Pyridine and pyrazine derivatives for the treatment of CF, COPD and bronchiectasis

文档序号：491523 发布日期：2022-01-04 浏览：29次中文

阅读说明：本技术 用于治疗cf、copd和支气管扩张的吡啶和吡嗪衍生物 (Pyridine and pyrazine derivatives for the treatment of CF, COPD and bronchiectasis ) 是由 S·S·格兰特 B·黑德雷尔 T·兰格尼克尔 D·J·罗兰兹 R·M·斯特里特田现斌于 2020-06-08 设计创作，主要内容包括：本发明提供了吡啶和吡嗪衍生物,所述吡啶和吡嗪衍生物恢复或增强突变型和/或野生型CFTR治疗支气管扩张、囊性纤维化、原发性睫状运动障碍、慢性支气管炎、慢性阻塞性肺疾病、哮喘、呼吸道感染、肺癌、口腔干燥症和干燥性角膜结膜炎、或便秘(例如,IBS、IBD、阿片样物质引起的)的功能。还包括包含此类衍生物的药物组合物。(The present invention provides pyridine and pyrazine derivatives that restore or enhance the function of mutant and/or wild-type CFTR to treat bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory infections, lung cancer, xerostomia and keratoconjunctivitis sicca, or constipation (e.g., IBS, IBD, opioid induced). Pharmaceutical compositions comprising such derivatives are also included.)

1. A method for treating bronchiectasis, the method comprising:

An effective amount of at least one compound of formula (I),

or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

a is N or CR^4a；

R¹Is H; c optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c₂-C₈An alkenyl group; c₂-C₈An alkynyl group; c₃-C₁₀A cycloalkyl group; c₅-C₁₀A cycloalkenyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; halogen; SO (SO)₂NR⁸R⁹；SO₂R¹⁰(ii) a S-C optionally substituted by one or more halogen atoms₁-C₈An alkyl group; S-C₆-C₁₄An aryl group; CN; NR (nitrogen to noise ratio)¹¹R¹²；C(O)NR¹³R¹⁴；NR¹³SO₂R¹⁵；NR¹³C(O)R¹⁵、CO₂R¹⁵、-(C₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are each optionally substituted with one or more Z substituents;

R²is C₁-C₄A haloalkyl group;

R³and R^4aEach independently being H or optionally substituted by one or more halogensC substituted by elemental atoms₁-C₈An alkyl group;

R⁴is H, or C optionally substituted by one or more halogens₁-C₈An alkyl group;

R⁵is- (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR'; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; - (C)₀-C₄Alkyl) -CO₂R¹⁵；-(C₀-C₄Alkyl) -C₆-C₁₄Aryl or a-3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said- (C) ₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents;

R⁶is C optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c₃-C₁₀A cycloalkyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; OH; CN; halogen; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said cycloalkyl, cycloalkenyl, - (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents; or

R⁶Is H, and R⁵Is- (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR', C optionally substituted by one OR more halogen atoms₁-C₈An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; - (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl containsHaving at least one heteroatom selected from N, O and S; or- (C)₀-C₄Alkyl) -CO₂R¹⁵Wherein- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents; or

R⁴And R⁶Together with the carbon atom to which they are bonded form a 3 to 8 membered carbocyclic ring system; or

R⁴And R⁵Together form an oxo group (C ═ O) and R ⁶Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl are each optionally substituted with one or more Z substituents; or

R⁵And R⁶A 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S together with the carbon atoms to which they are bonded, wherein said ring system is optionally substituted with one or more Z substituents; or

R⁴And R⁵And R⁶Together with the carbon atom to which they are bonded form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents;

r' is H, or C optionally substituted with one or more halogens₁-C₈An alkyl group;

m is 0, 1, 2 or 3;

R⁸、R¹¹、R¹³and R¹⁷Each independently being H, C optionally substituted by one or more halogen atoms₁-C₈Alkyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₄Alkyl) -C₃-C₈A cycloalkyl group;

R⁹、R¹⁰、R¹²、R¹⁴、R¹⁵、R¹⁶and R¹⁸Each independently is H; c optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c₂-C₈An alkenyl group; c ₂-C₈An alkynyl group; c₃-C₁₀A cycloalkyl group; c₅-C₁₀A cycloalkenyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S, wherein said cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are each optionally substituted with one or more Z substituents; or

R⁸And R⁹、R¹¹And R¹²、R¹³And R¹⁴And R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached may form a 4-to 14-membered heterocyclyl optionally substituted with one or more Z substituents;

z is independently OH, aryl, O-aryl, benzyl, O-benzyl, optionally substituted by one or more OH groups or NH₂Radical substituted C₁-C₆Alkyl, C optionally substituted by one or more halogen atoms₁-C₆Alkyl, optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₆Alkoxy, NR¹⁸(SO₂)R²¹、(SO₂)NR¹⁹R²¹、(SO₂)R²¹、NR¹⁸C(O)R²¹、C(O)NR¹⁹R²¹、NR¹⁸C(O)NR¹⁹R²¹、NR¹⁸C(O)OR¹⁹、NR¹⁹R²¹、C(O)OR¹⁹、C(O)R¹⁹、SR¹⁹、OR¹⁹Oxo, CN, NO₂Halogen or a 3 to 14 membered heterocyclyl wherein said heterocyclyl contains at least one heteroatom selected from N, O and S;

R¹⁹and R²¹Each is independentThe ground is H; c₁-C₈An alkyl group; c₃-C₈A cycloalkyl group; c₁-C₄alkoxy-C₁-C₄An alkyl group; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -aryl; optionally substituted by a group selected from halogen, oxo, C ₁-C₆Alkyl and C (O) C₁-C₆Substituted by one or more radicals of alkyl radicals (C)₀-C₄Alkyl) -a 3 to 14 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -O-aryl; and optionally is selected from halogen, C₁-C₆Alkyl or C (O) C₁-C₆Substituted by one or more radicals of alkyl radicals (C)₀-C₄Alkyl) -O-3 to 14 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S; wherein said alkyl group is optionally substituted by one or more halogen atoms, C₁-C₄Alkoxy, C (O) NH₂、C(O)NHC₁-C₆Alkyl or C (O) N (C)₁-C₆Alkyl radical)₂Substitution; or

R¹⁹And R²¹Together with the nitrogen atom to which they are attached form a 5 to 10 membered heterocyclic group comprising one or more further heteroatoms selected from N, O and S, which heterocyclic group is optionally substituted with one or more substituents selected from: OH; halogen; an aryl group; a 5 to 10 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S; s (O)₂-an aryl group; s (O)₂-C₁-C₆An alkyl group; c optionally substituted by one or more halogen atoms₁-C₆An alkyl group; optionally substituted by one or more OH groups or C ₁-C₄Alkoxy-substituted C₁-C₆An alkoxy group; and C (O) OC₁-C₆Alkyl, wherein the aryl and heterocyclic substituents are themselves optionally substitutedC₁-C₆Alkyl radical, C₁-C₆Haloalkyl or C₁-C₆Alkoxy substitution.

2. The method of claim 1, wherein A is CR^4a。

3. The method of claim 1 or claim 2, wherein R¹Is C optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; halogen; NR (nitrogen to noise ratio)¹¹R¹²、C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -5 to 6 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents.

4. The method of any preceding claim, wherein R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; or a halogen.

5. The method of any one of claims 1 to 3, wherein R¹Is aryl, wherein aryl is phenyl optionally substituted with one or more Z substituents.

6. The method of any preceding claim, wherein R²Is CF₃。

7. The method of any preceding claim, wherein

R⁴Is H or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group;

R⁵is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; - (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR'; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the arylheterocyclyl is optionally substituted with one or more Z substituents;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; or- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl, wherein the aryl is optionally substituted with one or more Z substituents; or

R⁴And R⁶Together with the carbon atom to which they are bonded form a 3 to 6 membered carbocyclic ring system; or

R⁵And R⁶Together with the carbon atom to which they are bonded form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents;

m is 0 or 1;

R¹⁷and R¹⁸Each independently is H; c optionally substituted by one or more halogen atoms₁-C₈An alkyl group.

8. The method of any one of the preceding claims, wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms ₁-C₄An alkyl group; or C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R²is CF₃；

R³Is H, CH₃Or CF₃；

R⁴Is H or Me;

R^4ais H;

R⁵is-NR¹⁷R¹⁸Or OH, and

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

9. The method according to claim 1, wherein the compound is represented by (II),

or a pharmaceutically acceptable salt;

wherein

A is N or CR^4a；

R^aIs H or C₁-C₄An alkyl group;

R¹is C optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; halogen; NR (nitrogen to noise ratio)¹¹R¹²、C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -5 to 6 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents;

R₃is H or CH₃；

R¹⁰¹Is that

10. The method of any one of the preceding claims, wherein the bronchiectasis is cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis.

