Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9440974-B2
Application number	US-201514868516-A
Country	US
Kind code	B2
Filing date	Sep 29, 2015
Priority date	Jun 6, 2013
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

Compounds of formula (I) described herein 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 method of treating a disease or condition selected from the group consisting of chronic eosinophilic pneumonia, asthma, COPD, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy, and airways disease that is associated with pulmonary hypertension, comprising administering, to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein
W is N substituted with —H;
Y is —O—;
R 1 is a group (IIc):

X 2 , X 3 , X 4 and X 5 are each independently a carbon atom, a nitrogen atom, a group —(CH)— or a group —NH—; such that each combination thereof forms an aromatic ring system;
R 11 is linked to X 4 and is selected from the group consisting of —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 ; and (C 3 -C 7 )heterocycloalkyl, wherein said (C 3 -C 7 )heterocycloalkyl may be optionally substituted with one, two, or three C 1 -C 6 alkyl groups;
R A and R B are at each occurrence independently —H, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl being optionally substituted by a group C 1 -C 3 alkyl C 3 -C 7 cycloalkyl, —OR D , —CN or halo; alternatively, R A and R B , may form together with the nitrogen atom to which they are attached an azetidine or a 4-11-membered saturated heterocyclic monocyclic or bicyclic ring system which is optionally substituted by one or more groups —OR D , —CN, halo, C 1 -C 6 alkyl, (C 1 -C 6 )hydroxyalkyl or C 3 -C 7 cycloalkyl, said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl being optionally substituted by a group C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, —OR D , —CN or halo; and which 4-11-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 group C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —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 —H, C 1 -C 6 alkyl, (C 1 -C 4 )hydroxyalkyl or C 3 -C 6 cycloalkyl, said C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl being optionally substituted by a group C 1 -C 3 alkyl, —OR D , —CN or halo;
alternatively R C may be linked to one carbon atom of the —(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 D is at each occurrence independently —H, —CH 3 or —C 2 H 5 ;
R 13 is —H, C 1 -C 6 alkyl, or halogen;
A is a divalent cycloalkylene radical having 6 ring atoms; said cycloalkylene ring being attached to W and Y and fused to a phenyl ring;
R 2 is a radical of formula (IIIb):

wherein
R 17 is a group of general formula (IV)

wherein
R 20 is —CH 3 ;
R 21 is —CH 3 ;
R 18 is selected from the group consisting of aryl and heteroaryl, wherein any of said aryl or heteroaryl is substituted by two or more groups independently selected from the group consisting of —CN, —OH, ═O, halo, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-NR H R J , and —O—(C 2 -C 6 alkylene)-NR H R J , wherein any of said C 1 -C 6 alkyl portion in the above listed groups may be optionally substituted by a group —OR L ;
R H and R J are each C 1 -C 6 alkyl; alternatively, R H and R J may form together with the nitrogen atom to which they are attached a 4-11-membered saturated monocyclic or bicyclic heterocyclic ring system which is optionally substituted by one or more groups —OR M or NR O R P ; and which 4-11-membered saturated monocyclic or bicyclic heterocyclic ring optionally contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C 1 -C 6 alkyl;
R L is —H;
R M is at each occurrence independently —H or C 1 -C 6 alkyl;
R O and R P are each C 1 -C 6 alkyl; and
z 1 is CH, z 2 is C, and z 3 and z 4 are N.

2. A method according to claim 1 , wherein
R A and R B form together with the nitrogen atom to which they are attached an azetidine or a 4-11-membered saturated heterocyclic monocyclic or bicylcic ring system which is optionally substituted by one or more groups —OR D , —CN, halo, C 1 -C 6 alkyl, (C 1 -C 6 )hydroxyalkyl or C 3 -C 7 cycloalkyl, said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl being optionally substituted by a group C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, —OR D , —CN or halo; and which 4-11-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 group C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —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.

3. A method according to claim 1 , wherein A is group

R 1 is a group of formula (IIca) which is connected to the group Y through the carbon adjacent to X 2

X 4 is a carbon atom, X 5 is a nitrogen atom, X 3 is a nitrogen atom and X 2 is a group —CH—, and R 13 is —H;
R 11 is a group:

wherein R 25 is optionally present and represents one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 4 )hydroxyalkyl, C 3 -C 7 cycloalkyl, hydroxyl and halo; and wherein the asterisk represents the point of attachment for group R 11 to the rest of the molecule via X 4 ;
z 1 =—CH—, z 2 =C, z 3 and z 4 are N
R 18 is aryl substituted by two or more groups independently selected from the group consisting of —CN, —OH, halo, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), (C 1 -C 6 alkylene)-NR H R J , and —O—(C 2 -C 6 alkylene)-NR H R J , wherein any of said C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-, and —(C 2 -C 6 alkylene)- portion may be optionally substituted by a group OR L or halo;
R H and R J are independently —H or C 1 -C 6 alkyl; or R H and R J may form together with the nitrogen atom to which they are attached a 4-11-membered saturated monocyclic or bicyclic heterocyclic ring system which 4-11-membered saturated monocyclic or bicyclic heterocyclic ring optionally contain a fur

Assignees

• Chiesi Farm Spa

Inventors

• Alcaraz Lilian
• Hurley Christopher
• Cridland Andrew Peter
• Jennings Andrew Stephen Robert

Classifications

• A61P29/00

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07C53/06

  Salts thereof · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title