# US 2014/0155431 A1 · Modulators of atp-binding cassette transporters

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- Number: US 2014/0155431 A1
- Document ID: US20140155431A1
- Status: Published application
- Kind: A1
- Application number: 14/135,204
- Filed: 2013-12-19
- Published: 2014-06-05
- Earliest claimed: 2004-06-24
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Vertex Pharmaceuticals Incorporated
- Inventors: Sara Hadida-Ruah; Anna Hazlewood; Peter Grootenhuis; Fredrick Van Goor; Ashvani Singh; Jinglan Zhou; Jason McCartney
- Web page: https://patentgrep.com/patent/US20140155431A1

## CPC

- C07D 471/10: Spiro-condensed systems
- A61K 8/4926: {having six membered rings}
- A61K 31/04: Nitro compounds
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/265: of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/4747: spiro-condensed
- A61K 31/538: ortho- or peri-condensed with carbocyclic ring systems
- A61K 31/5415: ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/10: of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 5/18: of the parathyroid hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/08: Bronchodilators
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 205/11: having nitro groups bound to carbon atoms of six-membered aromatic rings
- C07C 205/58: the carbon skeleton being further substituted by halogen atoms
- C07C 209/00: Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C 211/17: containing only non-condensed rings
- C07C 211/50: with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C 211/52: the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
- C07C 215/28: and containing six-membered aromatic rings
- C07C 215/70: with rings other than six-membered aromatic rings being part of the carbon skeleton
- C07C 215/76: of the same non-condensed six-membered aromatic ring
- C07C 215/78: containing at least two hydroxy groups bound to the carbon skeleton
- C07C 217/76: having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C 217/80: having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C 217/84: the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
- C07C 219/34: having amino groups and esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C 229/52: having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C 255/58: containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C 271/20: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 311/08: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/39: having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07D 209/04: Indoles; Hydrogenated indoles
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 209/12: Radicals substituted by oxygen atoms
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 209/18: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/20: substituted additionally by nitrogen atoms, e.g. tryptophane
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/94: containing carbocyclic rings other than six-membered
- C07D 209/96: Spiro-condensed ring systems
- C07D 213/20: Quaternary compounds thereof
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 215/227: only one oxygen atom which is attached in position 2
- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 215/38: Nitrogen atoms (nitro radicals C07D215/18)
- C07D 215/56: with oxygen atoms in position 4
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D 265/36: condensed with one six-membered ring
- C07D 279/16: condensed with one six-membered ring
- C07D 311/58: other than with oxygen or sulphur atoms in position 2 or 4
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- G01N 33/48728: {Investigating individual cells, e.g. by patch clamp, voltage clamp (investigating individual particles in general G01N15/10)}
- G01N 33/5035: {on sub-cellular localization}
- G01N 33/566: using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- C07C 2601/14: The ring being saturated
- C07C 2601/18: with a ring being at least seven-membered
- C07C 2602/10: the other ring being six-membered, e.g. tetraline
- C07C 2603/74: Adamantanes
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar1 has m substituents each independently selected from —WRW;