11. A method for the treatment of bronchiectasis, said method comprising administering an effective amount of a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide The compound of group (la) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

12. The method of claim 11, wherein the compound is 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof.

13. The method according to claim 11 or claim 12, wherein the bronchiectasis is cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis.

14. A method for inhibiting or reducing the level of colonization by at least one pathogenic bacterium in the lungs of a subject, the method comprising administering to the subject a compound of formula (I),

or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

a is N or CR^4a；

R²Is C₁-C₄A haloalkyl group;

R³and R^4aEach independently being H or C optionally substituted by one or more halogen atoms₁-C₈An alkyl group;

R⁴is H, or C optionally substituted by one or more halogens₁-C₈An alkyl group;

R⁵is- (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR'; c optionally substituted by one or more halogen atoms₁-C₈Alkoxy radicalA group; - (C)₀-C₄Alkyl) -CO₂R¹⁵；-(C₀-C₄Alkyl) -C₆-C₁₄Aryl or a-3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents;

R⁶Is H, and R⁵Is- (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR', C optionally substituted by one OR more halogen atoms ₁-C₈An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; - (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; or- (C)₀-C₄Alkyl) -CO₂R¹⁵Wherein- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents; or

R⁴And R⁶Together with the carbon atom to which they are bonded form a 3-to 8-membered ringA carbocyclic ring system; or

R⁴And R⁵Together form an oxo group (C ═ O) and R⁶Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl are each optionally substituted with one or more Z substituents; or

R' is H, or C optionally substituted with one or more halogens₁-C₈An alkyl group;

m is 0, 1, 2 or 3;

R⁹、R¹⁰、R¹²、R¹⁴、R¹⁵、R¹⁶and R¹⁸Each independently is H; c optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c₂-C₈An alkenyl group; c₂-C₈An alkynyl group; c₃-C₁₀A cycloalkyl group; c₅-C₁₀A cycloalkenyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S, wherein said cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are each optionally substituted with one or more Z substituents; or

z is independently OH, aryl, O-aryl, benzyl, O-benzyl, optionally substituted by one or more OH groups or NH₂Radical substituted C₁-C₆Alkyl, C optionally substituted by one or more halogen atoms₁-C₆Alkyl, optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₆Alkoxy, NR¹⁸(SO₂)R²¹、(SO₂)NR¹⁹R²¹、(SO₂)R²¹、NR¹⁸C(O)R²¹、C(O)NR¹⁹R²¹、NR¹⁸C(O)NR¹⁹R²¹、NR¹⁸C(O)OR¹⁹、NR¹⁹R²¹、C(O)OR¹⁹、C(O)R¹⁹、SR¹⁹、OR¹⁹Oxo, CN, NO ₂Halogen or a 3 to 14 membered heterocyclyl wherein said heterocyclyl contains at least one heteroatom selected from N, O and S;

R¹⁹and R²¹Each independently is H; c₁-C₈An alkyl group; c₃-C₈A cycloalkyl group; c₁-C₄alkoxy-C₁-C₄An alkyl group; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -aryl; (C)₀-C₄Alkyl) -3 to 14 membered heterocyclic group, said heterocyclic group comprisingContaining one or more heteroatoms selected from N, O and S, optionally substituted by a group selected from halogen, oxo, C₁-C₆Alkyl and C (O) C₁-C₆One or more groups of alkyl are substituted; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -O-aryl; and (C)₀-C₄Alkyl) -O-3 to 14 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S, optionally substituted by a group selected from halogen, C₁-C₆Alkyl or C (O) C₁-C₆One or more groups of alkyl are substituted; wherein said alkyl group is optionally substituted by one or more halogen atoms, C₁-C₄Alkoxy, C (O) NH₂、C(O)NHC₁-C₆Alkyl or C (O) N (C)₁-C₆Alkyl radical)₂Substitution; or

R¹⁹And R²¹Together with the nitrogen atom to which they are attached form a 5 to 10 membered heterocyclic group comprising one or more further heteroatoms selected from N, O and S, which heterocyclic group is optionally substituted with one or more substituents selected from: OH; halogen; an aryl group; a 5 to 10 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S; s (O) ₂-an aryl group; s (O)₂-C₁-C₆An alkyl group; c optionally substituted by one or more halogen atoms₁-C₆An alkyl group; optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₆An alkoxy group; and C (O) OC₁-C₆Alkyl, wherein the aryl and heterocyclic substituents are themselves optionally substituted by C₁-C₆Alkyl radical, C₁-C₆Haloalkyl or C₁-C₆Alkoxy substitution.

15. A method for inhibiting or reducing the level of colonization by at least one pathogenic bacterium in the lung of a subject in need thereof, the method comprising administering an effective amount of a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof, is administered to the subject, optionally wherein the level of at least one pathogenic bacterium is measured in a sputum sample obtained from the subject, optionally wherein the level of at least one pathogenic bacterium is measured by 16S rRNA PCR.

16. The method according to claim 14 or claim 15, wherein the pathogenic bacteria are non-fermenting gram-negative bacteria.

17. The method according to any one of claims 14 to 16, wherein the pathogenic bacteria are selected from the group consisting of: moraxella catarrhalis (m.catarrhalis), staphylococcus aureus (s.aureus), Enterobacteriaceae (Enterobacteriaceae), stenotrophomonas Maltophilia (stenotrophomonas Maltophilia), haemophilus parainfluenzae (haemophilus parainfluenzae), haemophilus influenzae (haemophilus influenzae), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Moraxella (Moraxella), and Streptococcus pneumoniae (Streptococcus pneumoniae).

18. The method of any one of claims 14 to 17, wherein the level of colonization by pathogenic bacteria is reduced by at least one log.

19. A method for reducing the level of fibrinogen in the blood of a subject in need thereof, such as a bronchodilatory subject, the method comprising administering an effective amount of a compound selected from the group consisting of ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof is administered to the subject.

20. The method according to any one of the preceding claims, wherein the method further comprises:

a. reducing the use of a rescue medication (e.g., salbutamol/albuterol or a systemic antibiotic) by the subject when compared to a subject not administered the compound;

b. reducing the severity of exacerbations in a subject when compared to a subject not administered the compound;

c. increasing one or more of improved lung function or forced lung capacity of the subject, e.g., as measured by a spirometry, when compared to a patient not administered the compound; or

d. Any combination thereof.

21. The method of any one of claims 14 to 20, wherein the subject in need thereof is a bronchodilatory subject.

22. The method of any one of the preceding claims, wherein the compound is administered in an amount between about 300mg b.i.d. and about 450mg b.i.d., such as in an amount of 300mg b.i.d. or 450mg b.i.d..

23. The method of any one of the preceding claims, wherein the compound is administered to the subject in an amount of about 300mg b.i.d.

24. The method of any one of the preceding claims, wherein the compound is administered orally.

25. The method of any one of the preceding claims, wherein the compound is administered to the subject without a high fat meal.

26. The method of any one of the preceding claims, wherein the compound is administered in combination with at least one additional therapy.

27. The method of claim 26, wherein the additional therapy comprises:

a. long-acting beta agonists (LABA);

b. long Acting Muscarinic Antagonists (LAMA);

c. inhaled Corticosteroids (ICS);

d. a macrolide;

e. (ii) an antibiotic;

f. short Acting Muscarinic Antagonists (SAMA); or

g. Any combination thereof.

28. The method of any one of the preceding claims, wherein the bronchodilation is characterized by a worsening of three or more symptoms lasting at least 48 hours.

29. The method of claim 28, wherein the symptom is selected from the group consisting of: cough, sputum volume and/or consistency, sputum purulence, shortness of breath and/or exercise endurance, fatigue and/or discomfort, and hemoptysis.

2. Field of the invention

The present invention relates to pyridine and pyrazine compounds, their preparation and use as medicaments. The invention also relates to the use thereof as a medicament for the treatment of bronchiectasis, Chronic Obstructive Pulmonary Disorder (COPD), Cystic Fibrosis (CF), chronic bronchitis, primary ciliary dyskinesia, respiratory infections or asthma.

