MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

1 . A compound of formula V-A:

or a pharmaceutically acceptable salt thereof,

wherein:

T is an optionally substituted C 1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CO—, —CS—, —COCO—, —SO 2 —, —B(OH)—, or —B(O(C 1-6 alkyl))-;

each of R 1 ′ and R 1 ″ is independently H or —Z A R 5 , wherein Z A is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z A are optionally and independently replaced by —CO—, —CS—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A —, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —, wherein R 5 is independently R A , halo, —OH, —NH 2 —NO 2 —CN, —CF 3 , or —OCF 3 , wherein R A is independently an optionally substituted group selected from C 1-8 aliphatic group, a cycloaliphatic, a heterocycloaliphatic, an aryl, and a heteroaryl;

R D1 is attached to carbon 3″ or 4″;

each R D1 and R D2 is —Z D R 9 , wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 — or —NR E SO 2 NR E —;

R 9 is independently R E , halo, —OH, —NH 2 , —NO 7 , —CN, —CF 3 , or —OCF 3 ; and

each R E is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

2 - 61 . (canceled)

62 . A pharmaceutical composition comprising:

(i) a compound according to claim 1 ; and

(ii) a pharmaceutically acceptable carrier.

63 . The composition according to claim 62 , optionally further comprising a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent.

64 - 69 . (canceled)

70 . The composition of claim 62 , further comprising a CFTR modulator.

71 . The compound of claim 1 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-.

72 . The compound of claim 1 , wherein T is —CF 2 —.

73 . The compound of claim 1 , wherein R 1 ′ is H, methyl, ethyl, i-propyl, t-butyl, F, Cl, CF 3 , OCF 3 , CHF 2 , —OCH 3 , —OCH 2 CH 3 , —O-(i-propyl), or —O-(t-butyl).

74 . The compound of claim 1 , wherein R 1 ′ is methyl.

75 . The compound of claim 1 , wherein R 1 ″ is H, methyl, ethyl, i-propyl, t-butyl, F, Cl, CF 3 , OCF 3 , CHF 2 , —OCH 3 , —OCH 2 CH 3 , —O-(i-propyl), or —O-(t-butyl).

76 . The compound of claim 1 , wherein R 1 ″ is H.

77 . The compound of claim 1 , wherein for R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —OCO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —.

78 . The compound of claim 1 , wherein in R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —OCO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —; and R 9 is hydrogen, halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl.

79 . The compound of claim 1 , wherein R D1 is —CO 2 H.

80 . The compound of claim 1 , wherein R D2 is H, R E , halo, —OH, —(CH 2 ) r NR E R E , —(CH 2 ) r —OR E , —SO 2 —R E , —NR E —SO 2 —R E , —SO 2 NR E R E , —C(O)R E , —C(O)OR E , —OC(O)OR E , —NR E C(O)OR E , and —C(O)NR E R E ; wherein r is 0, 1, or 2.

81 . The compound of claim 1 , wherein R D2 is H, methyl, ethyl, n-propyl, i-propyl, t-butyl, F, Cl, CN, —NH 2 , —CH 2 NH 2 , —OH, —OCH 3 , —O-ethyl, —O-(i-propyl), —O-(n-propyl), —CH 2 OH, —SO 2 CH 3 , —NH—SO 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OH, —NHC(O)CH 3 , —C(O)NH 2 , or —C(O)N(CH 3 ) 2 .

82 . The compound of claim 1 , wherein R D2 is H.

83 . The compound of claim 1 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; and R 1 ′ is H, methyl, ethyl, i-propyl, or t-butyl.

84 . The compound of claim 1 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; R 1 ′ is H, methyl, ethyl, i-propyl, or t-butyl; and R 1 ″ is H, methyl, ethyl, i-propyl, or t-butyl.

85 . The compound of claim 1 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; R 1 ′ is H, methyl, ethyl, i-propyl, or t-butyl; R 1 ″ is H, methyl, ethyl, i-propyl, or t-butyl; and wherein in R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —; and R 9 is hydrogen, halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl.

86 . The compound of claim 1 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; R 1 ′ is H, methyl, ethyl, i-propyl, or t-butyl; R 1 ″ is H, methyl, ethyl, i-propyl, or t-butyl; wherein in R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —; R 9 is hydrogen, halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl; and R D2 is H, R E , halo, —OH, —(CH 2 ) r NR E R E , —(CH 2 ) r —OR E , —SO 2 —R E , —NR E —SO 2 —R E , —SO 2 NR E R E , —C(O)R E , —C(O)OR E , —OC(O)OR E , —NR E C(O)OR E , and —C(O)NR E R E ; wherein r is 0, 1, or 2.

