Urea derivatives useful as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9890185-B2
Application number	US-201415105912-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 20, 2013
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

There are provided compounds of formula I, wherein R 1 , R 1A , R 1C to R 1E , R a , R b , X 1 , E and G 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

What is claimed is:

1. A compound of formula I,

wherein
R 1 represents
-L 1 -C(O)N(R 2a )R 2b ,
-L 2a -S(O) 0-1 —R 2c1 ,
-L 2b -S(O) 2 —R 2c2 ,
-L 3 -P(O)R 2d R 2e ,
—CH 2 N(R 2d1 )-Q-R 2f ,
—O—S(O) 2 —N(R 2g )R 2h ,
—N═S(O)(CH 3 ) 2 ,
—S(═O)(═NR 2i )CH 3 or
—O—C(R 2x )(R 2y )(R 2z );

L 1 , L 2a , L 2b and L 3 independently represent a bond, —C(R 3a )(R 3b )— or —OC(R 3a )(R 3b )—, wherein the O-atom of the latter substituent is attached to the phenyl ring,
or L 1 , L 2b or L 3 represents O;
R 2a represents —[C(R 3a )(R 3b )]—[C 1-4 alkylene]-R 3c or, when L 1 is not a bond, R 2a may alternatively represent H or R 4 ;
R 2b represents H or C 1-6 alkyl,
or, when L 1 is not a bond, R 2a and R 2b , together with the N-atom to which they are attached, may alternatively form a 4- to 7-membered heterocyclic group that is fully saturated or partially unsaturated and which heterocyclic group contains one N atom (the atom to which R 2a and R 2b are attached) and, optionally, one or more further heteroatoms selected from the group consisting of O, S and N, and which heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of halo, OH, oxo, C 1-4 alkyl and C 1-4 alkoxy;
R 3c represents [O—CH 2 (CH 2 ) 0-1 CH 2 ] 1-12 —R 5a , Het 1 or Het 2 ;
R 2c1 and R 2c2 independently represent
methyl optionally substituted by one or more halo groups,
Het 1 ,
Het 2 or
C 3-7 cycloalkyl optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, OH and C 1-2 alkoxy,

or, when L 2a is not a bond, R 2c1 may alternatively represent R 2c3 ,
or, when L 2b is not a bond, R 2c2 may alternatively represent R 2c3 ;
R 2c3 represents C 2-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl or phenyl, which latter four groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, OH and C 1-2 alkoxy;
R 2d represents C 1-4 alkyl;
R 2e represents C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy or OH;
or R 2d and R 2e together combine to form C 3-6 alkylene;
R 2d1 represents H or R 2d ;
Q represents C(O) or S(O) 2 ;
R 2f represents R 4 or, when Q represents C(O), R 2f may alternatively represent H;
R 2g and R 2h independently represent H or R 4 ;
R 2i represents H or methyl;
R 2x represents C 1-6 alkyl substituted by one or more OH groups;
R 2y and R 2z independently represent H or C 1-4 alkyl optionally substituted by OH;
R 3a and R 3b represent, independently at each occurrence, H or methyl;
R 4 represents, independently at each occurrence, Het 1 , Het 2 , C 1-6 alkyl, C 3-7 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, oxo, OH, C 1-2 alkoxy and N(R 4a )R 4b ;
R 5a represents OR 5b or N(R 5c )R 5d ;
R 4a , R 4b and R 5b to R 5d independently represent H or C 1-4 alkyl optionally substituted by one or more halo or OH substituents, or R 5c and R 5d or R 4a and R 4b , 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 5C and R 5d or R 4a and R 4b are attached) and, optionally, one or more further heteroatoms selected from the group consisting of O, S and N, and which heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of halo, OH, oxo, C 1-4 alkyl and C 1-4 alkoxy;
R 1A represents
H, OH, halo, cyano,
C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, OH, and C 1-2 alkoxy,
Het 1 or phenyl, which latter group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1-2 alkyl and C 1-2 alkoxy;

R 1C and R 1E independently represent H, halo, cyano or methyl;
R 1D represents trimethylsilyl, Het 1 , Het 2 , trifluoromethyl, C 2-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl or phenyl, which latter five groups are optionally substituted by one or more substituents selected from the group consisting of C 1-2 alkyl, halo, OH and C 1-2 alkoxy;
Het 1 represents, independently at each occurrence, a 5- to 10-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from the group consisting of N, O and S and which group is optionally substituted by one or more substituents selected from the group consisting of OH, halo, N(R 4a )R 4b , C 1-2 alkyl and C 1-2 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
Het 2 represents, independently at each occurrence, a 4- to 8-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or more heteroatoms selected from the group consisting of N, O and S and which group is optionally substituted by one or more substituents selected from the group consisting of OH, oxo, N(R 4a )R 4b , C 1-2 alkyl and C 1-2 alkoxy;
R a and R b , 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 a and R b 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 a and R b 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 CH or N;
E represents N(G 1 ), O or S;
G represents
phenyl optionally substituted by one or more Y 1 ,
Het 3 optionally substituted by one or more Y 2 ,
R 6a or
C(O)R 6b ;

G 1 represents H or C 1-3 alkyl;
or G and G 1 together combine to form
C 3-6 n-alkylene,
C 4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O) 0-2 - or —N(R c )— or
C 6 n-alkylene interrupted between C2 and C3, or between C3 and C4, by —O—, —S(O) 0-2 - or —N(R c )—,

any of which n-alkylene groups are optionally substituted by one or more substituents selected from the group consisting of halo, OH, oxo, C 1-4 alkyl and C 1-4 alkoxy, which latter two groups are optionally substituted by one or more halo atoms or by OH;
each Y 1 is independently selected from the group consisting of
halo, OH, cyano, SF 5 , CO 2 H, —OC(O)NH 2 ,
P(O)R 6c R 6d ,
E 1 -N(R 6e )R 6f ,
E 2 -S(O) 2 R 6g ,
E 3 -[C(R 3a )(R 3b )(CH 2 ) 0-1 CH 2 —O] 2-8 —R 6h ,
—C≡C—R 6i ,
—N═S(O)R 6j R 6k ,
Het a ,
C 1-6 alkyl, C 3-6 cycloalkyl, alkoxy, C 3-6 cycloalkoxy, —S(O) 0-1 —C 1-6 alkyl and —S(O) 0-1 —C 3-6 cycloalkyl which latter six groups are optionally substituted by one or more substituents selected from the group consisting of halo, OH, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl;

each Y 2 independently represents oxo or Y 1 ;
E 1 represents
a direct bond,
—C(O)—,
—S(O) 2 —,
—[C(O)] p —C 1-8 alkyl

Assignees

• Respivert Ltd
• Topivert Pharma Ltd

Inventors

• Fyfe Matthew Colin Thor
• Thom Stephen Malcolm
• Baker Thomas Matthew
• Harbottle Gareth William
• Hasimbegovic Vedran
• Rigby Aaron

Classifications

• 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

• A61P37/06

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

• A61P37/08

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title