PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

1 . A pharmaceutical composition comprising:

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:

iii) 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

B. A Compound of Formula II

or pharmaceutically acceptable salts thereof, wherein:

ring A is selected from:

R 1 is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ;

R 2 is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH;

R 3 is hydrogen, —CH 3 , —OCH 3 , or —CN;

provided that both R 2 and R 3 are not simultaneously hydrogen;

optionally in combination with one or both of:

C. A Compound of Formula III

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

D. A Compound of Formula IV

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.

2 . The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and Compound of Formula II.

3 . The pharmaceutical composition of any one of claims 1 - 2 , comprising Compound 1 and Compound 2.

4 . The pharmaceutical composition of any one of claims 1 - 3 , further comprising one or both of Compound 3 and/or Compound 4.

5 . The pharmaceutical composition of claim 4 , comprising Compound 1, Compound 2, and Compound 3.

6 . The pharmaceutical composition of claim 1 , comprising Compound 1, Compound 2, and Compound 4.

7 . The pharmaceutical composition of claim 4 , comprising Compound 1, Compound 2, Compound 3 and Compound 4.

8 . A pharmaceutical composition comprising at least one component from Column A of Table I, at least one component from Column B of Table 1, and optionally an additional component from one or both of Column C and/or Column D.

TABLE I

Column A

Column B

Column C

Column D

Embodiments

Embodiments

Embodiments

Embodiments

Section

Heading

Section

Heading

Section

Heading

Section

Heading

II.A.1.

Compounds

II.B.1.

Compounds

II.C.1.

Compounds

II.D.1.

Compounds

of Formula

of Formula

of Formula

of Formula

I

II

III

IV

II.A.2.

Compound 1

II.B.2.

Compound 2

II.C.2.

Compound 3

II.D.2.

Compound 4

III.A.1.a.

Compound 1

III.B.1.a.

Compound 2

III.C.1.a.

Compound 3

III.D.1.a.

Compound 4

Form C

Form A

Form I

Form A

IV.A.1.a.

Compound 1

III.B.2.a.

Compound 2

III.C.2.a.

Compound 3

III.D.2.a.

Compound 4

First

Form

Solvate

Amorphous

Formulation

A-HCL

Form A

Form

IV.A.2.a.

Compound 1

III.B.3.a.

Compound 2

III.C.3.a.

Compound 3

IV.C.1.a.

Compound 4

Tablet and SDD

Form

HCL Salt

Tablet

Formulation

B-HCL

Form A

Formulation

III.B.4.a.

Compound 2

IV.B.1.a.

Compound 3

Form B

Form I

Aqueous

Formulation

IV.B.2.a.

Compound 3

Form I

Capsule

Formulation

IV.B.3.a.

Compound 3

Form I

Tablet

Formulation

9 . The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1, the Column B Component is Compound 2, and the third Component is any of the embodiments listed in Column C of Table I.

10 . The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1, the Column B Component is Compound 2, and the third Component is any of the embodiments listed in Column D of Table I.

11 . The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1, the Column B Component is Compound 2, the third component is any of the embodiments listed in Column C of Table I, and the fourth Component is any of the embodiments listed in Column D of Table I.

12 . The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1, the Column B Component is Compound 2, and the third Component is Compound 3.

13 . The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1, the Column B Component is Compound 2, and the third Component is Compound 4.

14 . The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1, the Column B Component is Compound 2, the third component is Compound 3, and the fourth Component is Compound 4.

15 . A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to any one of claims 1 - 14 .

16 . The method of claim 15 , 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.

17 . The method of any one of claims 15 - 16 , wherein the CFTR mediated disease is cystic fibrosis, COPD, emphysema, dry-eye disease or osteoporosis.

18 . The method of any one of claims 15 - 17 , wherein the CFTR mediated disease is cystic fibrosis.

19 . The method according to any one of claims 15 - 18 , wherein the patient possesses one or more of the following mutations of human CFTR: ΔF508, R117H, and G551D.

20 . The method according to any one of claims 15 - 19 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR.

21 . The method according to any one of claims 15 - 20 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR.

22 . The method according to any one of claims 15 - 21 , 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.

23 . The method according to any one of claims 15 - 22 , 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.

24 . The method according to any one of claims 15 - 23 , 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.

25 . The method according to any one of claims 15 - 24 , 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.

26 . A kit for use in measuring the activity of a CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising:

(i) a pharmaceutical composition according to any one of claims 1 - 14 ;

(ii) instructions for:

a) contacting the composition with the biological sample;

b) measuring activity of said CFTR or a fragment thereof.

27 . The kit of claim 26 , further comprising instructions for

a) contacting an additional compound with the biological sample;

b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and

c) comparing the activity of said CFTR or fragment thereof in the presence of said additional compound with the activity of the CFTR or fragment thereof in the presence of a pharmaceutical composition according to any one of claims 1 - 14 .

28 . The kit of claim 27 , wherein the step of comparing the activity of said CFTR or fragment thereof provides a measure of the density of said CFTR or fragment thereof.