87 . The compound of claim 1 , wherein T is —CF 2 —; R 1 ′ is methyl; and R 1 ″ is H.

88 . The compound of claim 1 , wherein T is —CF 2 —; R 1 ′ is methyl; R 1 ″ is H; R D1 is —CO 2 H; and R D2 is H.

89 . The compound of claim 1 , wherein the compound has formula VI-A-i:

or a pharmaceutically acceptable salt thereof,

wherein:

T is an optionally substituted C 1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CO—, —CS—, —COCO—, —SO 2 —, —B(OH)—, or —B(O(C 1-6 alkyl))-;

R 1 ′ is H or an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy;

each R D1 and R D2 is —Z D R 9 , wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —;

R 9 is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; and

each R E is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

90 . The compound of claim 89 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-.

91 . The compound of claim 89 , wherein T is —CF 2 —.

92 . The compound of claim 89 , wherein R 1 ′ is an optionally substituted C 1-6 aliphatic.

93 . The compound of claim 89 , wherein R 1 ′ is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

94 . The compound of claim 89 , wherein R 1 ′ is methyl.

95 . The compound of claim 89 , wherein for R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —.

96 . The compound of claim 89 , wherein in R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —; and R 9 is hydrogen, halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl.

97 . The compound of claim 89 , wherein R D1 is —CO 2 H.

98 . The compound of claim 89 , wherein R D2 is H, R E , halo, —OH, —(CH 2 ) r NR E R E , —(CH 2 ) r —OR E , —SO 2 —R E , —NR E —SO 2 —R E , —SO 2 NR E R E , —C(O)R E , —C(O)OR E , —OC(O)OR E , —NR E C(O)OR E , and —C(O)NR E R E ; wherein r is 0, 1, or 2.

99 . The compound of claim 89 , wherein R D2 is H, methyl, ethyl, n-propyl, i-propyl, t-butyl, F, Cl, CN, —NH 2 , —CH 2 NH 2 , —OH, —OCH 3 , —O-ethyl, —O-(i-propyl), —O-(n-propyl), —CH 2 OH, —SO 2 CH 3 , —NH—SO 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OH, —NHC(O)CH 3 , —C(O)NH 2 , or —C(O)N(CH 3 ) 2 .

100 . The compound of claim 89 , wherein R D2 is H.

101 . The compound of claim 89 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; and R 1 ′ is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

102 . The compound of claim 89 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; R 1 ′ is methyl, ethyl, propyl, butyl, pentyl, or hexyl; and wherein in R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —; and R 9 is hydrogen, halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl.

103 . The compound of claim 89 , wherein T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 -, —B(OH)—, or —CH(OEt)-; R 1 ′ is methyl, ethyl, propyl, butyl, pentyl, or hexyl; wherein in R D1 , Z D is an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is replaced by —CO—, —SO—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —; R 9 is hydrogen, halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl; and R D2 is H, methyl, ethyl, n-propyl, i-propyl, t-butyl, F, Cl, CN, —NH 2 , —CH 2 NH 2 , —OH, —OCH 3 , —O-ethyl, —O-(i-propyl), —O-(n-propyl), —CH 2 OH, —SO 2 CH 3 , —NH—SO 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OH, —NHC(O)CH 3 , —C(O)NH 2 , or —C(O)N(CH 3 ) 2 .

104 . The compound of claim 89 , wherein T is —CF 2 — and R 1 ′ is methyl.

105 . The compound of claim 89 , wherein T is —CF 2 —; R 1 ′ is methyl; and R D1 is —CO 2 H.

106 . The compound of claim 1 , wherein the compound is selected from the following table:

1

2

3

4

5

7

8

9

10

11

13

14

15

16

17

18

19

21

22

23

25

26

27

28

30

31

32

34

35

36

38

39

42

43

44

45

46

47

48

51

54

55

56

57

58

59

60

61

64

66

67

68

70

72

73

74

75

76

77

78

79

81

82

83

84

85

89

90

93

94

95

97

100

101

102

103

106

108

109

111

112

117

118

119

120

121

122

123

124

125

126

127

129

131

132

133

134

135

136

137

140

141

143

146

148

151

154

156

157

158

159

160

161

162

163

168

172

173

175

176

177

178

180

182

184

197

199

203

205

208

212

218

232

233

234

241

244

249

256

261

263

267

268

270

273

275

276

285

287

292

304

306

307

311

312

316

325

330

332

335

336

338

339

342

344

347

358

360

364

366

368

373

376

385

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

410

411

412

414

415

417

418

419

420

421

422