W is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, —NR′SO2NR′—;
RW is independently R′, halo, NO2, CN, CF3, or OCF3;
m is 0-5;
each of R1, R2, R3, R4, and R5 is independently —X—RX;
X is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
RX is independently R′, halo, NO2, CN, CF3, or OCF3;
R6 is hydrogen, CF3, —OR′, —SR′, or an optionally substituted C1-8 aliphatic group;
R7 is hydrogen or a C1-6 aliphatic group optionally substituted with —X—RX;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 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;
provided that:
i) when R1, R2, R3, R4, R5, R6 and R7 are hydrogen, then Ar1 is not phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarboxylic acid phenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-methylphenyl, 3-carboxylic-acid phenyl, 2-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl, 2-ethylphenyl, or 4-ethoxycarbonylphenyl;
ii) when R1, R2, R3, R5, R6 and R7 are hydrogen, and R4 is methoxy, then Ar1 is not 2-fluorophenyl or 3-fluorophenyl;
iii) when R1, R3, R4, R5, R6 and R7 are hydrogen, R2 is 1,2,3,4-tetrahydroisoquinolin-1-yl-sulfonyl, then Ar1 is not 3-trifluoromethylphenyl;
iv) when R1, R2, R3, R4, R5 and R7 are hydrogen, R6 is methyl, then Ar1 is not phenyl;
v) when R1, R4, R5, R6 and R7 are hydrogen, R2 and R3, taken together, are methylenedioxy, then Ar1 is not 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo-benzothiazol-2-yl, 6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazol-2-yl.
vi) when R1, R4, R5, R6 and R7 are hydrogen, R2 and R3, taken together, are methylenedioxy, then Ar1 is not 4-substituted phenyl wherein said substituent is —SO2NHRxx, wherein Rxx is 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl;
vii) when R1, R2, R3, R4, R5, R6, and R7 are hydrogen, then Ar1 is not thiazol-2-yl, 1H-1,2,4-triazol-3-yl, or 1H-1,3,4-triazol-2-yl;
viii) when R1, R2, R3, R5, R6, and R7 are hydrogen, and R4 is CF3, OMe, chloro, SCF3, or OCF3, then Ar1 is not 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl, 1-methyl-1,2-(1H)-pyrazol-5-yl, pyridine-2-yl, phenyl, N-methyl-imidazol-2-yl, imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,3-oxazol-2-yl, or 1,3,5-(1H)-triazol-2-yl;
ix) when R1, R2, R3, R4, R5, R6, and R7 each is hydrogen, then Ar1 is not pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 4-methoxy-6-methyl-1,3,5-triazin-2-yl; 5-bromo-pyridin-2-yl, pyridin-2-yl, or 3,5-dichloro-pyridin-2-yl;
x) when R1, R2, R3, R4, R5 and R7 each is hydrogen, R6 is hydroxy, then Ar1 is not 2,6-dichloro-4-aminosulfonyl-phenyl;
xi) when R2 or R3 is an optionally substituted N-piperazyl, N-piperidyl, or N-morpholinyl, then Ar1 is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl, or indazolyl;
xii) when R2 is optionally substituted cyclohexylamino, then Ar1 is not optionally substituted phenyl, pyridyl, or thiadiazolyl;
xiii) Ar1 is not optionally substituted tetrazolyl;
xiv) when R2, R4, R5, R6, and R7 each is hydrogen, and R1 and R3 both are simultaneously CF3, chloro, methyl, or methoxy, then Ar1 is not 4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl, or [3,5-bis(trifluoromethyl)-1H-1-pyrazol-1-yl]phenyl;
xv) when R1, R4, R5, R6, and R7 each is hydrogen, and Ar1 is thiazol-2-yl, then neither R2 nor R3 is isopropyl, chloro, or CF3;
xvi) when Ar1 is 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl, then:
a) when R1, R2, R4, R5, R6, and R7 each is hydrogen, then R3 is not methoxy; or
b) when R1, R3, R4, R5, R6, and R7 each is hydrogen, then R2 is not chloro; or
c) when R1, R2, R3, R5, R6, and R7 each is hydrogen, then R4 is not methoxy; or
d) when R1, R3, R4, R6, and R7 each is hydrogen, and R5 is ethyl, then R2 is not chloro;
e) when R1, R2, R4, R5, R6, and R7 each is hydrogen, then R3 is not chloro;
xvi) when R1, R3, R4, R5, R6, and R7 each is hydrogen, and R2 is CF3 or OCF3, then Ar1 is not [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl;
xvii) when R1, R2, R4, R5, R6, and R7 each is hydrogen, and R3 is hydrogen or CF3, then Ar1 is not a phenyl substituted with —OCH2CH2Ph, —OCH2CH2(2-trifluoromethyl-phenyl), —OCH2CH2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl), or substituted 1H-pyrazol-3-yl; and
xviii) the following two compounds are excluded:

### Claim 2 (depends on 1)

The compound according to claim 1, wherein Ar1 is selected from:
wherein ring A1 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
A1 and A2, together, is an 8-14 aromatic, bicyclic or tricyclic aryl ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein A1 is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms, wherein said heteroatom is nitrogen.

### Claim 4 (depends on 2)

The compound according to claim 2, wherein A1 is an optionally substituted phenyl.

### Claim 5 (depends on 2)

The compound according to claim 2, wherein A2 is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 6 (depends on 2)

The compound according to claim 2, wherein A2 is an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 7 (depends on 2)

The compound according to claim 2, wherein A2 is a 5-membered aromatic ring having 1-2 nitrogen atoms.

### Claim 8 (depends on 2)

The compound according to claim 2, wherein A2 is selected from:
wherein ring A2 is fused to ring A1 through two adjacent ring atoms.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R5 and R6 is hydrogen.

### Claim 10 (depends on 9)

The compound according to claim 9, wherein R3 and R4 are simultaneously hydrogen; R1 is hydrogen or —OH; and R2 is hydrogen or fluoro.

### Claim 11 (depends on 10)

The compound according to claim 10, R7 is hydrogen.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein each occurrence of WRW is independently —C1-C3 alkyl, C1-C3 perhaloalkyl, —O(C1-C3 alkyl), —CF3, —OCF3, —SCF3, —F, —Cl, —Br, or —COOR′, —COR′, —O(CH2)2N(R′)(R′), —O(CH2)N(R′)(R′), —CON(R′)(R′), —(CH2)2OR′, —(CH2)OR′, optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfone, optionally substituted 5-membered heteroaryl ring, —N(R′)(R′), —(CH2)2N(R′)(R′), or —(CH2)N(R′)(R′).

### Claim 13 (depends on 12)

The compound according to claim 12, wherein each occurrence of WRW is selected from halo, cyano, CF3, CHF2, OCHF2, Me, Et, CH(Me)2, CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF3, SCHF2, SEt, CH2CN, NH2, NHMe, N(Me)2, NHEt, N(Et)2, C(O)CH3, C(O)Ph, C(O)NH2, SPh, SO2-(amino-pyridyl), SO2NH2, SO2Ph, SO2NHPh, SO2—N-morpholino, SO2—N-pyrrolidyl, N-pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2yl, furan-2-yl, 4-methyl-4H-[1,2,4]triazol-3-yl, 3-(4′-chlorophenyl)-[1,2,4]oxadiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph, NHSO2Me, 2-indolyl, 5-indolyl, —CH2CH2OH, —OCF3, O-(2,3-dimethylphenyl), 5-methylfuryl, —SO2—N-piperidyl, 2-tolyl, 3-tolyl, 4-tolyl, O-butyl, NHCO2C(Me)3, CO2C(Me)3, isopropenyl, n-butyl, O-(2,4-dichlorophenyl), NHSO2PhMe, O-(3-chloro-5-trifluoromethyl-2-pyridyl), phenylhydroxymethyl, 2,5-dimethylpyrrolyl, NHCOCH2C(Me)3, O-(2-tert-butyl)phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethyl phenyl, 4-dimethylaminophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-cyanomethylphenyl, 4-isobutylphenyl, 3-pyridyl, 4-pyridyl, 4-isopropylphenyl, 3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-methylthiophenyl, 4-methylthiophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF3-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 2-fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl, 5-isopropyl-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonyl phenyl, 3-isopropyloxycarbonylphenyl, 3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfinyl-phenyl, 4-methanesulfonyl-phenyl, 4-N-(2-N,N-dimethylaminoethyl)carbamoylphenyl, 5-acetyl-2-thienyl, 2-benzothienyl, 3-benzothienyl, furan-3-yl, 4-methyl-2-thienyl, 5-cyano-2-thienyl, N′-phenylcarbonyl-N-piperazinyl, —NHCO2Et, —NHCO2Me, —NHSO2(CH2)2N-piperidine, —NHSO2(CH2)2N-morpholine, —NHSO2(CH2)2N(Me)2, COCH2N(Me)COCH2NHMe, —CO2Et, O-propyl, —CH2CH2NHCO2C(Me)3, hydroxy, aminomethyl, pentyl, adamantyl, cyclopentyl, ethoxyethyl, C(Me)2CH2OH, C(Me)2CO2Et, —CHOHMe, CH2CO2Et, —C(Me)2CH2NHCO2C(Me)3, O(CH2)2OEt, O(CH2)2OH, CO2Me, hydroxymethyl, 1-methyl-1-cyclohexyl, 1-methyl-1-cyclooctyl, 1-methyl-1-cycloheptyl, C(Et)2C(Me)3, C(Et)3, CONHCH2CH(Me)2, 2-aminomethyl-phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyl, cyclohexyl, 4-methylpiperidinyl, —OCO2Me, —C(Me)2CH2NHCO2CH2CH(Me)2, —C(Me)2CH2NHCO2CH2CH2CH3, —C(Me)2CH2NHCO2Et, —C(Me)2CH2NHCO2Me, —C(Me)2CH2NHCO2CH2C(Me)3, —CH2NHCOCF3, —CH2NHCO2C(Me)3, —C(Me)2CH2NHCO2(CH2)3CH3, C(Me)2CH2NHCO2(CH2)2OMe, C(OH)(CF3)2, —C(Me)2CH2NHCO2CH2-tetrahydrofuran-3-yl, C(Me)2CH2O(CH2)2OMe, or 3-ethyl-2,6-dioxopiperidin-3-yl.