3. Background of the invention

Cystic Fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), an epithelial cell anion channel involved in the activation of protein kinase a (pka) for salt and fluid transport in multiple organs, including the lung. Most CF mutations reduce the number of CFTR channels on the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or transduction mutations), or both. The present invention discloses compounds that restore or enhance the function of mutant and/or wild-type CFTR to treat bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory infections, lung cancer, xerostomia and keratoconjunctivitis sicca (keratojunctional sirie), or constipation (e.g., IBS, IBD, opioid induced).

Bronchiectasis is a chronic disease characterized by abnormal and permanent dilation of the bronchi, resulting in chronic cough, sputum production, and recurrent bacterial infections of the airways (Martinez-Garcia et al, Chest. [ american academy of thoracic physicians ] 8 months 2005; 128(2): 739-45; Wilson et al, Eur Respir J. [ european respiratory journal ] 8 months 1997; 10(8): 1754-60). Bronchiectasis is generally classified as cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis (King et al, Intern Med J. [ journal of medical science ] 200636 (11): 729-. Patients with bronchiectasis suffer from high morbidity due to frequent exacerbations, compromising quality of life and promoting tolerance to antibiotics, resulting in reduced lung function. There is also a high socioeconomic impact through frequent use of primary and secondary healthcare, where the economic burden is estimated to be similar to COPD (Polverino et al, Eur Respir J. [ european respiratory journal ]2017, 9 months and 9 days; 50 (3)). Age-adjusted mortality is approximately two-fold higher in patients with bronchiectasis compared to the general population (Quint et al, Eur Respir J. [ European respiratory journal ]2016 month 1; 47(1): 186-93). Patients with bronchiectasis have some similarities to those with CF, such as radiologic dilation of the airways, thickening of the bronchial walls, mucus plugging, and over-inflation.

The medical need for treatment of bronchiectasis is significantly unmet and there is currently no approved therapy for reducing exacerbations. The European Respiratory Society (ERS)2017 guidelines for adult bronchodilation management show that no other treatment is recommended beyond the treatment of acute exacerbation antibiotics (Polverino et al, Eur Respir J. [ European Respiratory journal ]2017, 9 months 9, 50 (3)).

A one log unit reduction in colony forming units of potentially pathogenic microorganisms in spontaneous sputum relative to baseline correlates with a significant reduction in the risk of exacerbations in patients with bronchiectasis of approximately 20%, which is considered clinically relevant (Chalmers et al, Am J Respir Crit Care Med. [ American journal of respiratory and Severe Care medicine ] 10/1/2012; 186(7): 657-65).

Recent evidence also suggests that the molecular mechanism of reduced mucociliary clearance (MCC) in bronchodilation may be involved in the dysfunction of wild-type and mutant CFTR (Amaral et al Trends Pharmacol Sci [ Trends in pharmacology science ]]Month 7, 2007; 334 to 41 parts by weight of 28 (7); see alsoEt al, BMC palm Med [ BMC Lung medicine]2018; 18:79). Bronchodilatory patients may also have components of ion channel dysfunction including CFTR (Amaral, et al, Trends Pharmacol Sci. [ pharmacologic Trends in science.) ]Month 7, 2007; 28(7):334-41). 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, referred to herein as compound a, is a potent CFTR potentiator that has been shown to lower MCC, resulting in reduced bacterial colonization, reduced small airway inflammation, improved lung function (FEV1), and ultimately less exacerbation in COPD patients. In addition, the data indicate that compound a reduces bacterial colonization and small airway inflammation by reducing fibrinogen levels in COPD patients. Compound a has also shown significant improvement in lung function (FEV1) in patients with CF after two weeks of treatment and significant improvement in patients with COPD after four weeks of treatment.

Compounds are disclosed that restore or enhance the function of mutant and/or wild-type CFTR in the treatment of bronchiectasis. In addition, the present invention discloses compounds that provide improved MCC, resulting in reduced bacterial colonization, reduced small airway inflammation, improved forced expiratory volume per second (FEV1), and ultimately less exacerbation, thereby treating bronchiectasis.

4. Summary of the invention

In one aspect, the present invention provides a method of treating bronchiectasis, the method comprising administering at least one compound according to formula (I):

Or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

a is N or CR^4a；

R²is C₁-C₄A haloalkyl group;

R³and R^4aEach independently being H or C optionally substituted by one or more halogen atoms₁-C₈An alkyl group;

R⁴is H, or C optionally substituted by one or more halogens₁-C₈An alkyl group;

R⁵is- (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR'; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; - (C)₀-C₄Alkyl) -CO₂R¹⁵；-(C₀-C₄Alkyl) -C₆-C₁₄Aryl or a-3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C) ₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents;

R⁶Is H, and R⁵Is- (CH)₂)_m-NR¹⁷R¹⁸、-(CH₂)_m-OR', C optionally substituted by one OR more halogen atoms₁-C₈An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; - (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; or- (C)₀-C₄Alkyl) -CO₂R¹⁵Wherein- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents; or

R⁴And R⁶Together with the carbon atom to which they are bonded form a 3 to 8 membered carbocyclic ring system; or

R⁴And R⁵Together form an oxo group (C ═ O) and R⁶Is C optionally substituted by one or more halogen atoms ₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl are each optionally substituted with one or more Z substituents; or

r' is H, or C optionally substituted with one or more halogens₁-C₈An alkyl group;

m is 0, 1, 2 or 3;

R⁹、R¹⁰、R¹²、R¹⁴、R¹⁵、R¹⁶and R¹⁸Each independently is H; c optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c₂-C₈An alkenyl group; c₂-C₈An alkynyl group; c₃-C₁₀A cycloalkyl group; c₅-C₁₀A cycloalkenyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; - (C) ₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S, wherein said cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are each optionally substituted with one or more Z substituents; or

R¹⁹and R²¹Each independently is H; c₁-C₈An alkyl group; c₃-C₈A cycloalkyl group; c₁-C₄alkoxy-C₁-C₄An alkyl group; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -aryl; (C)₀-C₄Alkyl) -3 to 14 membered heterocyclic group comprising one or more groups selected from N, O and S is optionally substituted by a hetero atom selected from halogen, oxo, C₁-C₆Alkyl and C (O) C₁-C₆One or more groups of alkyl are substituted; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -O-aryl; and (C)₀-C₄Alkyl) -O-3 to 14 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S, optionally substituted by a group selected from halogen, C₁-C₆Alkyl or C (O) C₁-C₆One or more groups of alkyl are substituted; wherein said alkyl group is optionally substituted by one or more halogen atoms, C₁-C₄Alkoxy, C (O) NH₂、C(O)NHC₁-C₆Alkyl or C (O) N (C)₁-C₆Alkyl radical)₂Substitution; or

R¹⁹And R²¹Together with the nitrogen atom to which they are attached form a 5 to 10 membered heterocyclic group comprising one or more further heteroatoms selected from N, O and S, which heterocyclic group is optionally substituted with one or more substituents selected from: OH; halogen; an aryl group; a 5 to 10 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S; s (O)₂-an aryl group; s (O)₂-C₁-C₆An alkyl group; c optionally substituted by one or more halogen atoms₁-C₆An alkyl group; optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₆An alkoxy group; and C (O) OC₁-C₆Alkyl, wherein the aryl and heterocyclic substituents are themselves optionally substituted by C ₁-C₆Alkyl radical, C₁-C₆Haloalkyl or C₁-C₆Alkoxy substitution.

Various embodiments of the invention are described herein. It is to be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments.

In embodiments of the invention as described anywhere herein, a is N.

In embodiments of the invention as described anywhere herein, a is CR^4a。

In embodiments of the invention as described anywhere herein, R¹Is selected from H; c optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; halogen; c₆-C₁₄An aryl group; - (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; and NR¹¹R¹²Wherein said aryl and heterocyclic groups are each optionally substituted with one or more Z substituents.

In embodiments of the invention as described anywhere herein, R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group. For example, -CH₃Or CF₃。

In embodiments of the invention as described anywhere herein, R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group. For example, -OCH ₃or-OCF₃。

In embodiments of the invention as described anywhere herein, R¹Is aryl, wherein aryl is phenyl optionally substituted with one or more Z substituents, specific examples being 4-fluorophenyl, 4-chloro-2-methylphenyl, or 2, 4-dichlorophenyl.

In embodiments of the invention as described anywhere herein, R¹Is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is pyridyl, optionally substituted with one or more Z substituents, a specific example being 1-methyl-4-pyridyl.

In embodiments of the invention as described anywhere herein, R¹Is Br, -CH₃、-CF₃、-OCH₃、-OCF₃4-fluorophenyl group, 4-chloro-2-methylphenyl group, or 2, 4-dichlorophenyl group.

