The present invention provides pyridine and pyrazine derivatives which restore or enhance the function of mutant and/or wild type CFTR to treat cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced). Pharmaceutical compositions comprising such derivatives are also encompassed.

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Patent
   RE46757
Priority
Mar 19 2010
Filed
Jun 30 2015
Issued
Mar 20 2018
Expiry
Mar 14 2031

TERM.DISCL.
Inventors
Baettig, U…
Assg.orig
Novartis AG
Assg.curr
Novartis AG
Entity
Large
Referenced by
1
References
198
Maint.:
currently ok
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0. 15. A method for the symptomatic treatment of COPD comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from:
3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
#8# 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; and
#14# 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
or a pharmaceutically acceptable salt thereof.
0. 14. A method for the symptomatic treatment of asthma comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from:
3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
#8# 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; and
#14# 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
or a pharmaceutically acceptable salt thereof.
0. 13. A method for the symptomatic treatment of cystic fibrosis comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from:
3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
#8# 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; and
#14# 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;
or a pharmaceutically acceptable salt thereof.
9. The A #8# compound represented by formula II,
##STR00119##
or a pharmaceutically acceptable salt thereof #14# ;
wherein
A is n or cr4a;
Ra R4a is H or C1-C4 alkyl;
R1 is C1-C8 alkyl optionally substituted by one or more halogen atoms; C1-C8 alkoxy optionally substituted by one or more halogen atoms; halogen; NR11R12,; C6-C14 aryl; or —(C0-C4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents;
R11 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C3-C10 cycloalkyl or —(C1-C4 alkyl)-C3-C8 cycloalkyl;
R12 is H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; —C1-C4 alkyl-C3-C8 cycloalkyl; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R11 and R12 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, (SO2)NR19R21, (SO2)R21, C(O)NR19R21, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)- 3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from n, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from n, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)n(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from n, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from n, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
R3 R3 is H or CH3;
R101 is
##STR00120## ##STR00121##
1. A compound of formula I
##STR00118##
#8# or a pharmaceutically acceptable salt thereof, wherein:
A is n or cr4a;
R #14# 1 is H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; —C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; halogen; SO2NR8R9; SO2R10; S—C1-C8alkyl optionally substituted by one or more halogen atoms; S—C6-C14 aryl; CN; NR11R12; C(O)NR13R14; NR13SO2R15; NR13C(O)R15, CO2R15, —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R2 is C1-C4 haloalkyl;
R3 and R4a are each independently H or C1-C8 alkyl optionally substituted by one or more halogen atoms;
R4 is H, or C1-C8 alkyl optional optionally substituted with one or more halogen atoms;
R5 is —(CH2)m—NR17R18, —(CH2)m—OR′, C1-C8 alkoxy optionally substituted by one or more halogen atoms; —(C0-C4 alkyl)-CO2R15; —(C0-C4 alkyl)-C6-C14 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S; wherein the —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R6 is C1-C8 alkyl optionally substituted by one or more halogen atoms; C3-C10 cycloalkyl; —C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S; wherein the cycloalkyl, cycloalkenyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R6 is H, and R5 is —(CH2)m—NR17R18, —(CH2)m—OR′, C1-C8 alkoxy optionally substituted by one or more halogen atoms; —(C0-C4 alkyl)-C6-C14 aryl; —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S; or —(C0-C4 alkyl)-CO2R15, wherein —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or
R4 and R6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R4 and R5 together form an oxo group (C═O) and R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R5 and R6 together with the carbon atoms to which they are bound 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 by one or more Z substituents; or