### Claim 14 (depends on 2)

The compound according to claim 2, wherein said compound has formula IIA or formula IIB:

### Claim 15 (depends on 2)

The compound according to claim 2, wherein said compound has formula IIIA, formula IIIB, formula IIIC, formula IIID, or formula IIIE:
wherein:
each of X1, X2, X3, X4, and X5 is independently selected from CH or N; and
X6 is O, S, or NR′.

### Claim 16 (depends on 15)

The compound according to claim 15, wherein X1, X2, X3, X4, and X5, taken together with WRW and m, is optionally substituted phenyl.

### Claim 17 (depends on 15)

The compounds according to claim 15, wherein X1, X2, X3, X4, and X5 taken together in compound of formula IIIA is an optionally substituted ring selected from:

### Claim 18 (depends on 15)

The compound according to claim 15, wherein X1, X2, X3, X4, X5, or X6, taken together with ring A2 in compounds of formula IIIB, formula IIIC, formula IIID, or formula IIIE, is an optionally substituted ring selected from:

### Claim 19 (depends on 15)

The compound according to claim 15, wherein said compound has formula IVA, formula IVB, or formula IVC:

### Claim 20 (depends on 19)

The compound according to claim 19, wherein ring A2 is an optionally substituted, saturated, unsaturated, or aromatic 5-7 membered ring with 0-3 heteroatoms selected from O, S, or N.

### Claim 21 (depends on 19)

The compound according to claim 19, wherein said compound has formula VA-1:
wherein each of WRW2 and WRW4 is independently selected from hydrogen, CN, CF3, halo, C1-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-C10 heteroaryl or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WRW2 and WRW4 is independently and optionally substituted with up to three substituents selected from —OR′, —CF3, —OCF3, SR′, S(O)R′, SO2R′, —SCF3, halo, CN, —COOR′, —COR′, —O(CH2)2N(R′)(R′), —O(CH2)N(R′)(R′), —CON(R′)(R′), —(CH2)2OR′, —(CH2)OR′, CH2CN, optionally substituted phenyl or phenoxy, —N(R′)(R′), —NR′C(O)OR′, —NR′C(O)R′, —(CH2)2N(R′)(R′), or —(CH2)N(R′)(R′); and
WRW5 is selected from hydrogen, —OH, NH2, CN, CHF2, NHR′, N(R)2, —NHC(O)R′, —NHC(O)OR′, NHSO2R′, —OR′, CH2OH, CH2N(R′)2, C(O)OR′, SO2NHR′, SO2N(R′)2, or CH2NHC(O)OR′. Or, WRW4 and WRW5 taken together form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, O, or S, wherein said ring is optionally substituted with up to three WRW substituents.

### Claim 22 (depends on 21)

The compound according to claim 21, wherein:
each of WRW2 and WRW4 is independently selected from hydrogen, CN, CF3, halo, C1-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, or phenyl, wherein said WRW2 and WRW4 is independently and optionally substituted with up to three substituents selected from —OR′, —CF3, —OCF3, —SCF3, halo, —COOR′, —COR′, —O(CH2)2N(R′)(R′), —O(CH2)N(R′)(R′), —CON(R′)(R′), —(CH2)2OR′, —(CH2)OR′, optionally substituted phenyl, —N(R′)(R′), —NC(O)OR′, —NC(O)R′, —(CH2)2N(R′)(R′), or —(CH2)N(R′)(R′); and
WRW5 is selected from hydrogen, —OH, NH2, CN, NHR′, N(R′)2, —NHC(O)R′, —NHC(O)OR′, NHSO2R′, —OR′, CH2OH, C(O)OR′, SO2NHR′, or CH2NHC(O)O—(R′).