In embodiments of the invention as described anywhere herein, R²Is CF₃CF₂-、(CF₃)₂CH-、CH₃-CF₂-、CF₃CF₂-、CF₃、CF₂H-、CH₃-CCl₂-、CF₃CFCClH-、CBr₃、CBr₂H-CF₃CF₂CHCF₃Or CF₃CF₂CF₂CF₂-。

In embodiments of the invention as described anywhere herein, R²Is CF₃。

In embodiments of the invention as described anywhere herein, R³Is H or methyl.

In further embodiments of the invention as described anywhere herein, R^4aIs H.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein R⁵The heteroatom is provided with two carbons from the amide nitrogen, wherein the heteroatom is oxygen or nitrogen.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

R⁴Is H, C optionally substituted by one or more halogen atoms₁-C₄Alkyl, or absent;

R⁵is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; - (CH)₂)_m-NR¹⁷R¹⁸；-(CH₂)_m-OR^’Or OH;

m is 0, or 1;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; OH; CN; halogen; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S, wherein said aryl and heterocyclyl are each optionally substitutedSubstituted with one or more Z substituents; or

R⁴And R⁵Together form an oxo group (C ═ O); or

R¹⁷and R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is halogen, C optionally substituted by one or more halogen atoms ₁-C₄Alkyl, or C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R²is C₁-C₄A haloalkyl group;

R³is H;

R⁴is H or Me;

R^4ais H;

R⁵is- (CH)₂)_m-NR¹⁷R¹⁸；-(CH₂)_m-OR^’(ii) a Or OH;

m is 0, or 1;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; or

R⁵And R⁶Together with the carbon atom to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents; and is

R¹⁷And R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is halogen, C optionally substituted by one or more halogen atoms₁-C₄Alkyl, or C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R²is C₁-C₄A haloalkyl group;

R³is H;

R^4ais H;

R⁴and R⁵Together form an oxo group (C ═ O); and is

R⁶Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl are each optionally substituted with one or more Z substituents.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group;

R²is C₁-C₄A haloalkyl group;

R³is H;

R⁴is H or Me;

R^4ais H;

R⁵is- (CH)₂)_m-NR¹⁷R¹⁸；-(CH₂)_m-OR^’(ii) a Or OH;

m is 0, or 1;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; or

R¹⁷And R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R²is C₁-C₄A haloalkyl group;

R³is H;

R⁴is H or Me;

R^4ais H;

R⁵is- (CH)₂)_m-NR¹⁷R¹⁸；-(CH₂)_m-OR; or OH;

m is 0, or 1;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; or

R¹⁷And R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; (ii) a

R²Is C₁-C₄A haloalkyl group;

R³is H;

R⁴is H or Me;

R^4ais H;

R⁵is-NR¹⁷R¹⁸(ii) a Or OH;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; or

R¹⁷And R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group;

R²is C₁-C₄A haloalkyl group;

R³is H;

R⁴is H or Me;

R^4ais H;

R⁵is-NR¹⁷R¹⁸(ii) a Or OH;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; and is

R¹⁷And R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms ₁-C₄An alkyl group.

Embodiments of the invention as defined above provide compounds according to formula (I), wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R²is C₁-C₄A haloalkyl group;

R³is H;

R⁴is H or Me;

R^4ais H;

R⁵is-NR¹⁷R¹⁸(ii) a Or OH;

R⁶is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group; and is

R¹⁷And R¹⁸Each independently is H; or C optionally substituted by one or more halogen atoms₁-C₄An alkyl group.

In an embodiment of the invention as described anywhere herein, wherein

Z is independently OH, optionally substituted by one or more OH groups or NH₂Radical substituted C₁-C₄Alkyl, C optionally substituted by one or more halogen atoms₁-C₄Alkyl, optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₄Alkoxy, NR¹⁹R²¹、C(O)OR¹⁹、C(O)R¹⁹、SR¹⁹、OR¹⁹、CN、NO₂Or halogen;

R¹⁹and R²¹Each independently is H; c₁-C₄An alkyl group; c₃-C₆A cycloalkyl group; or C₁-C₄alkoxy-C₁-C₄Alkyl, wherein all alkyl groups are optionally substituted with halogen.

In an embodiment of the invention as described anywhere herein, wherein

Z independentIs immediately OH, optionally substituted by one or more OH groups or NH₂Radical substituted C₁-C₄Alkyl, C optionally substituted by one or more halogen atoms ₁-C₄Alkyl, optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₄Alkoxy, C (O) OR¹⁹、C(O)R¹⁹、OR¹⁹CN, or halogen;

R¹⁹is H; c₁-C₄An alkyl group; c₃-C₆A cycloalkyl group; or C₁-C₄alkoxy-C₁-C₄Alkyl, wherein all alkyl groups are optionally substituted with halogen.

In an embodiment of the invention as described anywhere herein, wherein

Z is independently C optionally substituted with one or more halogen atoms₁-C₄Alkyl radical, C₁-C₄Alkoxy or halogen.

Another embodiment of the invention as described above provides a compound of formula (I) in the form of a substantially pure enantiomer having the R configuration.

Another embodiment of the invention as described above provides a compound of formula (I) in the form of a substantially pure enantiomer having the S configuration.

Another embodiment of the invention as described above provides that the bronchiectasis is cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis. In certain embodiments, the compound of formula (I) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered in combination with additional therapy. In certain embodiments, the additional therapy comprises: a) long-acting beta agonists (LABA); b) long Acting Muscarinic Antagonists (LAMA); c) inhaled Corticosteroids (ICS); d) a macrolide; e) (ii) an antibiotic; f) short Acting Muscarinic Antagonists (SAMA); or g) any combination thereof. In certain embodiments, the bronchodilation is characterized by a worsening of three or more symptoms lasting at least 48 hours. In certain embodiments, the symptom is selected from the group consisting of: cough, sputum volume and/or consistency, sputum purulence, shortness of breath and/or exercise endurance, fatigue and/or discomfort, and hemoptysis. In certain embodiments, the method further comprises: a) reducing the use of a rescue medication (e.g., salbutamol/albuterol or a systemic antibiotic) by the subject when compared to a subject not administered the compound; b) reducing the severity of exacerbations in a subject when compared to a subject not administered the compound; c) increasing one or more of improved lung function or forced lung capacity of the subject, e.g., as measured by a spirometry, when compared to a patient not administered the compound; or d) any combination thereof.

Another embodiment of the invention as described above provides that the compound of formula (I) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered in an amount between about 300mg b.i.d. and about 450mg b.i.d., such as 300mg b.i.d. or 450mg b.i.d. to the subject. In a specific embodiment, a compound of formula (I) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject in an amount of about 300mg b.i.d.. In yet another embodiment, the compound of formula (I) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered orally. In another embodiment, the compound of formula (I) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject without a high fat meal.

Another embodiment of the present invention provides a method of treating bronchiectasis, the method comprising administering to a subject in need thereof at least one compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein A, R is administered to a subject in need thereof¹、R²And R³Has the definition of formula (I), and

R¹⁰¹is that

In a further embodiment of the invention as described above, there are provided compounds according to formula (II) wherein a is CR^4aWherein R is^4aIs H.

In a further embodiment of the invention as described above, there is provided a compound according to formula (II), wherein R is ¹Is selected from H; c optionally substituted by one or more halogen atoms₁-C₄An alkyl group; c optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; halogen; c₆-C₁₄An aryl group; - (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; and NR¹¹R¹²Wherein said aryl and heterocyclic groups are each optionally substituted with one or more Z substituents.

In a further embodiment of the invention as described above, there is provided a compound according to formula (II), wherein R is¹Is C optionally substituted by one or more halogen atoms₁-C₄Alkyl, C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group; halogen; c₆An aryl group; or a 6 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S, wherein said aryl and heterocyclyl are each optionally substituted with one or more Z substituents.

In a further embodiment of the invention as described above, there is provided a compound according to formula (II), wherein R is ³Is H or methyl.

