Pyridine and pyrazine derivative for the treatment of CF

Patent metadata

Field	Value
Publication number	US-10117858-B2
Application number	US-201615156528-A
Country	US
Kind code	B2
Filing date	May 17, 2016
Priority date	Mar 19, 2010
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

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.

First claim

We claim:

1. A method for the treatment of primary ciliary dyskinesia in a subject in need of treatment thereof comprising administering an effective amount of at least one compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
A is N or CR 4a ;
R 1 is H; C 1 -C 8 alkyl optionally substituted by one or more halogen atoms; C 2 -C 8 alkenyl; C 2 -C 8 alkynyl; C 3 -C 10 cycloalkyl; C 5 -C 10 cycloalkenyl; —C 1 -C 4 alkyl-C 3 -C 8 cycloalkyl; C 1 -C 8 alkoxy optionally substituted by one or more halogen atoms; halogen; SO 2 NR 8 R 9 ; SO 2 R 10 ; S—C 1 -C 8 alkyl optionally substituted by one or more halogen atoms; S—C 6 -C 14 aryl; CN; NR 11 R 12 ; C(O)NR 13 R 14 ; NR 13 SO 2 R 15 ; NR 3 C(O)R 15 , CO 2 R 15 , —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; or —(C 0 -C 4 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;
R 2 is C 1 -C 4 haloalkyl;
R 3 and R 4a are each independently H or C 1 -C 8 alkyl optionally substituted by one or more halogen atoms;
R 4 is H, or C 1 -C 8 alkyl optional substituted with one or more halogen atoms;
R 5 is —(CH 2 ) m —NR 17 R 18 , —(CH 2 ) m —OR′; C 1 -C 8 alkoxy optionally substituted by one or more halogen atoms; —(C 0 -C 4 alkyl)-CO 2 R 15 ; —(C 0 -C 4 alkyl)-C 6 -C 14 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 —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R 6 is C 1 -C 8 alkyl optionally substituted by one or more halogen atoms; C 3 -C 10 cycloalkyl; —C 1 -C 4 alkyl-C 3 -C 8 cycloalkyl; C 1 -C 8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; or —(C 0 -C 4 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, —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R 6 is H, and R 5 is —(CH 2 ) m —NR 17 R 18 , —(CH 2 ) m —OR′, C 1 -C 8 alkoxy optionally substituted by one or more halogen atoms; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —(C 0 -C 4 alkyl)-CO 2 R 15 , wherein —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or
R 4 and R 6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R 4 and R 5 together form an oxo group (C═O) and R 6 is C 1 -C 4 alkyl optionally substituted by one or more halogen atoms; C 1 -C 4 alkoxy optionally substituted by one or more halogen atoms; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; or —(C 0 -C 4 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
R 5 and R 6 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
R 4 and R 5 and R 6 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 C 1 -C 8 alkyl optional substituted with one or more halogen atoms;
m is 0, 1, 2 or 3;
R 8 , R 11 , R 13 and R 17 are each independently H, C 1 -C 8 alkyl optionally substituted by one or more halogen atoms, C 3 -C 10 cycloalkyl or —(C 1 -C 4 alkyl)-C 3 -C 8 cycloalkyl;
R 9 , R 10 , R 12 , R 14 , R 15 , R 16 and R 18 are each independently H; C 1 -C 8 alkyl optionally substituted by one or more halogen atoms; C 2 -C 8 alkenyl; C 2 -C 8 alkynyl; C 3 -C 10 cycloalkyl; C 5 -C 10 cycloalkenyl; —C 1 -C 4 alkyl-C 3 -C 8 cycloalkyl; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; or —(C 0 -C 4 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
R 8 and R 9 , R 11 and R 12 , R 13 and R 14 , and R 17 and R 18 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, C 1 -C 6 alkyl optionally substituted by one or more OH groups or NH 2 groups, C 1 -C 6 alkyl optionally substituted by one or more halogen atoms, C 1 -C 6 alkoxy optionally substituted by one or more OH groups or C 1 -C 4 alkoxy, (SO 2 )NR 19 R 21 , (SO 2 )R 21 , C(O)NR 19 R 21 , C(O)OR 19 , C(O)R 19 , SR 19 , OR 19 , oxo, CN, NO 2 , halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R 19 and R 20 are each independently H; C 1 -C 8 alkyl; C 3 -C 8 cycloalkyl; C 1 -C 4 alkoxy-C 1 -C 4 alkyl; (C 0 -C 4 alkyl)-aryl optionally substituted by one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; (C 0 -C 1 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, C 1 -C 6 alkyl and C(O)C 1 -C 6 alkyl; (C 0 -C 4 alkyl)-O-aryl optionally substituted by one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and (C 0 -C 4 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, C 1 -C 6 alkyl or C(O)C 1 -C 6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C 1 -C 4 alkoxy, C(O)NH 2 , C(O)NHC 1 -C 6 alkyl or C(O)N(C 1 -C 6 alkyl) 2 ; or
R 19 and R 20 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 —C 1 -C 6 alkyl; C 1 -C 6 alkyl optionally substituted by one or more halogen atoms; C 1 -C 6 alkoxy optionally substituted by one or more OH groups or C 1 -C 4 alkoxy; and C(O)OC 1 -C 6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy to a subject in need of such treatment.

2. The method according to claim 1 , wherein A is CR 4a .

3. The method according to claim 1 , wherein
R 1 is C 1 -C 8 alkyl optionally substituted by one or more halogen atoms; C 1 -C 8 alkoxy optionally substituted by one

Assignees

• Novartis Ag

Inventors

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

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title