PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

1 - 8 . (canceled)

9 . A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition wherein said pharmaceutical composition comprises a pharmaceutically acceptable carrier and:

A. A Compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

Each of WR W2 and WR W4 is independently selected from CN, CF 3 , halo, C 2-6 straight or branched alkyl, C 3-12 membered cycloaliphatic, phenyl, a 5-10 membered heteroaryl or 3-7 membered heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR W2 and WR W4 is independently and optionally substituted with up to three substituents selected from —OR′, —CF 3 , —OCF 3 , SR′, S(O)R′, SO 2 R′, —SCF 3 , halo, CN, —COOR′, —COR′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 )N(R′) 2 , —CON(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 )OR′, —CH 2 CN, optionally substituted phenyl or phenoxy, —N(R′) 2 , —NR′C(O)OR′, —NR′C(O)R′, —(CH 2 ) 2 N(R′) 2 , or —(CH 2 )N(R′) 2 ;

WR W5 is selected from hydrogen, —OCF 3 , —CF 3 , —OH, —OCH 3 , —NH 2 , —CN, —CHF 2 , —NHR′, —N(R′) 2 , —NHC(O)R′, —NHC(O)OR′, —NHSO 2 R′, —CH 2 OH, —CH 2 N(R′) 2 , —C(O)OR′, —SO 2 NHR′, —SO 2 N(R′) 2 , or —CH 2 NHC(O)OR′; and

Each R′ is independently selected from an optionally substituted group selected from a C 1-8 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;

provided that:

WR W2 and WR W4 are not both —Cl;

WR W2 , WR W4 and WR W5 are not —OCH 2 CH 2 Ph, —OCH 2 CH 2 (2-trifluoromethyl-phenyl), —OCH 2 CH 2 -(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl), or substituted 1H-pyrazol-3-yl;

and one or both of the following:

B. A Compound of Formula II

or pharmaceutically acceptable salts thereof, wherein:

T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, or —C(O)—;

R 1 ′ is H, C 1-6 aliphatic, halo, CF 3 , CHF 2 , O(C 1-6 aliphatic); and

R D1 or R D2 is Z D R 9

wherein:

Z D is a bond, CONH, SO 2 NH, SO 2 N(C 1-6 alkyl), CH 2 NHSO 2 , CH 2 N(CH 3 )SO 2 , CH 2 NHCO, COO, SO 2 , or CO; and

R 9 is H, C 1-6 aliphatic, or aryl; and/or

C. A Compound of Formula III

or pharmaceutically acceptable salts thereof, wherein:

R is H, OH, OCH 3 or two R taken together form —OCH 2 O— or —OCF 2 O—;

R 4 is H or alkyl;

R 5 is H or F;

R 6 is H or CN;

R 7 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH;

R 8 is H, OH, —CH 2 CH(OH)CH 2 OH, —CH 2 OH, or R 7 and R 8 taken together form a five membered ring.

10 . The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, 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's, 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, Osteoporosis, Osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia.

11 . The method of claim 10 , wherein the CFTR mediated disease is cystic fibrosis, COPD, emphysema, dry-eye disease or osteoporosis.

12 . The method of claim 11 , wherein the CFTR mediated disease is cystic fibrosis.

13 . The method according to claim 12 , wherein the patient possesses one or more of the following mutations of human CFTR: ΔF508, R117H, and G551D.

14 . The method according to claim 13 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR.

15 . The method according to claim 13 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR.

16 . The method according to claim 14 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR on at least one allele.

17 . The method according to claim 14 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR on both alleles.

18 . The method according to claim 15 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on at least one allele.

19 . The method according to claim 15 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on both alleles.

20 .- 22 . (canceled)

23 . The method of claim 9 , wherein the pharmaceutical composition comprises a compound of Formula I and a compound of Formula II.

24 . The method of claim 9 , wherein the pharmaceutical composition comprises a compound of Formula I and a compound of Formula III.

25 . The method of claim 9 , wherein the pharmaceutical composition comprises a compound of Formula I, a compound of Formula II, and a compound of Formula III.

26 . The method of claim 9 , wherein the pharmaceutical composition comprises a compound of Formula I, wherein said compound of Formula I is Compound 1

27 . The method of claim 9 , wherein the pharmaceutical composition comprises a compound of Formula II, wherein said compound of Formula II is Compound 2

28 . The method of claim 9 , wherein the pharmaceutical composition comprises a compound of Formula III, wherein said compound of Formula III is Compound 3

29 . A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition, wherein said pharmaceutical composition comprises a component selected from any embodiment described in Column A of Table I in combination with one or both of the following:

a) a component selected from any embodiment described in Column B of Table I; and/or

b) a component selected from any embodiment described in Column C of Table I.

TABLE I

Column A

Column B

Column C

Embodiments

Embodiments

Embodiments

Section

Heading

Section

Heading

Section

Heading

II.A.1.

Compounds of

II.B.1.

Compounds of

II.C.1.

Compounds of

Formula 1

Formula II

Formula III

II.A.2.

Compound 1

II.B.2.

Compound 2

II.C.2.

Compound 3

III.A.1.a.

Compound 1

III.B.1.a.

Compound 2

III.C.1.a.

Compound 3

Form C

Form I

Form A

IV.A.1.a.

Compound 1

III.B.2.a.

Compound 2

III.C.2.a.

Compound 3

First

Solvate

Amorphous

Formulation

Form A

Form

IV.A.2.a.

Compound 1

III.B.3.a.

Compound 2

IV.B.1.a.

Compound 3

Tablet and

HCl Salt

Tablet

SDD

Form A

Formulation

Formulation