Pyrazolyl-ureas as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2020002311-A1
Application number	US-201916366103-A
Country	US
Kind code	A1
Filing date	Mar 27, 2019
Priority date	Feb 14, 2014
Publication date	Jan 2, 2020
Grant date	—

Abstract

There are provided compounds of formula (I) as defined in the specification which are p38 MAP kinase inhibitors for use as medicaments for the treatment inter alia of inflammatory diseases.

First claim

1 . A compound of formula (I):

wherein:
R 1 represents

Q represents N or CH;
R 2a , R 2b and R 2c are independently selected from hydrogen, hydroxyl, halogen, —C 1-6 alkyl, —C 1-6 haloalkyl, C 3-5 cycloalkyl; —C 1-3 alkylene-OH, —OC 2-3 alkylene-OH, —C 1-6 alkoxy, —C 1-3 alkylene-N—(C 1-3 alkyl) 2 , —N(C 1-3 alkyl) 2 , —SC 1-3 alkyl and —C 1-3 alkylene-S—C 1-3 alkyl;
R 2d and R 2e are defined as follows: either
(i) R 2d represents hydrogen, —C 1-8 alkyl in which 1 to 3 carbon atoms are optionally substituted by halogen, —C 0-2 alkylene-Cyc, —C 0-2 alkylene-Het, —CH 2 -J,
—C≡C—CH 2 -J, —NR 3 R 4 , —OR 5 or —CN; and R 2e represents hydrogen or —C 1-6 alkyl; or

(ii) R 2e represents —C 0-2 alkylene-Cyc, —C 0-2 alkylene-Het, —CO—K-Cyc, —CO—K′-Het, —CO—K′-HetAr, —CH 2 -J, —CO-J′, or —C 1-8 alkyl in which 1 to 3 carbon atoms are optionally substituted by halogen; and R 2d represents hydrogen or —C 1-6 alkyl; or
(iii) R 2d and R 2e are joined and together represent a C 3-5 alkylene chain in which one carbon atom of said alkylene chain, not being in a position adjacent to the pyrazine ring, is optionally replaced by O or NR 2f wherein R 2f represents H or C 1-3 alkyl and wherein a carbon atom of said alkylene chain is optionally substituted by one or more groups selected from halogen, oxo and methyl;

J and J′ independently represent a C 1-10 alkyl moiety in which 1, 2 or 3 carbon atoms are replaced by a heteroatom selected from O and N provided that any two heteroatoms if present are separated by at least two carbon atoms and wherein 1 or 2 carbon atoms are optionally substituted by oxo and which moiety is optionally substituted by 1 to 3 halogen groups provided that J′ does not represent OH;
K and K′ independently represent a bond or a C 1-10 alkylene chain in which 1, 2 or 3 carbon atoms are optionally replaced by a heteroatom selected from O and N provided that any two heteroatoms if present are separated by at least two carbon atoms and provided that neither K nor K′ represents O;
R 3 and R 4 independently represent H or —C 1-8 alkyl optionally substituted by 1 to 3 groups selected from hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen and wherein 1 or 2 carbon atoms of said alkyl are optionally substituted by oxo; or R 3 and R 4 are joined such that —NR 3 R 4 together represents a 4-7 membered heterocyclic ring optionally substituted by one to three groups selected from C 1-3 alkyl, hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen in which a carbon atom separated by at least two carbon atoms from the nitrogen atom is optionally replaced by a heteroatom selected from O and N; and wherein a methylene group is optionally substituted by oxo; or R 3 represents C 3-6 cycloalkyl and R 4 represents hydrogen;
R 5 represents —C 1-8 alkyl optionally substituted by 1 to 3 groups selected from hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen and wherein 1 to 3 carbon atoms are optionally substituted by halogen;
Het represents a 4 to 7 membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms selected from O, S and N or an 8 to 10 membered non-aromatic bicyclic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S and N in either case optionally substituted by one to three groups selected from C 1-3 alkyl, hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl-, C 1-3 haloalkyl, halogen, oxo, —N(C 1-3 alkyl) 2 , —C(═O)C 1-3 alkyl, —C(═O)OC 1-3 alkyl, —C 1-3 alkylene-N—(C 1-3 alkyl) 2 , —C 1-3 alkylene-O—C 1-3 alkyl, C 3-6 cycloalkyl and a 4-6 membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms selected from O, S and N optionally substituted by methyl, provided that Het is not directly attached to the pyrazine ring via a heteroatom and wherein a methylene group is optionally substituted by oxo;
Cyc represents a 3 to 7 membered non-aromatic carbocyclic ring optionally substituted by 1 to 3 groups selected from C 1-3 alkyl, hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen and wherein a methylene group is optionally substituted by oxo; and
HetAr represents a 5- or 6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S and optionally substituted by one to three groups selected from C 1-3 alkyl, hydroxyl, C 1-3 alkoxy, hydroxyC 1-4 alkyl-, halogen and C 1-3 haloalkyl;
or a pharmaceutically acceptable salt thereof.

