Isothiazole derivatives as CFTR modulators

1. A compound having a structure of Formula II, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein R 1 is a hydrogen, —NHR 5 , a halogen, a hydroxyl, an alkyl having 1 to 5 carbon atoms, a cyano, or a nitro;

R 2 is a hydrogen, a halogen, a hydroxyl, an alkyl having 1 to 5 carbon atoms, an amino, a cyano, or a nitro group;

R 3 is a halogen, a hydroxyl, a halogenated alkyl having 1 to 5 carbon atoms, an alkoxyl being optionally substituted with a halogen, an amino, a cyano, or a nitro group;

R 4 is a 4 to 8 membered optionally substituted aryl, heteroaryl, cycloalkyl, or heterocyclyl, and the hetero atom on the heteroaryl or heterocyclyl is a nitrogen, an oxygen, or a sulfur; R 4 is optionally substituted by one or more group that is a halogen, a hydroxyl, a cyano, an amino, a C 1-4 alkylamine, a C 1-4 alkyl, a C 3-6 cycloalkyl, a C 1-4 alkoxyl, a nitro, a carboxy, a carbonyl, or a C 1-4 carboalkoxy;

R 5 is a hydrogen or an alkyl having 1 to 5 carbon atoms;

R 7 is an alkyl having 1 to 8 carbon atoms and being optionally substituted by an amino, a hydroxyl, a halogen, a methyl, an ethyl, a halogenated methyl, or a halogenated ethyl,

or a group having a formula:

or a group having a formula:

Wherein each of R 8 and R 9 is a hydrogen, a halogen, or a hydroxyl;

each of R 10 and R 11 is independently selected from a hydrogen or an alkyl having 1 to 3 carbon atoms, and

m1 is 2, 3, 4, or 5,

m2 is 0, 1, or 2,

Ring A is a 4 to 8 membered optionally substituted aryl, heteroaryl, or cycloalkyl, and the heteroaryl has 1 or 2 hetero atoms that are independently selected from an oxygen, a nitrogen, or a sulfur, and

each of R 12 , R 13 , R 14 is independently selected from a hydrogen, a halogen, a hydroxyl group, an amino, or an alkyl group having 1 to 5 carbon atoms.

2. The compound according to claim 1 , wherein R 7 is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidyl, pyrrolidinyl, piperidinyl, azepanyl, oxetyl, tetrahydrofuryl, or tetrahydropyranyl, and the cyclic group on R 7 is optionally substituted with up to three substitutents, and each of the substitutent is an amino, a hydroxy, or a methyl;

R 1 is a hydrogen, an amino, or a fluoro;

R 2 is a hydrogen, a halogen, or a methyl;

R 3 is a halogen, a hydroxyl, a halogenated C 1-3 alkyl, an alkoxyl having 1 to 3 carbon atoms and being optionally substituted with a halogen, an amino, a cyano, or a nitro group; and

R 4 is a substituted or unsubstituted phenyl, wherein the substituted phenyl group is substituted with up to three substituents that is a cyano, a nitro, a halogen, a hydroxyl, an amino, a C 1-4 alkylamine, an alkyl having 1 to 4 carbon atoms, or a cycloalkyl having 3 to 6 carbon atoms.

3. The compound according to claim 2 , wherein R 7 is a substituted or unsubstituted cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, or azepanyl group;

when the cyclic group on R 7 group is substituted, it has up to three substitutents that is an amino, a hydroxy, or a methyl;

R 1 is a hydrogen, an amino, or a fluoro;

R 2 is a hydrogen, a halogen, or a methyl;

R 3 is a halogen, a methoxyl, a CF 3 , or a OCF3; and

R 4 is a substituted or unsubstituted phenyl, and the substituted phenyl group is substituted with up to three substituents that is a cyano, a nitro group, a halogen, or a hydroxyl.

4. The compound according to claim 3 , wherein R 1 is a hydrogen or an amino; R 2 is hydrogen; R 3 is a halogen; R 4 is a substituted or unsubstituted phenyl, and the substituted phenyl is substituted with up to three substituents that is a halogen.

5. The compound according to claim 1 , wherein R 7 is a substituted or unsubstituted cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, azetidylmethyl, pyrrolidinylmethyl, piperidinylmethyl, azepanylmethyl, oxetylmethyl, tetrahydrofurylmethyl, or tetrahydropyranylmethyl group;

when the cyclic group on R 7 group is substituted, it has up to three substitutents that is an amino, a hydroxy, or a methyl;

R 1 is a hydrogen, an amino, or a fluoro;

R 2 is a hydrogen, a halogen, or a methyl;

R 3 is a halogen, a hydroxyl, a halogenated C 1-3 alkyl, alkoxyl having 1 to 3 carbon atoms and being optionally substituted with a halogen, an amino, a cyano, or a nitro group; and

R 4 is a substituted or unsubstituted phenyl, wherein the substituted phenyl group is substituted with up to three substituents that is a cyano, a nitro, a halogen, a hydroxyl, an amino, a C 1-4 alkylamine, an alkyl having 1 to 4 carbon atoms, or a cycloalkyl having 3 to 6 carbon atoms.