### Claim 23 (depends on 22)

The compound according to claim 22, wherein:
WRW2 is a phenyl ring optionally substituted with up to three substituents selected from —OR′, —CF3, —OCF3, SR′, S(O)R′, SO2R′, —SCF3, halo, CN, —COOR′, —COR′, —O(CH2)2N(R′)(R′), —O(CH2)N(R′)(R′), —CON(R′)(R′), —(CH2)2OR′, —(CH2)OR′, CH2CN, optionally substituted phenyl or phenoxy, —N(R′)(R′), —NR′C(O)OR′, —NR′C(O)R′, —(CH2)2N(R′)(R′), or —(CH2)N(R′)(R′);
WRW4 is C1-C6 straight or branched alkyl; and
WRW5 is OH.

### Claim 24 (depends on 22)

The compound according to claim 22, wherein each of WRW2 and WRW4 is independently selected from CF3, halo, CN, or C1-C6 straight or branched alkyl.

### Claim 25 (depends on 24)

The compound according claim 24, wherein each of WRW2 and WRW4 is independently selected from optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-(ethoxycarbonyl)-ethyl, 1,1-dimethyl-3-(t-butoxycarbonyl-amino) propyl, or n-pentyl.

### Claim 26 (depends on 25)

The compound according claim 25, wherein each of WRW2 and WRW4 is C1-C6 straight or branched alkyl.

### Claim 27 (depends on 21)

The compound according to claim 21, wherein WRW5 is selected from hydrogen, CHF2, NH2, CN, NHR′, N(R′)2, CH2N(R′)2, —NHC(O)R′, —NHC(O)OR′, —OR′, C(O)OR′, or SO2NHR′.

### Claim 28 (depends on 21)

The compound according to claim 21, wherein WRW5 is selected from hydrogen, NH2, CN, CHF2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), —CH2NHC(O)O(C1-C6 alkyl), —NHC(O)O(C1-C6 alkyl), —OH, —O(C1-C6 alkyl), C(O)O(C1-C6 alkyl), CH2O(C1-C6 alkyl), or SO2NH2.

### Claim 29 (depends on 28)

The compound according to claim 28, wherein WRW5 is selected from —OH, OMe, NH2, —NHMe, —N(Me)2, —CH2NH2, CH2OH, NHC(O)OMe, NHC(O)OEt, CN, CHF2, —CH2NHC(O)O(t-butyl), —O-(ethoxyethyl), —O-(hydroxyethyl), —C(O)OMe, or —SO2NH2.

### Claim 30 (depends on 21)

The compound according to claim 21, wherein said compound has one, preferably more, or more preferably all, of the following features:
a. WRW2 is hydrogen;
b. WRW4 is C1-C6 straight or branched alkyl or monocyclic or bicyclic aliphatic; and
c. WRW5 is selected from hydrogen, CN, CHF2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), —NHC(O)O(C1-C6 alkyl), —CH2C(O)O(C1-C6 alkyl), —OH, —O(C1-C6 alkyl), C(O)O(C1-C6 alkyl), or SO2NH2.

### Claim 31 (depends on 21)

The compound according to claim 21, wherein said compound has one, preferably more, or more preferably all, of the following features:
a. WRW2 is halo, C1-C6 alkyl, CF3, CN, or phenyl optionally substituted with up to 3 substituents selected from C 1-C4 alkyl, —O(C1-C4 alkyl), or halo;
b. WRW4 is CF3, halo, C1-C6 alkyl, or C6-C10 cycloaliphatic; and
c. WRW5 is OH, NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl).

### Claim 32 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-A-2:
wherein:
Y is CH2, C(O)O, C(O), or S(O)2; and
m is 0-4.

### Claim 33 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-A-3:
wherein:
Q is W;
RQ is RW;
m is 0-4; and
n is 0-4.

### Claim 34 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-A-4:

### Claim 35 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-A-5:
wherein:
m is 0-4.

### Claim 36 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-A-6:
wherein:
ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences of -Q-RQ;
Q is W;
RQ is RW;
m is 0-4; and
n is 0-4.

### Claim 37 (depends on 36)

The compound according to claim 36, wherein ring B is a 5-7 membered monocyclic, heterocyclic ring having up to 2 heteroatoms selected from O, S, or N, optionally substituted with up to n occurrences of -Q-RQ.

### Claim 38 (depends on 36)

The compound according to claim 36, wherein ring B is a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroatoms selected from O, S, or N, optionally substituted with up to n occurrences of -Q-RQ.

