Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9751837-B2
Application number	US-201514872527-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Oct 1, 2014
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

There are provided compounds of formula I,

wherein R 1A to R 1E , R 2 to R 4 , R 5a , L and X 1 to X 3 have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

First claim

The invention claimed is:

1. A compound of formula I,

wherein:
R 1A represents
C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, which latter four groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, hydroxy, —OP(O)(OH) 2 and C 1-2 alkoxy,
H, halo, cyano,
phenyl or Het 1 , which latter two groups are optionally substituted with one or more substituents selected from the group consisting of C 1-2 alkyl and C 1-2 alkoxy,
or R 1A and R 1B together represent a structural fragment selected from the following

wherein the wavy lines represent the points of attachment to the phenyl ring;
A represents O, S or N(R A2 );
R A1 represents H, C 1-4 alkyl or hydroxy;
R A2 represents H or C 1-4 alkyl;
R 1B represents —NR X S(O) 2 R Y1 , —C(O)NR X R Y , H, halo, cyano, —C 1-4 alkylene-CN, —C 1-4 alkylene-OH, —NR X R X1 , —C(O)OR X , —S(O) 2 NR X R Y , —NR X C(O)R Y , —NR X2 S(O) 2 NR X R Y , —NR X P(O)R Y1 R Y2 , —NR X C(O)OR Y1 or Het 1 optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C 1-2 alkyl and C 1-2 alkoxy;
R X and R X1 independently represent H or C 1-6 alkyl optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, —OP(O)(OH) 2 and C 1-2 alkoxy, or R X and R X1 together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O— or —N(R X2 )—, or R X1 represents Het 1 optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C 1-2 alkyl and C 1-2 alkoxy;
R Y , R Y1 and R Y2 independently represent C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, benzyl, Het 1 or Het 2 , which latter six groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, hydroxy, —OP(O)(OH) 2 , C 1-2 alkoxy, C(O)OH, C(O)O—(C 1-4 alkyl) and —N(R a )(R b ), and/or which Het 2 group is substituted with one or more oxo groups,
or R Y represents H,
or R X and R Y together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O) n — or —N(R X2 )—;
R a and R b independently represent H, methyl or —C(R c )(R d )—C 1-3 alkyl, the C 1-3 alkyl portion of which latter group is optionally substituted by one or more hydroxy substituents,
or R a and R b together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O) m — or —N(R X2 )—;
R c and R d independently represent H or methyl;
each R X2 independently represents H or C 1-4 alkyl;
R 1C and R 1E independently represent H, halo, cyano or methyl;
provided that at least one of R 1A , R 1B , R 1C and R 1E is other than H;
R 1D represents trimethylsilyl, C 2-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter seven groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, cyano, hydroxy, —OP(O)(OH) 2 and C 1-2 alkoxy;
R 2 and R 3 , together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from the group consisting of C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo,
or one of R 2 and R 3 represents H, halo, cyano, C 1-3 alkyl or C 1-3 haloalkyl and the other independently represents halo, cyano, C 1-3 alkyl or C 1-3 haloalkyl,

or R 2 and R 3 together combine to form C 3-5 alkylene or C 3-5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from the group consisting of C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo;
X 1 represents N or CH;
L represents a direct bond or C 1-2 alkylene;
X 2 represents CR Z or N;
X 3 represents CR 5b or N;
R Z represents H, halo, cyano, hydroxy, C 1-3 alkyl or C 1-3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
R 4 represents
-Q 1 -[C(R 6c )(R 6d )—(CH 2 ) 0-1 CH 2 —Z] 1-12 —CH 2 (CH 2 ) 0-1 CH 2 —R 6a ,
-Q 2 -C(R 6c )(R 6d )—[C 1-5 alkylene]-R 6a , which C 1-5 alkylene group is optionally substituted by oxo and/or by one or more R 6e ,
-Q 3 -[C 1-4 alkylene] 0-1 -Het x1 , which C 1-4 alkylene group is optionally substituted by oxo and/or by one or more R 6e and which Het x1 group is optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, oxo, C 3-6 cycloalkyl, C 1-3 alkoxy and —[C(O)] 0-1 —C 1-4 alkyl, the C 1-4 alkyl part of which latter group is optionally substituted by one or more R 6e ,
-Q 22 -[C 1-4 alkylene] 0-1 -phenyl, which C 1-4 alkylene group is optionally substituted by oxo and/or by one or more R 6e , and which phenyl group is substituted by —[C(O)] 0-1 —C 1-4 alkyl, the C 1-4 alkyl part of which latter group is optionally substituted by one or more R 6e , and which phenyl group is optionally further substituted by one or more substituents selected from the group consisting of halo, hydroxy, oxo, C 3-6 cycloalkyl and C 1-3 alkoxy,
—S(O) p R 6b ,
—[C 1-4 alkylene] 01 -CO 2 H,
Het x2 which Het x2 group is optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, oxo, C 1-3 alkyl and C 1-3 alkoxy,
—COR 6b ,
—CH 2 OH,
—CH 2 OP(O)(OH) 2 or
-Q 4 -P(O)(OR 9 )(R 7 );
Z represents, independently upon each occurrence, O, C(O)N(R 8 ) or N(R 8 )C(O);
R 5a and R 5b independently represent C 1-3 alkoxy or C 1-3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R 5a and R 5b independently represent —N(R e )(R f ), C 2-3 alkynyl, H, cyano, —C(O)NH 2 , hydroxy, halo or —S(O) 0-2 —C 1-3 alkyl;
R 6a represents OR 7a , —S(O) 0-2 R 7aa , N(R 7b )R 7c or CO 2 H;
R 6b represents C 1-8 alkyl, C 3-8 cycloalkyl, phenyl, Het 1 or Het 2 , which latter five groups are optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, —OP(O)(OH) 2 , C 1-3 alkyl, C 1-3 alkoxy, —C 1-3 alkylene-R 6e and CO 2 H,
or R 6b represents —C 1-4 alkylene-Het 3 , which Het 3 group is optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, oxo, C 3-6 cycloalkyl, C 1-3 alkoxy and —[C(O)] 0-1 —C 1-3 alkyl, which C 1-3 alkyl group is optionally substituted by one or more R 6e ,
or, when p is 1 or 2, R 6b may alternatively represent OH,
or, when p is 2, R 6b may alternatively represent —N(R 7b )R 7c or —N(R 7b )—C(O)—R 7c ;
R 6e represents, independently upon each occurrence, halo, hydroxy, —OP(O)(OH) 2 , C 1-3 alkoxy, —N(R g )(R h ) or —CO 2 H;
R 7a to R 7c independently represent H or C 1-4 alkyl optionally substituted by one or more halo atoms or by —CO 2 H,
or R 7a represents P(O)(OH) 2 or Het 3 , which latter group is optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, oxo, C 3-6 cycloalkyl, C 1-3 alkoxy and —[C(O)] 0-1 —C 1-3 alkyl, which C 1-3 alkyl group is optionally substituted by one or more R 6e ,
or R 7b and/or R 7c represents —[C a alkylene]-[C b alkylene]-OR 7d ,
or R 7b and R 7c together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R 7b and R 7c are attached) and, optionally, one or more further heteroatoms selected from the group

Assignees

• Respivert Ltd
• Topivert Pharma Ltd

Inventors

• Baker Thomas Matthew
• Fyfe Matthew Colin Thor
• Jones Geraint
• Thom Stephen Malcolm

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title