Embodiments of the invention as defined above provide compounds according to formula (II) wherein

A is CR^4a；

R¹Is halogen;

R³is H;

R^4ais H;

R¹⁰¹is that

Embodiments of the invention as defined above provide compounds according to formula (II) wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkyl group;

R³is H;

R^4ais H;

R¹⁰¹is that

Embodiments of the invention as defined above provide compounds according to formula (II) wherein

A is CR^4a；

R¹Is C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R³is H;

R^4ais H;

R¹⁰¹is that

Embodiments of the invention as defined above provide compounds according to formula (II) wherein

A is CR^4a；

R¹Is halogen, C optionally substituted by one or more halogen atoms₁-C₄Alkyl, or C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R³is H;

R^4ais H;

R¹⁰¹is that

Embodiments of the invention as defined above provide compounds according to formula (II) wherein

A is CR^4a；

R¹Is halogen, C optionally substituted by one or more halogen atoms₁-C₄Alkyl, or C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R³is H;

R^4ais H;

R¹⁰¹is that

Embodiments of the invention as defined above provide compounds according to formula (II) wherein

A is CR^4a；

R¹Is halogen, C optionally substituted by one or more halogen atoms₁-C₄Alkyl, or C optionally substituted by one or more halogen atoms₁-C₄An alkoxy group;

R³is H;

R^4ais H;

R¹⁰¹is that

Another embodiment of the invention as described above provides a compound of formula (II) in the form of a substantially pure enantiomer having the R configuration.

Another embodiment of the invention as described above provides a compound of formula (II) in the form of a substantially pure enantiomer having the S configuration.

Another embodiment of the invention as described above provides that the bronchiectasis is cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis. In certain embodiments, the compound of formula (II) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered in combination with an additional therapy. In certain embodiments, the additional therapy comprises: a) long-acting beta agonists (LABA); b) long Acting Muscarinic Antagonists (LAMA); c) inhaled Corticosteroids (ICS); d) a macrolide; e) (ii) an antibiotic; f) short Acting Muscarinic Antagonists (SAMA); or g) any combination thereof. In certain embodiments, the bronchodilation is characterized by a worsening of three or more symptoms lasting at least 48 hours. In certain embodiments, the symptom is selected from the group consisting of: cough, sputum volume and/or consistency, sputum purulence, shortness of breath and/or exercise endurance, fatigue and/or discomfort, and hemoptysis. In certain embodiments, the method further comprises: a) reducing the use of a rescue medication (e.g., salbutamol/albuterol or a systemic antibiotic) by the subject when compared to a subject not administered the compound; b) reducing the severity of exacerbations in a subject when compared to a subject not administered the compound; c) increasing one or more of improved lung function or forced lung capacity of the subject, e.g., as measured by a spirometry, when compared to a patient not administered the compound; or d) any combination thereof.

Another embodiment of the invention as described above provides that the compound of formula (II) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered in an amount between about 300mg b.i.d. and about 450mg b.i.d., such as 300mg b.i.d. or 450mg b.i.d. to the subject. In a specific embodiment, the compound of formula (II) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject in an amount of about 300mg b.i.d.. In yet another embodiment, the compound of formula (II) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered orally. In another embodiment, the compound of formula (II) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject without a high fat meal.

Another embodiment of the present invention provides a method of treating bronchiectasis, the method comprising administering at least one compound of formula (III),

or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

a is N or CR^4a；

X is NR^yOr O;

R¹is C optionally substituted by one or more halogen atoms₁-C₈An alkyl group; c₃-C₁₀A cycloalkyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; optionally, optionallyC substituted by one or more halogen atoms ₁-C₈An alkoxy group; halogen; CN; NR (nitrogen to noise ratio)¹¹R¹²；C(O)NR¹³R¹⁴；NR¹³C(O)R¹⁵、CO₂R¹⁵、-(C₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said cycloalkyl, aryl and heterocyclyl are each optionally substituted with one or more Z substituents;

R²is C₁-C₄A haloalkyl group;

R³and R^4aEach independently being H or C optionally substituted by one or more halogen atoms₁-C₈An alkyl group;

R⁴is H, or C optionally substituted by one or more halogens₁-C₈An alkyl group;

R^5ais H, C optionally substituted by one or more halogens₁-C₈Alkyl, - (C)₀-C₄Alkyl) -C₆-C₁₄Aryl or a-3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents;

R^yis H, C optionally substituted by one or more halogens₁-C₈Alkyl, - (C)₀-C₄Alkyl) -C₆-C₁₄Aryl or a-3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said- (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents;

R⁶is C optionally substituted by one or more halogen atoms ₁-C₈An alkyl group;C₃-C₁₀a cycloalkyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; c optionally substituted by one or more halogen atoms₁-C₈An alkoxy group; OH; CN; halogen; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; wherein said cycloalkyl, cycloalkenyl, - (C)₀-C₄Alkyl) -C₆-C₁₄Aryl and- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl is each optionally substituted with one or more Z substituents; or

R⁴And R⁶Together with the carbon atom to which they are bonded form a 3 to 8 membered carbocyclic ring system; or

R^5aAnd R⁶A 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S together with the atoms to which they are bonded, wherein said ring system is optionally substituted with one or more Z substituents; or

R^5aAnd R^yA 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S together with the atoms to which they are bonded, wherein said ring system is optionally substituted with one or more Z substituents;

R¹¹and R¹³Each independently being H, C optionally substituted by one or more halogen atoms₁-C₈Alkyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₄Alkyl) -C₃-C₈A cycloalkyl group;

R¹²、R¹⁴and R¹⁵Each independently is H; c optionally substituted by one or more halogen atoms ₁-C₈An alkyl group; c₂-C₈An alkenyl group; c₂-C₈An alkynyl group; c₃-C₁₀A cycloalkyl group; c₅-C₁₀A cycloalkenyl group; -C₁-C₄alkyl-C₃-C₈A cycloalkyl group; - (C)₀-C₄Alkyl) -C₆-C₁₄An aryl group; or- (C)₀-C₄Alkyl) -3 to 14 membered heterocyclyl, wherein said heterocyclyl contains at least one heteroatom selected from N, O and S, wherein said cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are each optionally substituted with one or more Z substituents; or

R¹¹And R¹²And R¹³And R¹⁴Together with the nitrogen atom to which they are attached may form a 4-to 14-membered heterocyclyl optionally substituted with one or more Z substituents;

R¹⁹and R²¹Each independently is H; c₁-C₈An alkyl group; c₃-C₈A cycloalkyl group; c₁-C₄alkoxy-C₁-C₄An alkyl group; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -aryl; (C)₀-C₄Alkyl) -3 to 14 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S, optionally substituted by one or more substituents selected from halogen, oxo, C ₁-C₆Alkyl and C (O) C₁-C₆One or more of alkylSubstituted by groups; is optionally selected from C₁-C₆Alkyl radical, C₁-C₆(C) substituted by one or more groups selected from alkoxy and halogen₀-C₄Alkyl) -O-aryl; and (C)₀-C₄Alkyl) -O-3 to 14 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S, optionally substituted by a group selected from halogen, C₁-C₆Alkyl or C (O) C₁-C₆One or more groups of alkyl are substituted; wherein said alkyl group is optionally substituted by one or more halogen atoms, C₁-C₄Alkoxy, C (O) NH₂、C(O)NHC₁-C₆Alkyl or C (O) N (C)₁-C₆Alkyl radical)₂Substitution; or

R¹⁹And R²¹Together with the nitrogen atom to which they are attached form a 5 to 10 membered heterocyclic group comprising one or more further heteroatoms selected from N, O and S, which heterocyclic group is optionally substituted with one or more substituents selected from: OH; halogen; an aryl group; a 5 to 10 membered heterocyclic group comprising one or more heteroatoms selected from N, O and S; s (O)₂-an aryl group; s (O)₂-C₁-C₆An alkyl group; c optionally substituted by one or more halogen atoms₁-C₆An alkyl group; optionally substituted by one or more OH groups or C₁-C₄Alkoxy-substituted C₁-C₆An alkoxy group; and C (O) OC₁-C₆Alkyl, wherein the aryl and heterocyclic substituents are themselves optionally substituted by C ₁-C₆Alkyl radical, C₁-C₆Haloalkyl or C₁-C₆Alkoxy substitution.

Another embodiment of the invention as described above provides a compound of formula (III) in the form of a substantially pure enantiomer having the R configuration.

Another embodiment of the invention as described above provides a compound of formula (III) in the form of a substantially pure enantiomer having the S configuration.

