PYRIMIDINE DERIVATIVES AS CFTR MODULATORS

• US 20170101395A1
• Filed: 10/06/2016
• Published: 04/13/2017
• Est. Priority Date: 10/07/2015
• Status: Active Grant

• Current Assignee: Nubridge Biosciences
• Original Assignee: Nubridge Biosciences
• Inventors: ZHANG, Lin
• Granted Patent: US 9,981,945 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

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

The compound is useful as CFTR modulator. Further, a method of using the compound and pharmaceutical composition comprising the compound are provided for treating diseases in lungs, pancreas, gastrointestinal system, sinuses, reproductive system, and the sweat glands.

Claims

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

2. The compound according to claim 1, wherein R₇ is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidyl, pyrrolidinyl, piperidinyl, azepanyl, oxetyl, tetrahydrofuryl, or tetrahydropyranyl group;

when the cyclic group on R₇ group is substituted, it can have up to three substitutents that is an amino, a hydroxy, or a methyl;

R₁ is a hydrogen, an amino, or a fluoro;

R₂ is a hydrogen, a halogen, or a methyl;

R₃ is a halogen, a hydroxyl, a halogenated C_1-3 alkyl, a substituted or unsubstituted C_1-3 alkyl, alkenyl, alkynyl, alkoxyl, an amino, a cyano, or a nitro group; and

R₄ 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 R₇ is a substituted or unsubstituted cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, or azepanyl group;

when the cyclic group on R₇ group is substituted, it has up to three substitutents that is an amino, a hydroxy, or a methyl;

R₁ is a hydrogen, an amino, or a fluoro;

R₂ is a hydrogen, a halogen, or a methyl;

R₃ is a halogen, a methyl;

a methoxyl, a CF₃, or a OCF3; and

R₄ 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 R₁ is a hydrogen or an amino;

R₂ is hydrogen;

R₃ is a halogen;

R₄ 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 R₇ 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 substitutents that is an amino, a hydroxy, or a methyl;

R₁ is a hydrogen, an amino, or a fluoro;

R₂ is a hydrogen, a halogen, or a methyl;

R₃ is a halogen, a hydroxyl, a halogenated C_1-3 alkyl, a substituted or unsubstituted C_1-3 alkyl, alkenyl, alkynyl, alkoxyl, an amino, a cyano, or a nitro group; and

R₄ 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 R₇ 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 substitutents that is an amino, a hydroxy, or a methyl;

R₁ is a hydrogen, an amino, or a fluoro;

R₂ is a hydrogen, a halogen, or a methyl;

R₃ is a halogen, a methyl;

a methoxyl, a CF₃, or a OCF3; 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 R₁ is a hydrogen or an amino;

R₂ is hydrogen;

R₃ is a halogen; and

R₆ 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 C_2-5 alkyl,

the substituted R₇ group is substituted at any position on substituent with up to four substitutents that is an amino, an alkylamino, a hydroxy, a halogen, a methyl, an ethyl, a halogenated methyl, or a halogenated ethyl group;

R₁ is a hydrogen, or an amino;

R₂ is a hydrogen;

R₃ is a halogen; and

R₄ is a substituted or unsubstituted phenyl, and the substituted phenyl is substituted with up to three substituents that is a halogen.

10. A method for using the compound of claim 1, comprising

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

wherein the treatment is for treating diseases in lungs, pancreas, gastrointestinal system, sinuses, reproductive system, and the 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.

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

antibiotics, antihistamines, anti-inflammatory agents, bronchodilatory agents, ENaC blockers, osmotic agents, or a combination thereof.

