Pyrimidine derivatives as CFTR modulators

• US 9,981,945 B2
• Filed: 10/06/2016
• Issued: 05/29/2018
• Est. Priority Date: 10/07/2015
• Status: Active Grant

• Current Assignee: Nubridge Biosciences
• Original Assignee: Nubridge Biosciences
• Inventors: Zhang, Lin, Ge, Yu
• Primary Examiner(s): Klinkel, Kortney L.
• Assistant Examiner(s): Bori, Ibrahim D
• Application Number:
  US15/287,542
• Publication Number:
  US 20170101395A1
• Time in Patent Office: 600 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, a 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 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 halogenated alkyl having 1 to 3 carbon atoms; 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 azepany 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 CF₃; 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 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 halogenated C_1-3 alkyl; 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.

5. The compound according to claim 4, 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 halogenated C_1-4 alkyl; 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.

6. 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 helogenated 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.

7. A pharmaceutical composition comprising a compound of claim 1 as an active pharmaceutical ingredient, and pharmaceutically acceptable carriers and adjuvants.

8. A CFTR modulator, wherein the CFTR modulator is a compound that is, 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.

9. A pharmaceutical composition comprising a compound of claim 8 as an active pharmaceutical ingredient, and pharmaceutically acceptable carriers and adjuvants.