Another embodiment of the invention as described above provides that the bronchiectasis is cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis. In certain embodiments, the compound of formula (III) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered in combination with an additional therapy. In certain embodiments, the additional therapy comprises: a) long-acting beta agonists (LABA); b) long Acting Muscarinic Antagonists (LAMA); c) inhaled Corticosteroids (ICS); d) a macrolide; e) (ii) an antibiotic; f) short Acting Muscarinic Antagonists (SAMA); or g) any combination thereof. In certain embodiments, the bronchodilation is characterized by a worsening of three or more symptoms lasting at least 48 hours. In certain embodiments, the symptom is selected from the group consisting of: cough, sputum volume and/or consistency, sputum purulence, shortness of breath and/or exercise endurance, fatigue and/or discomfort, and hemoptysis. In certain embodiments, the method further comprises: a) reducing the use of a rescue medication (e.g., salbutamol/albuterol or a systemic antibiotic) by the subject when compared to a subject not administered the compound; b) reducing the severity of exacerbations in a subject when compared to a subject not administered the compound; c) increasing one or more of improved lung function or forced lung capacity of the subject, e.g., as measured by a spirometry, when compared to a patient not administered the compound; or d) any combination thereof.

Another embodiment of the invention as described above provides that the compound of formula (III) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered in an amount between about 300mg b.i.d. and about 450mg b.i.d., e.g., 300mg b.i.d. or 450mg b.i.d. to the subject. In a specific embodiment, the compound of formula (III) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject in an amount of about 300mg b.i.d.. In yet another embodiment, the compound of formula (III) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered orally. In another embodiment, the compound of formula (III) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject without a high fat meal.

Another embodiment of the present invention as described above provides a method of treating bronchiectasis, the method comprising administering to a subject in need thereof at least one compound according to formula (I) and/or formula (II), the compound selected from the group consisting of:

3-amino-6-bromo-N- (imidazo [1,2-a ] pyridin-2-ylmethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6-bromo-N- ((1-methyl-1H-imidazol-4-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6-bromo-N- ((1-methyl-1H-pyrazol-3-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-N- (2- (4-fluorophenyl) -2-oxoethyl) -6- (1-methyl-1H-indol-6-yl) -5- (trifluoromethyl) picolinamide;

3-amino-6-bromo-N- ((1-methyl-1H-imidazol-2-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6- (6- (3- (dimethylamino) propoxy) pyridin-3-yl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

(R) -3-amino-6-bromo-N- ((4-methylpiperazin-2-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6-bromo-N- ((1-methyl-1H-imidazol-5-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6- (3- (N, N-dimethylsulfamoyl) phenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-6-bromo-N-isobutyl-N-methyl-5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6-bromo-N- ((1-methyl-1H-pyrazol-5-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

(3-amino-6-bromo-5- (trifluoromethyl) pyrazin-2-yl) (4-methylpiperazin-1-yl) methanone;

3-amino-6-bromo-N- (2- (pyridin-4-yl) ethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-N- (2- (4-fluorophenyl) -2-oxoethyl) -6- (1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5- (trifluoromethyl) picolinamide;

3-amino-6- (4-carbamoyl-2-methylphenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-6-bromo-N- (2- (pyridin-3-yl) ethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6- (3, 4-dimethylphenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-N-benzyl-6-bromo-N-methyl-5- (trifluoromethyl) pyrazine-2-carboxamide;

(S) -3-amino-6-bromo-N- ((1-ethylpyrrolidin-2-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide; and

3-amino-6-bromo-N- (imidazo [1,5-a ] pyridin-1-ylmethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide; or

A pharmaceutically acceptable salt thereof.

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

3- (3-amino-6-bromo-5- (trifluoromethyl) pyridinamido) propionic acid methyl ester;

3-amino-N- (benzo [ d ] isoxazol-3-ylmethyl) -6-bromo-5- (trifluoromethyl) picolinamide;

3-amino-6- (oxazol-2-yl) -N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-amino-6-bromo-N- (3,3, 3-trifluoro-2-methoxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-amino-N- (2-hydroxy-3-methyl-2- (trifluoromethyl) butyl) -6-methoxy-5- (trifluoromethyl) picolinamide;

3-amino-6-cyclopropyl-N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-amino-6-methoxy-N- (3,3, 3-trifluoro-2-hydroxy-2- (trifluoromethyl) propyl) -5- (trifluoromethyl) picolinamide;

5-amino-N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -3- (trifluoromethyl) -2, 4' -bipyridine-6-carboxamide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3-methyl-2-oxo-butyl) -amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluoro-phenyl) -2-oxo-ethyl ] -amide;

3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (2-methoxy-phenyl) -ethyl ] -amide;

3-amino-6- (1-methyl-1H-pyrazol-4-yl) -N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-amino-N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -5, 6-bis (trifluoromethyl) pyrazine-2-carboxamide;

n- (2- (1H-imidazol-2-yl) propyl) -3-amino-6-bromo-5- (trifluoromethyl) pyrazine-2-carboxamide;

3-amino-6-bromo-N- (2-morpholinoethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

(S) -3-amino-6-ethoxy-N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-amino-6- (pyrrolidin-1-yl) -N- (3,3, 3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-amino-N- (2-amino-3, 3, 3-trifluoro-2-methylpropyl) -6-methoxy-5- (trifluoromethyl) picolinamide; and

3-amino-6-methoxy-N- (3,3, 3-trifluoro-2- (4-methoxybenzylamino) -2-methylpropyl) -5- (trifluoromethyl) picolinamide; or

A pharmaceutically acceptable salt thereof.

Another embodiment of the present invention as described above provides a method for treating bronchiectasis, the method comprising administering an effective amount of a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

Another embodiment of the invention as described above provides a method for inhibiting or reducing the level of colonization by at least one pathogenic bacterium in the lung of a subject in need thereof, said method comprising administering an effective amount of a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof, to the subject, optionally wherein the level of at least one pathogenic bacterium is measured in a sputum sample obtained from the subject, optionally wherein the level of at least one pathogenic bacterium is measured by 16SrRNA PCR. In certain embodiments, the pathogenic bacteria are non-fermenting gram-negative bacteria. In still further embodiments, the pathogenic bacteria is selected from the group consisting of: moraxella catarrhalis (m.catarrhalis), staphylococcus aureus (s.aureus), Enterobacteriaceae (Enterobacteriaceae), stenotrophomonas Maltophilia (stenotrophomonas Maltophilia), haemophilus parainfluenzae (haemophilus parainfluenzae), haemophilus influenzae (haemophilus influenzae), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Moraxella (Moraxella), and Streptococcus pneumoniae (Streptococcus pneumoniae). In other embodiments, the level of colonization by pathogenic bacteria is reduced by at least one log.

Another embodiment of the present invention as described above provides a method for reducing the level of fibrinogen in the blood of a subject in need thereof, e.g. a bronchodilatory subject, said method comprising administering an effective amount of a compound selected from the group consisting of ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and ((R) -3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-methyl-propyl) -amide Administering to said subject a compound of the group consisting of acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the compound is 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject in need thereof is a bronchodilatory subject. In other embodiments, the compound is administered in an amount between about 300mg b.i.d. and about 450mg b.i.d., for example, 300mg b.i.d. or 450mg b.i.d. to a subject. In a specific embodiment, the compound is administered to the subject in an amount of about 300mg b.i.d. In other embodiments, the compound is administered orally. In some embodiments, the compound is administered to the subject without a high fat meal. In certain embodiments, the compound is administered in combination with an additional therapy. In certain embodiments, the additional therapy comprises: a) long-acting beta agonists (LABA); b) long Acting Muscarinic Antagonists (LAMA); c) inhaled Corticosteroids (ICS); d) a macrolide; e) (ii) an antibiotic; f) short Acting Muscarinic Antagonists (SAMA); or g) any combination thereof. In other embodiments, the bronchodilation is characterized by three or more exacerbations lasting at least 48 hours. In some embodiments, the symptom is selected from the group consisting of: cough, sputum volume and/or consistency, sputum purulence, shortness of breath and/or exercise endurance, fatigue and/or discomfort, and hemoptysis. In certain embodiments, the method further comprises: a) reducing the use of a rescue medication (e.g., salbutamol/albuterol or a systemic antibiotic) by the subject when compared to a subject not administered the compound; b) reducing the severity of exacerbations in a subject when compared to a subject not administered the compound; c) increasing one or more of improved lung function or forced lung capacity of the subject, e.g., as measured by a spirometry, when compared to a patient not administered the compound; or d) any combination thereof.

It should be understood that any and all embodiments of the present invention may be employed in conjunction with any other embodiment to describe additional embodiments of the present invention. Moreover, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments. It will be understood by those skilled in the art that combinations of substituents where not possible are not aspects of the present invention.

Particularly preferred specific compounds of formula (I) or formula (II) are those described in the examples below.