### Claim 39 (depends on 36)

The compound according to claim 36, wherein ring B is selected from N-morpholinyl, N-piperidinyl, 4-benzoyl-piperazin-1-yl, pyrrolidin-1-yl, or 4-methyl-piperidin-1-yl, benzimidazol-2-yl, 5-methyl-furan-2-yl, 2,5-dimethyl-pyrrol-1-yl, pyridine-4-yl, indol-5-yl, indol-2-yl, 2,4-dimethoxy-pyrimidin-5-yl, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl-thien-2-yl, 5-cyano-thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl.

### Claim 40 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-B-1:
wherein:
one of Q1 and Q3 is N(WRW) and the other of Q1 and Q3 is selected from O, S, or N(WRW);
Q2 is C(O), CH2—C(O), C(O)—CH2, CH2, CH2—CH2, CF2, or CF2—CF2; and
m is 0-3.

### Claim 41 (depends on 40)

The compound according to claim 40, wherein Q3 is N(WRW), wherein WRW is hydrogen, C1-C6 aliphatic, C(O)C1-C6 aliphatic, or C(O)OC1-C6 aliphatic.

### Claim 42 (depends on 41)

The compound according to claim 41, wherein Q2 is C(O), CH2, CH2—CH2, and Q1 is O.

### Claim 43 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-B-2:
wherein:
RW1 is hydrogen or C1-C6 aliphatic;
each of RW3 is hydrogen or C1-C6 aliphatic; or
both RW3 taken together form a C3-C6 cycloalkyl or heterocyclic ring having up to two heteroatoms selected from O, S, or NR′, wherein said ring is optionally substituted with up to two WRW substituents; and
m is 0-4.

### Claim 44 (depends on 43)

The compound according to claim 43, wherein WRW1 is hydrogen, C1-C6 aliphatic, C(O)C1-C6 aliphatic, or C(O)OC1-C6 aliphatic.

### Claim 45 (depends on 43)

The compound according to claim 43, wherein each RW3 is hydrogen, C1-C4 alkyl; or both RW3 taken together form a C3-C6 cycloaliphatic ring or 5-7 membered heterocyclic ring having up to two heteroatoms selected from O, S, or N, wherein said cycloaliphatic or heterocyclic ring is optionally substituted with up to three substitutents selected from WRW1.

### Claim 46 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-B-3:
wherein:
Q4 is a bond, C(O), C(O)O, or S(O)2;
RW1 is hydrogen or C1-C6 aliphatic; and
m is 0-4.

### Claim 47 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-B-4:
wherein:
m is 0-4.

### Claim 48 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-B-5:
wherein:
ring A2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WRW; and
m is 0-4.

### Claim 49 (depends on 48)

The compound according to claim 48, wherein ring A2 is selected from:
wherein said ring is optionally substituted.

### Claim 50 (depends on 19)

The compound according to claim 19, wherein said compound has formula V-B-5-a:
wherein:
G4 is hydrogen, halo, CN, CF3, CHF2, CH2F, optionally substituted C1-C6 aliphatic, aryl-C1-C6 alkyl, or a phenyl, wherein G4 is optionally substituted with up to 4 WRW substituents; wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—.;
G5 is hydrogen or an optionally substituted C1-C6 aliphatic;
wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRW.

### Claim 51 (depends on 50)

The compound according to claim 50, wherein G4 is hydrogen, and G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 alkyl, halo, cyano, or CF3, and wherein up to two methylene units of said C 1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—.

### Claim 52 (depends on 50)

The compound according to claim 50, wherein G4 is hydrogen, and G5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH2C(O)OMe, (CH2)2—NHC(O)O-tert-But, or cyclopentyl.

### Claim 53 (depends on 50)

The compound according to claim 50, wherein G5 is hydrogen, and G4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—.

### Claim 54 (depends on 50)

The compound according to claim 50, wherein G5 is hydrogen, and G4 is halo, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C(O)NH(CH2)2—NMe2)-phenyl, 2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, or piperidin-1-ylcarbonyl.

### Claim 55 (depends on 1)

The compound according to claim 1, wherein said compound is selected from Table 1.

