Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2016229852-A1
Application number	US-201615131401-A
Country	US
Kind code	A1
Filing date	Apr 18, 2016
Priority date	Dec 9, 2011
Publication date	Aug 11, 2016
Grant date	—

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

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 a group —S(O) p — wherein p is 0, 1 or 2; a group —O(CR 3 R 4 ) n —; a group —(CR 5 R 6 ) n —; a group —NR 7 —; a group —OC(O)—; a group —OC(O)NH—; or a group —OC(O)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 (IIa), (IIb), or (IIc):

R 8 and R 9 are each independently hydrogen or C 1 -C 6 alkyl, or R 8 and R 9 may form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or a fused or Spiro bicyclic ring system optionally containing a further heteroatom which is oxygen or nitrogen, said nitrogen atom being optionally substituted by C 1 -C 6 alkyl; wherein said C 1 -C 6 alkyl groups may be optionally substituted by a C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, hydroxyl, or halo;
X 1 , 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 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 11 is linked to X 4 and is hydrogen; —CN; C 1 -C 6 alkyl which is substituted by —CN, —OR C , —SR C , or halo; C 3 -C 6 cycloalkyl which is substituted by C 1 -C 4 alkyl, —CN, —OR C , —SR D , or halo; —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)N(R A R B ), —C(O)N(R 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 , —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 heterocycloalkyl)carbonyl, 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), (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 one, two or three groups R 25 which are 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; or
R 11 is linked to X 4 and is phenyl or 5- or 6-membered monocyclic heteroaryl, wherein such phenyl or 5- or 6-membered monocyclic heteroaryl is substituted by a group selected from the group consisting of C 1 -C 6 alkyl which is substituted by a group —CN; C 3 -C 6 cycloalkyl which is substituted by —CN, —OR C , —SR C or halo; —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 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)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 , —O—(C 3 -C 7 cycloalkylene)-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 , —N(R C )S(O) 2 R D , —(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, 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

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