Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9527846-B2
Application number	US-201615131401-A
Country	US
Kind code	B2
Filing date	Apr 18, 2016
Priority date	Dec 9, 2011
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof:

wherein R 2 , W, A, Y and R 1 are as defined in the specification, are p38 MAPK inhibitors, and are useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.

First claim

The invention claimed is:

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein;
W is N or O, wherein N is substituted with hydrogen, C 1 -C 6 alkyl, or C 3 -C 5 cycloalkyl;
Y is —O—;
R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, fluorine, or C 1 -C 6 alkyl, or, respectively, R 3 and R 4 , or R 5 and R 6 form, together with the carbon atom to which they are attached, a saturated 3-6 membered carbocyclic monocyclic ring optionally substituted by a group C 1 -C 6 alkyl, hydroxyl, or halo;
n is 0, 1, 2, or 3;
R 7 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl wherein said C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl are optionally substituted by a C 1 -C 3 alkyl group, C 3 -C 6 cycloalkyl group, hydroxyl, cyano, or halo;
R 1 is a group represented by formula (IIb)

X 1 is a group —(CH)—;
R 10 is hydrogen, —CN, —NR A R B , —N(R C )(C 2 -C 6 alkylene)-NR A R B , —N(R C )(C 3 -C 7 cycloalkylene)-NR A R B , —(C 1 -C 6 alkylene)-NR A R B , —(C 3 -C 7 cycloalkylene)-NR A R B , —O—(C 2 -C 6 alkylene)-NR A R B , —O—(C 3 -C 7 cycloalkylene)-NR A R B , —S—(C 2 -C 6 alkylene)-NR A R B , —S—(C 3 -C 7 cycloalkylene)-NR A R B , —N(R C )C(O)—(C 1 -C 6 alkylene)-NR A R B , —N(R C )C(O)—(C 3 -C 7 cycloalkylene)-NR A R B , —C(O)N(R C )—(C 2 -C 6 alkylene)-NR A R B , —C(O)N(R C )—(C 3 -C 7 cycloalkylene)-NR A R B , —C(O)N(R C )—(C 2 -C 6 alkylene)-OR D , —C(O)N(R C )—(C 3 -C 7 cycloalkylene)-OR D , —N(R C )C(O)NR A R B , —C(O)NR A R B , —N(R C )C(O)N(R C )—(C 2 -C 6 alkylene)-NR A R B , —N(R C )C(O)N(R C )—(C 3 -C 7 cycloalkylene)-NR A R B , —(C 2 -C 6 alkylene)-OR D , —(C 3 -C 7 cycloalkylene)-OR D , —O—(C 2 -C 6 alkylene)-OR D , —O—(C 3 -C 7 cycloalkylene)-OR D , —S—(C 2 -C 6 alkylene)-OR D , —S—(C 3 -C 7 cycloalkylene)-OR D , —N(R C )S(O) 2 —(C 1 -C 6 alkylene)-NR A R B , —N(R C )S(O) 2 —(C 3 -C 7 cycloalkylene)-NR A R B , —S(O) 2 N(R C )—(C 2 -C 6 alkylene)-NR A R B , —S(O) 2 N(R C )—(C 3 -C 7 cycloalkylene)-NR A R B , —S(O) 2 N(R C )—(C 2 -C 6 alkylene)-OR D , —S(O) 2 N(R C )—(C 3 -C 7 cycloalkylene)-OR D , —N(R C )S(O) 2 —(C 2 -C 6 alkylene)-OR D , —N(R C )S(O) 2 —(C 3 -C 7 cycloalkylene)-OR D , —S(O) 2 N(R A R B ), —N(R C )S(O) 2 R D , —N(R C )C(O)R C , —OR C , —SR C , —(C 3 -C 7 heterocycloalkyl), (C 5 -C 7 heterocycloalkyl)-(C 1 -C 6 alkyl), (C 5 -C 7 heterocycloalkyl)(C 3 -C 6 cycloalkyl)-, or C 3 -C 7 heterocycloalkylcarbonyl; wherein any of the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)-(C 2 -C 6 alkylene)-, —(C 3 -C 7 cycloalkylene)-, —(C 3 -C 7 heterocycloalkyl), (C 5 -C 7 heterocycloalkyl)-(C 1 -C 6 alkyl), (C 5 -C 7 heterocycloalkyl)-(C 3 -C 6 cycloalkyl) and (C 3 -C 7 heterocycloalkyl)carbonyl portion in the above listed groups may be optionally substituted by a C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, hydroxyl, or halo;
R A and R B are at each occurrence independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl, such C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl being optionally substituted by a C 1 -C 3 alkyl group, C 3 -C 7 cycloalkyl group, —OR D , —CN or halo; alternatively, R A and R B , form, together with the nitrogen atom to which they are attached, a 5-11- membered saturated heterocyclic monocyclic or bicyclic ring system which is optionally substituted by one or more of —OR D , —CN, halo, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, such C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl being optionally substituted by a C 1 -C 3 alkyl group, C 3 -C 7 cycloalkyl group, —OR D , —CN or halo; and which 5-11- membered saturated heterocyclic monocyclic or bicyclic ring optionally contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein any of said C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl may be optionally substituted by a C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, —OR D , —CN, or halo; or R A and R B may be linked to one carbon atom of the —(C 1 -C 6 alkylene)-, —(C 2 -C 6 alkylene)- or —(C 3 -C 7 cycloalkylene)- portion of the group linked to the nitrogen to which they are connected to form a saturated cycle of up to 6 ring atoms;
R C is at each occurrence independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, said C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl being optionally substituted by a C 1 -C 3 alkyl group, —OR D , —CN, or halo;
R D is at each occurrence independently hydrogen, —CH 3 , or —C 2 H 5 ;
R 12 is hydrogen, C 1 -C 6 alkyl, or halogen;
A is a divalent cycloalkylene radical having 5, 6, or 7 ring atoms; said cycloalkylene ring being attached to W and Y, and fused to a phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ring atoms, said phenyl or heteroaryl ring being optionally substituted by one or two groups R 24 ;
R 24 is at each occurrence independently C 1 -C 6 alkyl, halogen, or cyano;
R 2 is a group of formula (IIIb):