### Claim 56

A compound having formula A-I:
or a salt thereof;
wherein:
G1 is hydrogen, R′, C(O)R′, C(S)R′, S(O)R′, S(O)2R′, Si(CH3)2R′, P(O)(OR′)3, P(S)(OR′)3, or B(OR′)2;
G2 is halo, CN, CF3, isopropyl, or phenyl wherein said isopropyl or phenyl is optionally substituted with up to 3 substituents independently selected from WRW, wherein W and RW are as defined above for formula I and embodiments thereof;
G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from WRW, wherein W and RW are as defined above for formula I and embodiments thereof;
provided that when G1 is methoxy, G3 is tert-butyl, then G2 is not 2-amino-4-methoxy-5-tert-butyl-phenyl.

### Claim 57 (depends on 56)

The compound according to claim 56, wherein:
G1 is hydrogen;
G2 is halo or isopropyl, wherein said isopropyl is optionally substituted with up to 3 substituents independently selected from R′; and
G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R′.

### Claim 58 (depends on 57)

The compound according to claim 57, wherein:
G1 is hydrogen;
G2 is halo, preferably fluoro; and
G3 is a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from methyl, ethyl, propyl, or butyl.

### Claim 59 (depends on 56)

The compound according to claim 56, wherein:
G1 is hydrogen;
G2 is CN, halo, or CF3; and
G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R′.

### Claim 60 (depends on 56)

The compound according to claim 56, wherein:
G1 is hydrogen;
G2 is phenyl is optionally substituted with up to 3 substituents independently selected from —OC1-C4 alkyl, CF3, halo, or CN; and
G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R′.

### Claim 61 (depends on 56)

The compound according to claim 56, wherein G3 is selected from optionally substituted cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

### Claim 62 (depends on 56)

The compound according to claim 56, wherein G3 is C3-C8 branched aliphatic chain.

### Claim 63

A compound having formula A-II:
or a salt thereof, wherein:
G4 is hydrogen, halo, CN, CF3, CHF2, CH2F, optionally substituted C1-C6 aliphatic, aralkyl, or a phenyl ring optionally substituted with up to 4 WRW substituents;
G5 is hydrogen or an optionally substituted C1-C6 aliphatic;
provided that both, G4 and G5, are not simultaneously hydrogen;
wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRW.

### Claim 64 (depends on 63)

The compound according to claim 63, wherein G4 is hydrogen, and G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 alkyl, halo, cyano, or CF3, and wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—.

### Claim 65 (depends on 63)

The compound according to claim 63, wherein G4 is hydrogen, and G5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH2C(O)OMe, (CH2)2—NHC(O)O-tert-But, or cyclopentyl.

### Claim 66 (depends on 63)

The compound according to claim 63, wherein G5 is hydrogen, and G4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—.

### Claim 67 (depends on 63)

The compound according to claim 63, wherein G5 is hydrogen, and G4 is halo, CF3, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH2)2—NMe2, 2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, or piperidin-1-ylcarbonyl.

### Claim 68 (depends on 1)

A pharmaceutical composition comprising a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier or adjuvant.

### Claim 69 (depends on 68)

The composition according to claim 68, wherein said composition comprises an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR modulator, or a nutritional agent.

### Claim 70

A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar1 has m substituents each independently selected from WRW;
W is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, —NR′SO2NR′—;
RW is independently R′, halo, NO2, CN, CF3, or OCF3;
m is 0-5;
each of R1, R2, R3, R4, and R5 is independently —X—RX;
X is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
RX is independently R′, halo, NO2, CN, CF3, or OCF3;
R6 is hydrogen, CF3, —OR′, —SR′, or an optionally substituted C1-8 aliphatic group;
R7 is hydrogen or a C1-6 aliphatic group optionally substituted with —X—RX;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 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.

### Claim 71 (depends on 70)

The method according to claim 70, wherein said ABC transporter is CFTR.

### Claim 72 (depends on 70)

A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, said method comprising the step of administering to said patient an effective amount of a compound of formula I according to claim 70.

### Claim 73 (depends on 70)

A kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising:
(i) a composition comprising a compound of formula (I) according to claim 70;
(ii) instructions for:
a) contacting the composition with the biological sample;
b) measuring activity of said ABC transporter or a fragment thereof.

### Claim 74 (depends on 73)

The kit of claim 73, further comprising instructions for
a) contacting an additional composition with the biological sample;
b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and
c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I).

### Claim 75 (depends on 74)

The kit of claim 74, wherein the kit is used to measure the density of CFTR.