl)-C1-C6 aliphatic, wherein said heteroaryl contains up to 2 heteroatoms selected from O, S, or N.

19. The method of claim 10 , wherein R D is selected from imidazolylpropyl, furanylmethyl, or pyridinylethyl.

20. The method of claim 10 , wherein R D is selected from C 1-4 alkyl optionally substituted with —OH, or —O(C 1-4 alkyl).

21. The method of claim 10 , wherein R D is selected from C 1-4 alkyl optionally substituted with 5-6 membered heterocyclic ring containing up to 2 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from (C 1-4 aliphatic)-Y, wherein Y is halo, —OH, or —O(C 1-4 alkyl).

22. The method of claim 10 , wherein R D is selected from C 1-6 alkyl optionally substituted with —OH or —O(C 1-4 alkyl).

23. The method of claim 10 , wherein one of R AA and R BB is C1-C4 alkyl, and the other of R AA and R BB is selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, wherein said alkyl, alkenyl, or cycloalkenyl has up to 2 substituents selected from OH or —O(C1-C4 alkyl).

24. The method of claim 10 , wherein R AA and R BB , taken together with the nitrogen atom, forms a ring selected from pyrrolidinyl, piperidinyl, or morpholinyl, wherein said ring is optionally substituted with up to two substituents selected from hydroxy, COOH, acetoxy, hydroxymethyl, methoxymethyl, hydroxyethyl, methoxyethyl, or ethylenedioxy.

25. The method of claim 10 , wherein said compound has formula VB-3-i:

wherein X 9 is CH 2 or CF 2 ;

R AA and R BB are selected from hydrogen, C1-C6 alkyl, or —CH(C1-C6 alkyl)-CH 2 OH; or

R AA and R BB taken together form a pyrrolidinyl ring optionally substituted with (C1-C4 aliphatic) p -Y.

26. The method of claim 25 , wherein R AA and R BB taken together is 3-acetoxy-pyrrolidin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl, 2-hydroxymethyl-pyrrolidin-1-yl, (2-carboxypyrrolidin-1-yl), pyrrolidin-1-yl, or 3-hydroxy-pyrrolidin-1-yl.

27. The method of claim 25 , wherein R AA is hydrogen, and R BB is —CH(C1-C6 alkyl)-CH 2 OH.

28. The method of claim 27 , wherein said alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or isobutyl.

29. The method of claim 3 , wherein the compound selected from the following table:

Cmpd

#

Compound

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

30. The method of claim 3 , wherein XR X is hydrogen.

31. The method of claim 3 , where

in ZR Z is selected from halo, CF 3 , OCF 3 , C1-C4 alkoxy, methylenedioxy, or difluoromethylenedioxy.

32. The method of claim 3 , wherein z is 1-3.

33. The method of claim 3 , wherein the compound is