6. The compound according to claim 5 , wherein R 7 is a substituted or unsubstituted cyclohexylmethyl, cycloheptyl, pyrrolidinylmethyl, piperidinylmethyl, or azepanylmethyl group,

when the cyclic group on R 7 is substituted, it has up to three substitutents that is an amino, a hydroxy, or a methyl;

R 1 is a hydrogen, an amino, or a fluoro;

R 2 is a hydrogen, a halogen, or a methyl;

R 3 is a halogen, a methoxyl, a CF 3 , or an OCF3; and

R 4 is a substituted or unsubstituted phenyl, and the substituted phenyl group is substituted with up to three substituents that is a cyano, a nitro group, a halogen, or a hydroxyl.

7. The compound according to claim 6 , wherein R 1 is a hydrogen or an amino;

R 2 is hydrogen;

R 3 is a halogen; and

R 6 is a substituted or unsubstituted phenyl, and the substituted phenyl is substituted with up to three substituents that is a halogen.

8. The compound according to claim 1 , wherein R 7 is a substituted C 2-5 alkyl,

the substituted R 7 group is substituted at any position with up to four substitutents that is an amino, a halogen, a methyl, an ethyl, a halogenated methyl, or a halogenated ethyl;

R 1 is a hydrogen or an amino;

R 2 is a hydrogen;

R 3 is a halogen; and

R 4 is a substituted or unsubstituted phenyl, and the substituted phenyl is substituted with up to three substituents that is a halogen.

9. A CFTR modulator, wherein the CFTR modulator is

a compound that is 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide hydrochloride, N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-yloxy)isothiazol-4-yl)picolinamide hydrochloride, N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide hydrochloride, N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(5-(3-aminopropoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-(methylamino)propoxy)isothiazol-4-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(5-(3-(dimethylamino)propoxy)isothiazol-4-yl)-5-fluoropicolinamide hydrochloride, N-(5-(4-aminobutoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-(methylamino)butoxy)isothiazol-4-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxypropoxy)isothiazol-4-yl)picolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxybutoxy)isothiazol-4-yl)picolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-hydroxybutoxy)isothiazol-4-yl)picolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-((4-hydroxy-4-methylpentyl)oxy)isothiazol-4-yl)picolinamide, 6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxybutoxy)isothiazol-4-yl)-5-fluoropicolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(5-((tetrahydro-2H-pyran-4-yl)methoxy)isothiazol-4-yl)picolinamide, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide hydrochloride, 3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide hydrochloride, N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide hydrochloride, 3-amino-N-(5-(4-aminobutoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-5-fluoro-6-phenyl-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide hydrochloride, 3-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)-[2,4′-bipyridine]-6-carboxamide hydrochloride, N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-3-fluoropicolinamide hydrochloride, N-(5-(azepan-4-yloxy)isothiazol-4-yl)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)picolinamide hydrochloride, N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(5-((tetrahydro-2H-pyran-4-yl)methoxy)isothiazol-4-yl)-5-(trifluoromethyl)picolinamide, 3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-phenyl-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(5-(3-amino-2-(hydroxymethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(5-(3-amino-2-(hydroxymethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(5-(3-amino-2-(hydroxymethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(5-(3-amino-2-(hydroxymethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, or 3-amino-N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride.

10. A method for treating a subject having a disease caused by loss of cystic fibrosis transmembrane conductance regulator protein-mediated ion transport according to claim 1 , comprising

administering to the subject a therapeutically effective amount of the compound as described in claim 1 ,

wherein the disease is cystic fibrosis in lungs, pancreas, gastrointestinal system, sinuses, reproductive system, and sweat glands.

11. A method for treating a subject having a disease caused by loss of cystic fibrosis transmembrane conductance regulator protein-mediated ion transport according to claim 9 , comprising

administering to the subject a therapeutically effective amount of the compound as described in claim 9 ,

wherein the disease is cystic fibrosis in lungs, pancreas, gastrointestinal system, sinuses, reproductive system, and sweat glands.

12. A pharmaceutical composition according to claim 1 , comprising the compound of claim 1 as an active pharmaceutical ingredient, and pharmaceutically acceptable carriers and adjuvants.

13. A pharmaceutical composition according to claim 9 , comprising the compound of claim 9 as an active pharmaceutical ingredient, and pharmaceutically acceptable carriers and adjuvants.

14. The pharmaceutical composition according to claim 12 , further comprising

antibiotics, antihistamines, anti-inflammatory agents, bronchodilatory agents, epithelial sodium channel blockers, osmotic agents, or a combination thereof.

15. The pharmaceutical composition according to claim 13 , further comprising

antibiotics, antihistamines, anti-inflammatory agents, bronchodilatory agents, epithelial sodium channel blockers, osmotic agents, or a combination thereof.