Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9783556-B2
Application number	US-201314424240-A
Country	US
Kind code	B2
Filing date	Aug 28, 2013
Priority date	Aug 29, 2012
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

There are provided compounds of formula I, (I):

wherein R 1 to R 5 , X 1 , X 2 , Ar, L, E, A, A1, G and G 1 have meanings given in the description, which compounds have anti-inflammatory 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 1 and R 2 independently represent C 1-4 alkyl or C 3-6 cycloalkyl, or R 1 and R 2 together combine to form C 2-6 alkylene;
R 3 represents C 1-2 alkyl;
X 1 and X 2 are both N, or X 1 is C and X 2 is either O or S;
Ar is phenyl or a 5- or 6-membered heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S, which phenyl and heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, amino and cyano;
L is a direct bond or C 1-2 alkylene;
E represents:
(a) H, halo, hydroxy, NR 6a R 6b , cyano, C(O)OR 6c , C(O)NR 6d R 6e , SH, S(O) n R 8 , S(O) 2 NR 6f R 6g ,
(b) C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from the group consisting of halo and NR 7a R 7b ,
(c) C 3-8 cycloalkyl, Het 1 or Ar 1 , which latter three groups are optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy and C 1-3 alkyl;

R 6a to R 6g independently represent H or C 1-4 alkyl, or
any one or more of the pairs R 6a and R 6b , R 6d and R 6e , and R 6f and R 6g , when taken together with the N-atom to which each pair is attached, form a saturated 4- to 7-membered heterocyclic group, which heterocyclic group contains one N atom (the atom to which the pairs of substituents 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 C 1-2 alkyl groups;
R 7a and R 7b , independently on each occurrence, represent H or C 1-4 alkyl, or, together with the N-atom to which they are attached, form a 5- 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 7a and R 7b 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, hydroxy, oxo, C 1-4 alkyl and C 1-4 alkoxy;
R 8 represents C 1-4 haloalkyl, C 1-4 alkyl, C 3-8 cycloalkyl or Ar 2 , which latter three groups are optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy and C 1-3 alkyl;
Ar 1 and Ar 2 independently represent C 6-14 carbocyclic aryl groups, which groups may be monocyclic, bicyclic or tricyclic and which groups contain at least one ring which is fully aromatic,
n is 0, 1 or 2;
R 4 and R 5 are each independently C 1-3 alkyl, C 1-3 haloalkyl, cyano or halo,
or R 4 and R 5 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,
or R 4 and R 5 , together with the C-atoms to which they are attached, form a fused phenyl or Het 2 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;
Het 1 and Het 2 independently represent 5- to 7-membered heterocyclic groups that are fully saturated, partially unsaturated or fully aromatic, which heterocyclic groups contain one or more heteroatoms selected from the group consisting of N, O and S;
one of A and A 1 represents N and the other represents CH, or both of A and A 1 represent CH;
G represents
phenyl optionally substituted by one or more Y 1 or
Het 3 optionally substituted by one or more Y 2 ;

G 1 represents H;
or G and G 1 together combine to form C 3-6 alkylene optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy and C 1-3 alkyl, which latter group is optionally substituted by one or more halo atoms or by hydroxy;
each Y 1 is independently selected from the group consisting of
halo, hydroxy, cyano, SF 5 , —OC(O)NH 2 ,
P(O)R 9a R 9b ,
J 1 -N(R 9c )R 9d ,
J 2 -S(O) 2 R 9e ,
J 3 -[CH 2 (CH 2 ) 0-1 CH 2 —O] 2-8 —R 9f ,
—C≡C—R 9g ,
—N═S(O)R 9h R 9i ,
Het a ,
C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 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, hydroxy, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl;

each Y 2 independently represents oxo or Y 1 ;
J 1 represents
a direct bond,
—C(O)—
—[C(O)] p —C 1-8 alkylene,
—C(O)NR 10a —CH 2 —[C 1-7 alkylene]-,
-Q 1 -CH 2 —[C 1-5 alkylene]-,
the alkylene parts of which latter four groups are optionally substituted by one or more substituents selected from the group consisting of halo, C 1-3 alkyl and hydroxy;

J 2 represents
a direct bond,
—O—,
—NH—
C 1-6 alkylene or
-Q 2 -CH 2 —[C 1-5 alkylene]-,
the alkylene parts of which latter two groups are optionally substituted by one or more substituents selected from the group consisting of halo, C 1-3 alkyl and hydroxy;

J 3 represents —O— or S(O) 0-2 ;
Q 1 and Q 2 independently represent O or S(O) 0-2 ;
p represents 0 or 1;
R 9a and R 9b independently represent C 1-3 alkyl or C 1-3 alkoxy, or R 9a and R 9b together combine to form C 4-6 alkylene;
R 9c and R 9d independently represent H or C 1-8 alkyl, which latter group is optionally substituted by R 10b and/or one or more substituents selected from the group consisting of halo and hydroxy; or
R 9c and R 9d , 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 9c and R 9d 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, hydroxy, oxo, C 1-4 alkyl and C 1-4 alkoxy;
R 9e represents C 1-6 alkyl, C 3-6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl;
R 9f , R 9g , R 9h and R 9i independently represent C 1-4 alkyl optionally substituted by one or more halo atoms, or R 9f and R 9g independently represent H;
R 10a represents H or C 1-3 alkyl optionally substituted by one or more halo atoms;
R 10b represents C 1-4 alkoxy, S—C 1-4 alkyl, phenyl or Het 4 , which latter two groups are optionally substituted by one or more substituents selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, amino and cyano;
Het 3 represents a 5- to 10-membered heteroaromatic group, which group is monocyclic or bicyclic and contains at least one carbocyclic or heterocyclic ring that is fully aromatic, and which group contains one or more heteroatoms selected from the group consisting of N, O and S;
Het 4 represents a 4- to 10-membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic, which heterocyclic group contains one or more heteroatoms selected from the group consisting of N, O and S; and
Het a represents a 5- or 6-membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic, which group contains one or m

Assignees

• Respivert Ltd
• Topivert Pharma Ltd

Inventors

• Fyfe Matthew Colin Thor
• Meghani Premji
• Thom Stephen Malcolm

Classifications

• C07F7/0814 Primary

  said ring is substituted at a C ring atom by Si · CPC title

• A61K31/695

  Silicon compounds · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title