R4 and R5 and R6 together with the carbon atoms to which they are bound 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 by one or more Z substituents;
R′ is H, or C1-C8 alkyl optional optionally substituted with one or more halogen atoms;
m is 0, 1, 2 or 3;
R8, R11, R13 and R17 are each independently H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C3-C10 cycloalkyl or —(C1-C4 alkyl)-C3-C8 cycloalkyl;
R9, R10, R12, R14, R15, R16 and R18 are each independently H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; —C1-C4 alkyl-C3-C8 cycloalkyl; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R8 and R9, R11 and R12, R13 and R14, and R17 and R18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, (SO2)NR19R21, (SO2)R21, C(O)NR19R21, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from n, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from n, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)n(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from n, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from n, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is cr4a.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is C #8# 1-C8 alkyl optionally substituted by one or more halogen atoms; C1-C #14# 8 alkoxy optionally substituted by one or more halogen atoms; halogen; NR11R12, C6-C14 aryl; or —(C0-C4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents.
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein
R1 is C #8# 1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C #14# 4 alkoxy optionally substituted by one or more halogen atoms; or halogen.
5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein
R1 is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents. #8#
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2 is CF #8# 3.
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R4 is H or C #8# 1-C4 alkyl optionally substituted by one or more halogen atoms;
R #14# 5 is C1-C4 alkoxy optionally substituted by one or more halogen atoms; —(CH2)m—NR17R18, —(CH2)m—OR —(CH2)m—OR′; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from n, O and S, wherein the aryl heterocyclyl groups is optionally substituted by one or more Z substituents;
R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; or —(C0-C4 alkyl)-C6-C14 aryl wherein the aryl is optionally substituted by one or more Z substituents; or
R4 and R6 together with the carbon atoms to which they are bound form a 3 to 6 membered carbocyclic ring system; or
R5 and R6 together with the carbon atoms to which they are bound 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 by one or more Z substituents;
m is 0 or 1;
R17 and R18 are each independently H; or C1-C8 alkyl optionally substituted by one or more halogen atoms.
8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is cr4a; #8#
R1 is C1-C #14# 4 alkyl optionally substituted by one or more halogen atoms; or C1-C4 alkoxy optionally substituted by one or more halogen atoms;
R2 is CF3,
R3 is H, CH, or CF3;
R4 is H or Me;
R4a is H;
R5 is —NR17R18 or OH, and
R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms.
10. A pharmaceutical composition, comprising:
the compound according to claim 1, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
11. A pharmaceutical combination, comprising:
a first active comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and
a second active selected from osmotic agents, ENaC blockers, anti-inflammatory agents, bronchodilatory agents, antihistamine agents, anti-tussive agents, antibiotic agents and DNase drug substances, wherein the first and second actives may be in the same or different pharmaceutical composition. #8#
12. A method for the symptomatic treatment of cystic fibrosis, asthma, or COPD, comprising:
administering an effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. #8#
0. 16. The method according to claim 13 wherein the compound is in free form.
0. 17. The method according to claim 13 wherein the compound is a pharmaceutically acceptable salt.
0. 18. The method according to claim 14 wherein the compound is in free form.
0. 19. The method according to claim 14 wherein the compound is a pharmaceutically acceptable salt.
0. 20. The method according to claim 15 wherein the compound is in free form.
0. 21. A method according to claim 15 wherein the compound is a pharmaceutically acceptable salt.