2 . A compound of formula (I) according to claim 1 wherein:
R 1 represents

Q represents N or CH;
R 2a , R 2b and R 2c are independently selected from hydrogen, hydroxyl, halogen, —C 1-6 alkyl, —C 1-6 haloalkyl, C 3-5 cycloalkyl; —C 1-3 alkylene-OH, —OC 2-3 alkylene-OH, and —C 1-6 alkoxy;
R 2d and R 2e are defined as follows: either
(i) R 2d represents hydrogen, —C 1-8 alkyl in which 1 to 3 carbon atoms are optionally substituted by halogen, —C 0-2 alkylene-Cyc, —C 0-2 alkylene-Het, —CH 2 -J, —NR 3 R 4 , —OR 5 or —CN; and R 2e represents hydrogen or —C 1-6 alkyl; or
(ii) R 2e represents —C 1-8 alkyl in which 1 to 3 carbon atoms are optionally substituted by halogen, —C 0-2 alkylene-Cyc, —C 0-2 alkylene-Het, —CO—K-Cyc, —CO—K′-Het, —CH 2 -J, —CO-J′; and R 2d represents hydrogen or —C 1-6 alkyl; or
(iii) R 2d and R 2e are joined and together represent a C 3-5 alkylene chain in which one carbon atom of said alkylene chain, not being in a position adjacent to the pyrazine ring, is optionally replaced by O or NR 2f wherein R 2f represents H or C 1-3 alkyl and wherein a carbon atom of said alkylene chain is optionally substituted by one or more groups selected from halogen, oxo and methyl;

J and J′ independently represent a C 1-7 alkyl moiety in which 1, 2 or 3 carbon atoms are replaced by a heteroatom selected from O and N provided that any two heteroatoms if present are separated by at least two carbon atoms and wherein 1 or 2 carbon atoms are optionally substituted by oxo and which moiety is optionally substituted by 1 to 3 halogen groups provided that J′ does not represent OH;
K and K′ independently represent a bond or a C 1-7 alkylene chain in which 1, 2 or 3 carbon atoms are optionally replaced by a heteroatom selected from O and N provided that any two heteroatoms if present are separated by at least two carbon atoms and provided that neither K nor K′ represents O;
R 3 and R 4 independently represent H or —C 1-8 alkyl optionally substituted by 1 to 3 groups selected from hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen and wherein 1 or 2 carbon atoms of said alkyl are optionally substituted by oxo; or R 3 and R 4 are joined such that —NR 3 R 4 together represents a 4-7 membered heterocyclic ring optionally substituted by one to three groups selected from C 1-3 alkyl, hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen in which a carbon atom separated by at least two carbon atoms from the nitrogen atom is optionally replaced by a heteroatom selected from O and N; and wherein a methylene group is optionally substituted by oxo; or R 3 represents C 3-6 cycloalkyl and R 4 represents hydrogen;
R 5 represents —C 1-8 alkyl optionally substituted by 1 to 3 groups selected from hydroxyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl and halogen and wherein 1 to 3 carbon atoms are optionally substituted by halogen;
Het represents a 4-7 membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms selected from O and N optionally substituted by one to three groups selected fro

Assignees

• Respivert Ltd

Inventors

• Longshaw Alistair Ian
• Fordyce Euan Alexander Fraser
• Onions Stuart Thomas
• King-Underwood John
• Venable Jennifer Diane
• Walters Lain

Classifications

• A61P37/08

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

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title