9. A CFTR modulator, wherein the CFTR modulator is a compound that is 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-4-ylmethoxy)pyrimidin-5-yl)picolinamide hydrochloride, N-(4-(azetidin-3-ylmethoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-4-yloxy)pyrimidin-5-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(pyrrolidin-3-yloxy)pyrimidin-5-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-3-yloxy)pyrimidin-5-yl)picolinamide hydrochloride, N-(4-(azepan-4-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-3-ylmethoxy)pyrimidin-5-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(pyrrolidin-3-ylmethoxy)pyrimidin-5-yl)picolinamide hydrochloride, N-(4-(azetidin-3-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(4-((3-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(4-(3-aminopropoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(3-(methylamino)propoxy)pyrimidin-5-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-(3-(dimethylamino)propoxy)pyrimidin-5-yl)-5-fluoropicolinamide hydrochloride, N-(4-(4-aminobutoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(4-(methylamino)butoxy)pyrimidin-5-yl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(3-hydroxypropoxy)pyrimidin-5-yl)picolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(3-hydroxybutoxy)pyrimidin-5-yl)picolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(4-hydroxybutoxy)pyrimidin-5-yl)picolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-((4-hydroxy-4-methylpentyl)oxy)pyrimidin-5-yl)picolinamide, 6-(2,6-difluorophenyl)-N-(4-(3,4-dihydroxybutoxy)pyrimidin-5-yl)-5-fluoropicolinamide, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrimidin-5-yl)picolinamide, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-4-ylmethoxy)pyrimidin-5-yl)picolinamide, hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(4-(pyrrolidin-3-yloxy)pyrimidin-5-yl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-4-yloxy)pyrimidin-5-yl)picolinamide hydrochloride, 3-amino-N-(4-(azepan-4-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(4-(pyrrolidin-3-ylmethoxy)pyrimidin-5-yl)picolinamideyl)picolinamide hydrochloride, N-(4-((1-amino-3-chloropropan-2-yl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(4-(3-amino-2-(chloromethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-(azetidin-3-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-(azetidin-3-ylmethoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-((1-amino-3-chloropropan-2-yl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-(3-amino-2-(chloromethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-3-ylmethoxy)pyrimidin-5-yl)picolinamide hydrochloride, 3-amino-N-(4-(4-aminobutoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-((3-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-5-fluoro-6-phenyl-N-(4-(pyrrolidin-3-yloxy)pyrimidin-5-yl)picolinamide hydrochloride, 3-fluoro-N-(4-(piperidin-4-yloxy)pyrimidin-5-yl)-[2,4′

-bipyridine]-6-carboxamide hydrochloride, N-(4-(azepan-4-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-3-fluoropicolinamide hydrochloride, N-(4-(azepan-4-yloxy)pyrimidin-5-yl)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)picolinamide hydrochloride, N-(4-(azepan-4-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-(piperidin-4-ylmethoxy)pyrimidin-5-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-(azetidin-3-ylmethoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yloxy)pyrimidin-5-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 6-(2,6-difluorophenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrimidin-5-yl)-5-(trifluoromethyl)picolinamide, 3-amino-N-(4-(azepan-4-yloxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(4-(piperidin-4-ylmethoxy)pyrimidin-5-yl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(4-(azetidin-3-ylmethoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yloxy)pyrimidin-5-yl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-6-phenyl-N-(4-(pyrrolidin-3-yloxy)pyrimidin-5-yl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-(3-amino-2 (chloromethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(4-(3-amino-2-(chloromethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-(3-amino-2-(hydroxymethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, 3-amino-N-(4-(3-amino-2-(hydroxymethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride, N-(4-(3-amino-2-(hydroxymethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, 3-amino-N-(4-(3-amino-2-(hydroxymethyl)propoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, N-(4-((3-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride, or 3-amino-N-(4-((3-aminocyclohexyl)oxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-(trifluoromethyl)picolinamide hydrochloride.

11. A method for using the compound of claim 9, comprising

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

wherein the treatment is for treating diseases in lungs, pancreas, gastrointestinal system, sinuses, reproductive system, and the sweat glands.

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.

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

antibiotics, antihistamines, anti-inflammatory agents, bronchodilatory agents, ENaC blockers, osmotic agents, or a combination thereof.