wherein
R 17 is a group of formula (IV)

wherein
R 20 is —CH 3 , or —CH 2 OMe;
R 21 is —CH 3 ;
or
R 18 is lone electron pair, hydrogen, aryl, heteroaryl, —(C 1 -C 6 alkyl), —(C 3 -C 7 cycloalkyl), —(C 3 -C 7 heterocycloalkyl), (C 5 -C 7 heterocycloalkyl)-(C 1 -C 6 alkyl) or (C 5 -C 7 heterocycloalkyl)-(C 3 -C 6 cycloalkyl), wherein any of such aryl, heteroaryl, —(C 1 -C 6 alkyl), —(C 3 -C 7 cycloalkyl), —(C 3 -C 7 heterocycloalkyl), (C 5 -C 7 heterocycloalkyl)-(C 1 -C 6 alkyl) and (C 5 -C 7 heterocycloalkyl)-(C 3 -C 6 cycloalkyl) may be optionally substituted by —CN, —OH, halo, —COOR M , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O—(C 1 -C 6 alkyl), —O—(C 3 -C 6 cycloalkyl), —S—(C 1 -C 6 alkyl), —S—(C 3 -C 6 cycloalkyl), —NR H R J , —N(R L )(C 2 -C 6 alkylene)-NR H R J , —N(R L )(C 3 -C 7 cycloalkylene)-NR H R J , —(C 1 -C 6 alkylene)-NR H R J , —(C 3 -C 7 cycloalkylene)-NR H R J , —O—(C 2 -C 6 alkylene)-NR H R J , —O—(C 3 -C 7 cycloalkylene)-NR H R J , —S—(C 2 -C 6 alkylene)-NR H R J , —S—(C 3 -C 7 cycloalkylene)-NR H R J , —N(R L )C(O)—(C 1 -C 6 alkylene)-NR H R J , —N(R L )C(O)—(C 3 -C 7 cycloalkylene)-NR H R J , —C(O)N(R L )—(C 2 -C 6 alkylene)-NR H R J , —C(O)N(R L )—(C 3 -C 7 cycloalkylene)-NR H R J , —C(O)N(R L )—(C 2 -C 6 alkylene)-OR M , —C(O)N(R L )—(C 3 -C 7 cycloalkylene)-OR M , —N(R L )C(O)N(R H R J ), —C(O)N(R H R J ), —N(R L )C(O)N(R L )—(C 2 -C 6 alkylene)-NR H R J , —N(R L )C(O)N(R L )—(C 3 -C 7 cycloalkylene)-NR H R J , —O—(C 2 -C 6 alkylene)-OR M , —O—(C 3 -C 7 cycloalkylene)-OR M , —S—(C 2 -C 6 alkylene)-OR M , —S—(C 3 -C 7 cycloalkylene)-OR M , —N(R L )S(O) 2 —(C 1 -C 6 alkylene)-NR H R J , —N(R L )S(O) 2 —(C 3 -C 7 cycloalkylene)-NR H R J , —S(O) 2 N(R L )—(C 2 -C 6 alkylene)-NR H R J , —S(O) 2 N(R L )—(C 3 -C 7 cycloalkylene)-NR H R J , —S(O) 2 N(R L )—(C 2 -C 6 alkylene)-OR M , —S(O) 2 N(R L )—(C 3 -C 7 cycloalkylene)-OR M , —N(R L )S(O) 2 —(C 2 -C 6 alkylene)-OR M , —N(R L )S(O) 2 —(C 3 -C 7 cycloalkylene)-OR M , —S(O) 2 N(R H R J ), —N(R L )S(O) 2 R L , —N(R L )C(O)R L , OR L , SR L , —(C 3 -C 7 heterocycloalkyl), (C 5 -C 7 heterocycloalkyl)-(C 1 -C 6 alkyl) or (C 5 -C 7 heterocycloalkyl)-(C 3 -C 6 cycloalkyl), wherein any of such C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)- —(C 2 -C 6 alkylene)-, —(C 3 -C 7 cycloalkylene)-, —(C 3 -C 7 heterocycloalkyl), (C 5 -C 7 heterocycloalkyl)-(C 1 -C 6 alkyl) and (C 5 -C 7

Assignees

• Chiesi Farm Spa

Inventors

• Van Niel Monique Bodil
• Ray Nicholas Charles
• Alcaraz Lilian
• Panchal Terry Aaron
• Jennings Andrew Stephen Robert
• Armani Elisabetta
• Cridland Andrew Peter
• Hurley Christopher

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• 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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/06

  Antiasthmatics · CPC title