5. Description of the drawings

Figure 1 mean change in fibrinogen over time relative to baseline (SE) per treatment of COPD patients with compound a. The numbers presented in fig. 1 that are adjacent in the legend at each visit represent the number of patients.

Figure 2 depicts a flow chart of a randomized, blinded subject and investigator, placebo-controlled, parallel group study investigating the initial efficacy and safety of oral administration of compound a12 to subjects with bronchiectasis for weeks.

6. Detailed description of the preferred embodiments

6.1. Definition of

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

By "compound a" is meant 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof, having the structure:

"administration (administration, and administerer)" refers to the manner in which a compound described herein (e.g., compound a) is presented to a subject.

"optionally substituted" means that the group referred to may be substituted at one or more positions by any one or combination of the groups listed thereafter.

By "optionally substituted with one or more Z groups" is meant that the relevant group may include one or more substituents, each substituent being independently selected from the groups included within the definition of Z. Thus, where two or more Z group substituents are present, they may be the same or different.

As used herein, "halo" or "halogen" may be fluoro, chloro, bromo, or iodo.

"C" as used herein₁-C₈-alkyl "means a straight or branched chain alkyl group having 1 to 8 carbon atoms. If different numbers of carbon atoms are specified, such as C₆Or C₃Then the definition is modified accordingly, such as "C₁-C₄Alkyl "shall denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

"C" as used herein₁-C₈-alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms. If different numbers of carbon atoms are specified, such as C₆Or C₃Then the definition is modified accordingly, such as "C₁-C₄-alkoxy "shall denote methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

"C" as used herein₁-C₄By haloalkyl is meant a straight or branched chain alkyl group having 1 to 4 carbon atoms, at least one hydrogen of which is substituted by halogen. If different numbers of carbon atoms are specified, such as C₆Or C₃Then the definition is modified accordingly, such as "C₁-C₄Haloalkyl "shall denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, which have at least one hydrogen substituted by halogen, such as whereinThe halogen is fluorine: CF (compact flash)₃CF₂-、(CF₃)₂CH-、CH₃-CF₂-、CF₃CF₂-、CF₃、CF₂H-、CF₃CF₂CHCF₃Or CF₃CF₂CF₂CF₂-。

"C" as used herein₃-C₁₅-cycloalkyl "refers to a saturated or partially saturated cycloalkyl group having 3 to 15 ring carbon atoms, such as C₃-C₈-a cycloalkyl group. C₃-C₁₅Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or bicyclic groups such as bicyclooctyl, bicyclononyl (including indanyl and indenyl), and bicyclodecyl. If different numbers of carbon atoms are specified, such as C ₆The definition is modified accordingly.

"aryl" or "C" as used herein₆-C₁₅An aromatic carbocyclic group "means an aromatic group having 6 to 15 ring carbon atoms. C₆-C₁₅Examples of-aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, naphthyl, naphthylene, or anthracenylene. If different numbers of carbon atoms are specified, such as C₁₀The definition is modified accordingly.

"4-to 8-membered heterocyclic group", "5-to 6-membered heterocyclic group", "3-to 10-membered heterocyclic group", "3-to 14-membered heterocyclic group", "4-to 14-membered heterocyclic group" and "5-to 14-membered heterocyclic group" refer to a ring of a 4-to 8-membered, 5-to 6-membered, 3-to 10-membered, 3-to 14-membered, 4-to 14-membered and 5-to 14-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, respectively, which ring may be saturated, partially saturated or unsaturated (aromatic). The heterocyclic group includes monocyclic groups, fused ring groups and bridging groups. Examples of such heterocyclic groups include, but are not limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isothiazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1, 4-dioxane, 1, 4-oxathiane, indazole, quinoline, indazole, 8-aza-bicyclo [3.2.1] octane, or thiazole.

By "subject" is meant a living organism having one or more diseases or disorders described herein (e.g., bronchiectasis, COPD, CF, chronic bronchitis, primary ciliary dyskinesia, respiratory infections, or asthma) that can be treated by administration of a pharmaceutical composition described herein. Examples of subjects include mammals (e.g., humans and animals such as dogs, cows, horses, monkeys, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals). In certain embodiments, the subject is a human, e.g., a human having, at risk of having, or potentially capable of having a disease described herein (e.g., bronchiectasis, COPD, CF, chronic bronchitis, primary ciliary dyskinesia, a respiratory infection, or asthma). "treatment" includes prophylactic (prophylactic) and therapeutic treatment of a disease or disorder described herein (e.g., bronchiectasis, COPD, CF, chronic bronchitis, primary ciliary dyskinesia, respiratory infection or asthma) and delay of progression thereof. The term "delay of progression" as used herein means administration of a pharmaceutical composition to a patient at a pre-stage or early stage of a disease or disorder described herein to be treated (e.g. bronchiectasis, COPD, CF, chronic bronchitis, primary ciliary dyskinesia, respiratory infection or asthma), wherein the patient is e.g. diagnosed with a pre-form of the respective disease or the patient is in a condition during medical treatment in which the respective disease will likely progress.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

"pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention and is typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline (chlorethyluronate), citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, disodium acetate, disodium oleate, disodium acetate, disodium oleate, disodium salt, or mixtures of sodium and salts of sodium and/magnesium phosphate, disodium salt, Polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic Table of the elements. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; a cyclic amine; basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of additional suitable salts can be found, for example, in: "Remington's Pharmaceutical Sciences [ Remington Pharmaceutical Sciences ]", 20 th edition, Mack Publishing Company [ Mark Publishing Company ], Easton [ Inston ], Pa. [ state of Pennsylvania ], (1985); and Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use [ Handbook of Pharmaceutical Salts: properties, selections and uses ] "(Wiley-VCH [ Willi-VCH Press ], Weinheim [ Weinheim ], Germany, 2002).

Furthermore, the compounds of the present invention (including salts thereof) may also be obtained in the form of their hydrates, or include other solvents for their crystallization.

The compounds of the invention, i.e. compounds having formula (I), (II) or (III) containing groups capable of acting as hydrogen bond donors and/or acceptors, may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I), (II) or (III) by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting a compound having formula (I), (II) or (III) with a co-crystal former in solution under crystallization conditions, and isolating the co-crystal thus formed. Suitable eutectic formers include those described in WO 2004/078163. Accordingly, the invention further provides co-crystals comprising a compound of formula (I), (II) or (III).

The term "isomers" refers to different compounds having the same molecular formula but differing in the arrangement and configuration of the atoms.

"optical isomer" or "stereoisomer" refers to any of a variety of stereoisomeric configurations that may exist for a given compound of the invention and includes geometric isomers. It is understood that the substituent may be attached at a chiral center at a carbon atom. Thus, the present invention includes enantiomers, diastereomers or racemates of said compounds.

"enantiomers" are a pair of stereoisomers that do not overlap with each other in mirror image. The 1:1 mixture of enantiomeric pairs is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate.

"diastereoisomers" are stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry was assigned according to the Cahn-lngold-Prelog R-S system. When the compounds are pure enantiomers, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds with unknown absolute configuration can be assigned (+) or (-) depending on the direction of rotation of plane polarized light (dextro-or levorotatory) at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined as (R) -or (S) -according to absolute stereochemistry. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis-or trans-configuration. All tautomeric forms are also intended to be included.

Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configurations. In certain embodiments, each asymmetric atom has an (R) -or (S) -configuration with at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. The substituents on the atom having an unsaturated bond may be present in cis- (Z) -or trans- (E) -form, if possible.

Thus, as used herein, a compound of the invention may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as a substantially pure geometric (cis or trans) isomer, diastereomer, optical isomer (enantiomer), racemate or mixture thereof.

Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on the physicochemical differences of the components, e.g., by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods, for example by separating the diastereomeric salts thereof obtained with an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the compounds of the invention can thus be resolved into their optical enantiomers using a basic moiety, for example by fractional crystallization of a salt formed with an optically active acid, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O' -p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. The racemic product can also be resolved by chiral chromatography (e.g., High Pressure Liquid Chromatography (HPLC) using a chiral adsorbent).

Since the compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% is on a weight/weight basis). Impure preparations of the compounds may be used to prepare more pure forms for pharmaceutical compositions; these less pure compound preparations should contain at least 1%, more suitably at least 5% and preferably from 10% to 59% of the compounds of the invention.

