Pyridine 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, a cyano, or a nitro group;

R 2 is a hydrogen, —NHR 6 , a halogen, a hydroxyl, a substituted or unsubstituted alkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, an amino, a cyano, or a nitro group;

R 3 is a halogenated alkyl;

R 4 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or an alkyl ammo, substituents on the substituted R 4 group are selected from the group consisting of a halogen, a cyano, an amino, a C 1-4 alkylamine, a C 1-4 alkyl, a C 3-6 cycloalkyl, an alkoxyl, a nitro, a carboxy, a carbonyl, a carboalkoxy, and an aminocarboxy;

R 5 is a hydrogen, —C(═O)—R 6 , a substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 6 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, an amino, or a substituted amino group;

R 7 is an optionally substituted C 1-8 hydrocarbon group, or a group described in the following formula:

or a group described in the following formula:

Wherein each of R 8 , R 9 , R 10 , R 11 is independently selected from a hydrogen, a halogenated C 1-8 alkyl, a hydroxyl substituted C 1-8 alkyl, a substituted or unsubstituted C 1-8 hydrocarbon group, and

each of R 12 , R 13 , R 14 is independently selected from a hydrogen, a halogen, an OR 15 , a NR 16 R 17 , a C(═O)N R 18 R 19 , or an optionally substituted C 1 -C 8 hydrocarbon group; or R 12 , R 13 and R 14 , together with the atoms to which they are attached, may be joined together to form a chain so that the ring to which they are attached is a substituted C 6 -C 14 membered spiral ring, a bicyclic ring, or a fused ring group, and

m1 is 2, 3, 4, or 5, and

m2 is 0, 1, or 2, and

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

Each of R 15 , R 16 , R 17 , R 18 , R 19 , is independently selected from a. hydrogen or an optionally substituted C 1 -C 8 hydrocarbon group.

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 group;

when the cyclic group on R 7 group is substituted, it has up to three substitutents, and each of the substituents 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 halogenated C 1-3 alkyl; 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, an alkoxy, a substituted amino, an alkyl, or a cycloalkyl.

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

R 4 is a substituted or unsubstituted phenyl, and the substituted phenyl group is substituted with 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 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 R7 group is substituted, it has up to three substituents 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 halogenated C 1-3 alkyl; and

R 4 is a substituted or unsubstituted phenyl, wherein the substituted phenyl group is substituted with up to three substituents that is a hydrogen, a cyano, a nitro, a halogen, a hydroxyl, an amino, an alkoxy, a substituted amino, an alkyl, or a cycloalkyl.

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 R7 group is substituted, it has up to three substituents 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;

R3 is CF3; and

R4 is a substituted or unsubstituted phenyl, and the substituted phenyl group is substituted with up to three substituents that is a hydrogen, 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;

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 R7 is a substituted C2-5 alkyl, the substituted R 7 group is substituted at any position on substituent with up to four substituents that is an ambo, an alkylamino, a hydroxy, a halogen, a methyl, an ethyl, a halogenated methyl, or a halogenated ethyl group;

is a hydrogen, or an amino,

R 2 is a hydrogen;

and

R4 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 according to claim 1 , wherein the CFTR modulator is a compound that is N-(4-azepan-4-yloxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-(piperidin-4-ylmethoxy)pyridin-3-yl)-5-(trifluoromethy)picolinamide hydrochloride, N-(4-(azetidin-3-ylmethoxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yloxy)pyridin-3-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluororomethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)-5-(trifluoromethyl)picolinamide, 3-amino-N-(4-(azepan-4-yloxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(4-(piperidin-4-ylmethoxy)pyridin-3-yl)-5-(trifluoromethy)picolinamide hydrochloride, 3-amino-N-(4-(azetidin-3-yltmethoxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yloxy)pyridin-3-yl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(4-(((1r,4r)-4-methylcyclohexyl)oxy)pyridin-3-yl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-phenyl-N-(4-(pyrrolidin-3-yloxy)pyridin-3-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-(3-amino-2-(chloromethyl)propoxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(4-(3-amino-2-(chloromethyl)propoxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4(3-amino-2-(hydroxymethyl)propoxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(4-(3-amino-2-(hydroxymethyl)propoxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-((3-aminocyclohexyl)oxy)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, or 3-amino-N-(4((3-aminocyclohexyl)oxy)pyridin-3-yl)-6-(2, 6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride.

10. A pharmaceutical composition according to claim 1 , comprising the compound of claim 1 as an active pharmaceutical ingredient, and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition according to claim 9 , comprising the compound of claim 9 as an active pharmaceutical ingredient, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 10 , further comprising one or more selected from the group consisting of antibiotics, antihistamines, anti-inflammatory agents, bronchodilatory agents, ENaC blockers, osmotic agents, and a combination thereof.

13. The pharmaceutical composition according to claim 11 , further comprising one or more selected from the group consisting of antibiotics, antihistamines, anti-inflammatory agents, bronchodilatory agents, ENaC blockers, osmotic agents, and a combination thereof.