This application
R5 and R6 are each independently a group of the formula:
—(CH2)m—OR4; or
R4 and R5 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R5 and R6 together with the carbon atoms to which they are bound form a 5 to 8 membered carbocyclic ring system or 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 by one or more Z substituents;
R4, R5 and R6 cannot all be the same;
m is 0, 1, 2 or 3;
R8, R11, R13 and R17 are each independently H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C3-C10 cycloalkyl or —(C1-C4 alkyl)-C3-C8 cycloalkyl;
R9, R10, R12, R14, R15, R16 and R18 are each independently H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; —C1-C4 alkyl-C3-C8 cycloalkyl; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R8 and R9, R11 and R12, R13 and R14, and R17 and R18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, 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, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C8 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; or

R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 2

The compound of Formula I

##STR00106##
or pharmaceutically acceptable salts thereof, wherein:
A is N or CR4a;
R1 is H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C6 alkenyl; C2-C6 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; halogen; SO2NR8R9; SO2R10; S—C1-C8alkyl optionally substituted by one or more halogen atoms; S—C6-C14 aryl; CN; NR11R12; C(O)NR13R14; NR13SO2R15; NR13C(O)R15, CO2R15, —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R2 is C1-C4 haloalkyl;
R3 and R4a are each independently H or C1-C8 alkyl optionally substituted by one or more halogen atoms;
R4 is H, or C1-C8 alkyl optional substituted with one or more halogen;
R5 is —(CH2), —NR17R18, —(CH2)m—OR′; C1-C8 alkoxy optionally substituted by one or more halogen atoms; —(C0-C4 alkyl)-CO2R15; —(C0-C4 alkyl)-C6-C14 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R6 is C1C8 alkyl optionally substituted by one or more halogen atoms; C3-C10 cycloalkyl; —C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R6 is H, and R5 is —(CH2)m—NR17R18, —(CH2)m—OR′, C1-C8 alkoxy optionally substituted by one or more halogen atoms; —(C0-C4 alkyl)-C6-C14 aryl; —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —(C0-C4 alkyl)-CO2R15, wherein —(C0-C4 alkyl)-C8-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or
R4 and R6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R4 and R5 together form an oxo group (C—O) and R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; (C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R5 and R6 together with the carbon atoms to which they are bound 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 by one or more Z substituents; or
R4 and R5 and R6 together with the carbon atoms to which they are bound 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 by one or more Z substituents;
R′ is H, or C1-C8 alkyl optional substituted with one or more halogen;
m is 0, 1, 2 or 3;
R8, R11, R13 and R17 are each independently H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C3-C10 cycloalkyl or —(C1-C4 alkyl)-C3-C8 cycloalkyl;
R9, R10, R12, R14, R15, R16 and R18 are each independently H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; —C1-C4 alkyl-C3-C8 cycloalkyl; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R8 and R9, R11 and R12, R13 and R14, and R17 and R18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH, groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, 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, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl: C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 3

The compound according to embodiment 1 or 2, wherein

Embodiment 4

The compound according to embodiment 1 to 3, wherein

Embodiment 5

The compound according to embodiment 1 to 4, wherein

Embodiment 6

The compound according to embodiment 1, 2 or 3, wherein

Embodiment 7

The compound according to embodiment 1, 2, 3 or 6, wherein

Embodiment 8

The compound according to embodiments 1, 2 or 3, wherein R1 is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents,

Embodiment 9

The compound according to embodiment 1, 2, 3 or 8, wherein R1 is 4-fluorophenyl, 4-chloro-2-methylphenyl, or 2,4-dichlorophenyl.

Embodiment 10

The compound according to embodiment 1, 2 or 3, wherein R1 is pyridyl, oxazole, pyrrolidine or pyrazole and is optionally substituted by one or more Z substituents.

Embodiment 11

The compound according to embodiment 1, 2, 3 or 10, wherein R1 is 1-methyl-4-pyridyl, oxzaoyl-2-yl, 1-methyl-1H-pyrazole-4-yl or pyrrolidin- 1yl.

Embodiment 12

The compound according to embodiment 1 to 11, wherein R1 is Br, —CH3, —CF3, —OCH3, —OCH2CH3, —OCF3, 4-fluorophenyl, 4-chloro-2-methylphenyl, 2,4-dichlorophenyl, 1-methyl-4-pyridyl, 1-methyl-1H-pyrazole-4-yl, oxzaoyl-2-yl, or pyrrolidin-1-yl.

Embodiment 13

The compound according to embodiment 1 to 12, wherein R5 provides a heteroatom two carbons from the amide nitrogen, wherein the heteroatom is oxygen or nitrogen.