The compounds of the invention are obtained in free form, in the form of their salts, or in the form of their prodrug derivatives. The pharmaceutical dosages disclosed herein are calculated using the free base form of the compound of formula (I), (II), or (III) (e.g., compound a or a pharmaceutically acceptable salt thereof), e.g., in an amount between about 300mg twice daily (b.i.d.) and about 450mg b.i.d., such as administered in an amount of 300mg b.i.d., or 450mg b.i.d.). In a specific embodiment, a compound of formula (I), (II), or (III) (e.g., compound a or a pharmaceutically acceptable salt thereof) is administered to the subject in an amount of about 300mg b.i.d.. In a more specific embodiment, compound a is administered to the subject in an amount of about 300mg b.i.d.

When both basic and acidic groups are present in the same molecule, the compounds of the invention may also form internal salts, such as zwitterionic molecules.

Any formula given herein is also intended to represent the unlabeled form as well as the isotopically labeled form of the compound. Isotopically labeled compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl、¹²⁵I. The invention includes various isotopically-labeled compounds as defined herein, for example, in which a radioisotope (such as³H、¹³C. And¹⁴C) those compounds of (1). Such isotopically labeled compounds are useful in metabolic studies (using¹⁴C) Research on reaction kineticsPreferably (using e.g. the²H or³H) Detection or imaging techniques including drug or substrate tissue distribution determination, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), or may be used for radiation treatment of a patient. In particular, it is possible to use, for example,¹⁸f or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

In addition, with heavier isotopes, particularly deuterium (i.e.,²h or D) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements or improved therapeutic index). It is to be understood that deuterium in this context is considered as a substituent of the compound having formula (I), (II) or (III). The concentration of such heavier isotopes, in particular deuterium, may be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent in a compound of the invention refers to deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation on each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labelled compounds of formula (I), (II) or (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using an appropriate isotopically-labelled reagent in place of the unlabelled reagent previously used.

Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotopically substituted, for exampleSuch as D₂O、d₆-acetone, d₆-DMSO。

If there is a difference between the depicted structure and the chemical name given to the structure, the depicted structure should be given greater weight. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of a structure should be interpreted to include all stereoisomers of the structure or portion of the structure.

"high fat meal" means the definition (FDA 2019) by the U.S. Food and Drug Administration in the Draft Guidance on assistance of the Effects of Food on Drugs in IND and NDA (see also assistance of the Effects of Food on Drugs in Investigational New Drug Applications and New Drug Applications), the Draft Guidance for Industry Guidance Draft, the Availability, 84 Fed.Fed. 6151 EMA, 2019 and the corresponding Renyan guide for the year 2012, wherein the high fat meal contains at least 1000kcal (4184kJ) and at least 50% of the energy content is derived from fat. Examples of high fat meals may be:

Total nutrient energy value: 1000kcal

Wherein the protein is derived from: 150kcal

Wherein the protein is derived from a carbohydrate: 250kcal

Wherein the fat-derived: 600 kcal.

A "high fat free meal" is defined to mean a situation where the consumption of a high fat meal is not accompanied by the administration of a compound of formula (I) or a pharmaceutically effective salt thereof (e.g., compound a or a pharmaceutically effective salt thereof) or a situation where a high fat meal is not consumed within a certain time period before the administration of a compound of formula (I) or a pharmaceutically effective salt thereof to within a certain time period after the administration of a compound of formula (I) or a pharmaceutically effective salt thereof. In some embodiments, a high fat meal is not consumed within about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or about 1 minute prior to administration of a compound of formula (I) or a pharmaceutically effective salt thereof. In some embodiments, a high fat meal is not consumed within about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or about 1 minute after administration of a compound of formula (I) or a pharmaceutically effective salt thereof. In other embodiments, the consumption of a high fat meal is not in conjunction with the administration of a compound of formula (I) or a pharmaceutically effective salt thereof. In certain embodiments, a high fat meal is not consumed within about 30 minutes prior to administration of the compound of formula (I) or a pharmaceutically effective salt thereof.

By "one or more exacerbations" is meant a worsening of three or more of the following key symptoms for at least 48 hours:

cough with

Sputum volume and/or consistency;

purulent sputum;

shortness of breath and/or exercise endurance;

fatigue and/or discomfort;

hemoptysis

And

the clinician determines that a change in bronchodilation therapy is required (e.g., a need for systemic glucocorticosteroid therapy and/or systemic or inhaled antibiotics).

Exacerbations of symptoms that do not meet the above symptom definitions but are treated by the investigator with antibiotics or that do not meet the symptom definitions but are not treated with antibiotics are not considered to be exacerbations of lung disease in the study.

6.2. Pharmaceutical compositions and methods of use

6.2.1. Inflammatory or allergic disorders

One aspect of the present invention provides a compound of formula (I), (II) or (III) (e.g. compound a or a pharmaceutically acceptable salt thereof) as defined anywhere herein for use as a medicament.

A further aspect of the invention provides a method of treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), (II) or (III) (e.g. compound a or a pharmaceutically acceptable salt thereof).

A further aspect of the invention provides a compound of formula (I), (II) or (III) (e.g. compound a or a pharmaceutically acceptable salt thereof) for use in the treatment of an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration in a subject in need thereof.

A still further aspect of the invention provides the use of a compound of formula (I), (II) or (III) as defined in any preceding embodiment (e.g. compound a or a pharmaceutically acceptable salt thereof), in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment of an inflammatory or allergic disorder or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration, in a subject in need thereof.

A still further aspect of the invention provides the use of a compound of formula (I), (II) or (III) as defined in any preceding embodiment (e.g. compound a or a pharmaceutically acceptable salt thereof), in free or pharmaceutically acceptable salt form, for the treatment of an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration, in a subject in need thereof.

A still further aspect of the invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) as defined in any preceding embodiment (e.g. compound a or a pharmaceutically acceptable salt thereof), in free or pharmaceutically acceptable salt form, for use in treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration, in a subject in need thereof.

One aspect of the present invention provides a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof A salt for use as a medicament.

A further aspect of the invention provides a method of treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration, which comprises administering an effective amount of a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

A further aspect of the invention provides a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof A salt for use in treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration in a subject in need thereof.

Still a further aspect of the invention provides a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof Use of a salt of the receptor in the manufacture of a medicament for treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration in a subject in need thereof.

Still a further aspect of the invention provides a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof Use of a salt thereof for treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration in a subject in need thereof.

Still further aspects of the invention provide a compound comprising a compound selected from the group consisting of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, and 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, or a pharmaceutically acceptable salt thereof A pharmaceutical composition of an acceptable salt for use in treating an inflammatory or allergic condition or infection, in particular an inflammatory or obstructive airways disease or mucosal hydration in a subject in need thereof.

In some embodiments, the compound is a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof. In a specific embodiment, the compound is 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3, 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide or a pharmaceutically acceptable salt thereof. In certain embodiments, the bronchiectasis is cystic fibrosis bronchiectasis or non-cystic fibrosis bronchiectasis. In certain embodiments, the compound is administered in combination with at least one additional therapy. In certain embodiments, the additional therapy comprises: a) long-acting beta agonists (LABA); b) long Acting Muscarinic Antagonists (LAMA); c) inhaled Corticosteroids (ICS); d) a macrolide; e) antibiotics (e.g., macrolide antibiotics); f) short Acting Muscarinic Antagonists (SAMA); or g) any combination thereof. When administered in combination, the two or more agents may be administered sequentially or simultaneously, and may be administered in one or more compositions. In certain embodiments, the bronchodilation is characterized by a worsening of three or more symptoms lasting at least 48 hours. In certain embodiments, the symptom is selected from the group consisting of: cough, sputum volume and/or consistency, sputum purulence, shortness of breath and/or exercise endurance, fatigue and/or discomfort, and hemoptysis. Another embodiment of the invention as described above provides that the compound is administered in an amount between about 300mg b.i.d. and about 450mg b.i.d., for example 300mg b.i.d. or 450mg b.i.d. to the subject. In a specific embodiment, the compound is administered to the subject in an amount of about 300mg b.i.d. In yet another embodiment, the compound is administered orally. In another embodiment, the compound is administered to the subject without a high fat meal. In certain embodiments, the method further comprises: a) reducing the use of a rescue medication (e.g., salbutamol/albuterol or a systemic antibiotic) by the subject when compared to a subject not administered the compound; b) reducing the severity of exacerbations in a subject when compared to a subject not administered the compound; c) increasing one or more of improved lung function or forced lung capacity of the subject, e.g., as measured by a spirometry, when compared to a patient not administered the compound; or d) any combination thereof.

6.2.2. Bronchiectasis

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