Embodiment 14

The compound according to embodiment 1 to 13, wherein

Embodiment 15

The compound according to any proceeding embodiment, wherein

Embodiment 16

The compound according to any proceeding embodiment, wherein

Embodiment 17

The compound according to any proceeding claim, wherein

Embodiment 18

The compound according to embodiment 1 to 13, wherein

Embodiment 19

The compound according to embodiment 1 to 13 or 18, wherein

Embodiment 20

The compound according to embodiment 1 to 13 or 18 to 19, wherein

Embodiment 21

The compound according to embodiment 1 to 13, wherein the compound is represented by formula II,

##STR00107##
or a pharmaceutically acceptable salt thereof,
wherein,
R101 is selected from the following:

##STR00108## ##STR00109##

Embodiment 22

The compound according to embodiment 21, wherein

##STR00110##

Embodiment 23

The compound according to embodiment 21, wherein

##STR00111##

Embodiment 24

The compound according to embodiment 21, wherein

##STR00112##

Embodiment 25

The compound according to embodiment 21, wherein

##STR00113##

Embodiment 26

The compound according to embodiment 1 to 13, wherein

Embodiment 27

The compound according to embodiment 21 or 26, wherein

##STR00114##

Embodiment 28

The compound of formula III

##STR00115##
or pharmaceutically acceptable salts thereof, wherein:
A is N or CR4a;
X is NRy or O;
R1 is C1-C8 alkyl optionally substituted by one or more halogen atoms; C3-C10 cycloalkyl; —C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; halogen; CN; NR11R12; C(O)NR13R14; NR13C(O)R15, CO2R15, —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R2 is C1-C4 haloalkyl;
R3 and R4a are each independently H or C1-C8 alkyl optionally substituted by one or more halogen atoms;
R4 is H, or C1-C8 alkyl optional substituted with one or more halogen;
R5a is H, C1-C8 alkyl optional substituted with one or more halogen, —(C0-C4 alkyl)-C6-C14 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
Ry is H, C1-C8 alkyl optional substituted with one or more halogen, —(C0-C4 alkyl)-C6-C14 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R6 is C1-C8 alkyl optionally substituted by one or more halogen atoms; C3-C10 cycloalkyl; —C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R4 and R6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R5a and R6 together with the atoms to which they are bound 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 by one or more Z substituents; or
R5a and Ry together with the atoms to which they are bound 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 by one or more Z substituents;
R11 and R13 are each independently H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C3-C10 cycloalkyl or —(C1-C4 alkyl)-C3-C8 cycloalkyl;
R12, R14, and R15 are each independently H; C1-C8 alkyl optionally substituted by one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; —C1-C4 alkyl-C3-C8 cycloalkyl; —(C0-C4 alkyl)-C6-C14 aryl; or —(C0-C4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R11 and R12, and R13 and R14 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, 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, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)N C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 29

The compound according to embodiment 28, wherein

A is N or CR4a;

X is NRy or O;

R1 is alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; halogen; —(C0-C4 alkyl)-C6 aryl; or —(C0-C4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R2 is C1-C4 haloalkyl;
R3 and R4a are H;
R4 is H, or C1-C4 alkyl optional substituted with one or more halogen;
R5a is H, C1-C4 alkyl optional substituted with one or more halogen, —(C0-C4 alkyl)-C6 aryl or -5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C0-C4 alkyl)-C6 aryl and -5 to 8 membered heterocyclic group are each optionally substituted by one or more Z substituents;
Ry is H, C1-C4 alkyl optional substituted with one or more halogen, —(C0-C4 alkyl)-C6 aryl or -5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C0-C4 alkyl)-C6 aryl and -5 to 8 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; —(C0-C4 alkyl)-C6 aryl; or -5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —C6 aryl and -5 to 8 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R4 and R6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R5a and R6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z substituents; or
R5a and Ry together with the atoms to which they are bound 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 by one or more Z substituents;
Z is independently OH, aryl, O-aryl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR18C(O)R21, C(O)NR19R21, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, halogen or a 5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the heterocyclic group is option substituted by halogen, C1-C4 alkyl optionally substituted by halogen, C1-C4 alkoxy or —CN;
R18 is H or C1-C4 alkyl;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)N C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl: C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 30

The compound according to embodiment 28 or 29, wherein

A is N or CR4a;

X is NRy or O;

R1 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; or halogen;

R2 is CF3;

R3 and R4a are H;

R4 is H, or C1-C4 alkyl optional substituted with one or more halogen;

R5a is H, C1-C4 alkyl optional substituted with one or more halogen,

Ry is H, C1-C4 alkyl optional substituted with one or more halogen,

R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; or

R4 and R6 together with the carbon atoms to which they are bound form a 3 to 6 membered carbocyclic ring system; or

R5a and R6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z substituents; or

R5a and Ry together with the atoms to which they are bound 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 by one or more Z substituents;

Z is independently OH, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, or halogen;
R19 is H: C1-C8 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 6-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 31

The compound according to embodiment 28 to 30, wherein

A is N or CR4a;

X is NRy or O;

R1 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; or halogen;

R2 is CF3;

R3 and R4a are H;

R4 is H, or C1-C4 alkyl optional substituted with one or more halogen;

R5a is H, C1-C4 alkyl optional substituted with one or more halogen,

Ry is H, C1-C4 alkyl optional substituted with one or more halogen,

R6 is C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; or

R5a and R6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z substituents; or

R5a and Ry together with the atoms to which they are bound 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 by one or more Z substituents;

Z is independently OH, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, oxo, CN, NO2, or halogen;

Embodiment 32

The compound according to any of the proceeding embodiments, A is N.

Embodiment 33

The compound to embodiments 1 to 31, wherein A is CR4a.

Embodiment 34

The compound according to embodiment 33, wherein A is CR4a and R4a is H.

Embodiment 35

The compound according to any proceeding embodiment, wherein R2 is CF3CF2—, (CF3)2CH—, CH3—CF2—, CF3CF2—, CF3, CF2H—, CH3—CCl2—, CF3CFCClH—, CBr3, CBr2H—CF3CF2CHCF3 or CF3CF2CF2CF2—.

Embodiment 36

The compound according to any proceeding embodiment, wherein R2 is CF3.

Embodiment 37

The compound according to any proceeding embodiment, wherein the compound is a substantially pure enantiomer with the S configuration.

Embodiment 38

The compound according to embodiment 1 to 36, wherein the compound is a substantially pure enantiomer with the R configuration.

Embodiment 39

The compound according to embodiment 2, 21 or 28, wherein the compound is represented by:

Embodiment 40

The compound according to embodiment 39, wherein the compound is

Embodiment 41

The compound according to embodiment 2, 21 or 28, wherein the compound is

Embodiment 42

The compound according to embodiment 2, 21 or 28, wherein the compound is

Embodiment 43

The compound according to embodiment 39, wherein the compound is

Embodiment 44

Use of a compound according to embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of an inflammatory or obstructive airways disease or mucosal hydration.

Embodiment 45

Use of a compound according to embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of a disease mediated by CFTR.

Embodiment 46

Use of a compound according to embodiment 42 in the manufacture of a medicament for use in the treatment of a disease mediated by CFTR, wherein the disease is CF or COPD.

Embodiment 47

Use of a compound according to embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of cystic fibrosis.

Embodiment 48

A pharmaceutical composition for treating a disease or disorder mediated by CFTR, comprising:

Embodiment 49

A pharmaceutical composition, according to embodiment 48, wherein the disease or disorder is cystic fibrosis or COPD.

Embodiment 49

A pharmaceutical composition, according to embodiment 49, wherein the disease or disorder is cystic fibrosis.

Embodiment 50

A pharmaceutical combination, comprising:

Embodiment 51

A pharmaceutical combination according to embodiment 50, wherein the second active agent is an EnaC blocker.

Embodiment 52

A process for the preparation of compounds of formula (I), comprising:

##STR00116##

##STR00117##
wherein R1, R2, R3, R4, R5 and R6 are as defined herein and P is a suitable amino protecting group;

Embodiment 53

The process according to embodiment 48, wherein the peptide coupling condition is HATU in an aprotic solvent.

INVENTORS:

Baettig, Urs, Legrand, Darren Mark, Bala, Kamlesh Jagdis, Edwards, Lee, Budd, Emma, Spiegel, Katrin, Howsham, Catherine, Hughes, Glyn Alan

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