Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9850233-B2
Application number	US-201615207915-A
Country	US
Kind code	B2
Filing date	Jul 12, 2016
Priority date	Mar 14, 2013
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

There are provided compounds of formula I,

wherein:
Y represents NR 2 R 3 ;
one of R 2 and R 3 represents —[C 2-4 alkylene-O] 1-12 —[C 2-4 alkylene]-R 2a and the other of R 2 and R 3 has a meaning given in the description; and
R, R 1 , R 2a , R a , R b , Q, X and Y 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:
Q represents thienyl, phenyl or pyridinyl, either of which may optionally bear 1 to 3 substituents independently selected from, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, NH 2 , N(H)—C 1-6 alkyl, N(C 1-6 alkyl) 2 , -L-P(O)R′R″, C 1-6 alkylene-5-10 membered heterocycle and C 0-3 alkylene-O—C 0-6 alkylene-5-10 membered heterocycle;
L is a direct bond or C 1-2 alkylene;
R′ represents C 1-4 alkyl;
R″ represents C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy or hydroxy;
or R′ and R″ together combine to form C 3-6 n-alkylene, wherein one CH 2 of said n-alkylene group is optionally replaced by O, N(H) or N(C 1-4 alkyl);
X represents CH or N,
Y represents NR 2 R 3 ;
R is
C 1-6 alkyl,
C 2-6 alkenyl,
C 1-6 hydroxyalkyl,
C 1-6 haloalkyl,
C 1-6 alkyl substituted by C 2-3 alkynyl, C 1-3 alkoxy or cyano,
C 0-2 alkylene-C 3-8 cycloalkyl optionally substituted with C 1-3 alkyl,
a 4-5 membered heterocycle optionally substituted with C 1-3 alkyl or Si(R 1a )(R 1b )(R 1c );

R 1a and R 1b independently represent C 1-4 alkyl or C 3-6 cycloalkyl, or R 1a and R 1b together combine to form C 2-6 alkylene;
R 1c represents C 1-2 alkyl;
R a and R b , together with the C-atoms to which they are attached, form a fused phenyl ring that is optionally substituted by one or more substituents selected from 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 represent C 3-5 n-alkylene, which alkylene group is optionally substituted by one or more methyl substituents and/or which alkylene group optionally contains one C—C double bond between two C-atoms of the n-alkylene chain;
R 1 is selected from hydrogen, OH, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-6 cycloalkyl, C 0-3 alkylene-O—C 1-3 alkylene-C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 0-3 alkylene-SO 2 C 1-3 alkyl, C 0-3 alkylene-SO 2 NR 4 R 5 , and C 0-3 alkylene-NR 6 R 7 and C 0-3 alkylene-NCOR 6 R 7 ;
one of R 2 and R 3 represents —[C 2-4 alkylene-O] 1-12 —[C 2-4 alkylene]-R 2a and the other of R 2 and R 3 is selected from H, C 1-8 alkyl, C 0-6 alkylene aryl, C 0-6 alkylene heteroaryl, —[C 2-4 alkylene-O] 0-12 —[C 2-4 alkylene]-R 2a , C 0-6 alkylene-4-10 membered heterocycle, and C 0-3 alkylene-O—C 0-6 alkylene-4-10 membered heterocycle with the proviso that when the said heterocycle is linked through nitrogen there are at least two C-atoms in the alkylene chain that links that nitrogen atom to the essential O atom of the substituent, wherein independently each alkyl or alkylene group optionally bears 1 oxo substituent, and optionally one or two carbon atoms in the alkyl or alkylene chain may each be replaced by a heteroatom selected from O, N or S(O) p , such that when said alkyl or alkylene comprises an amine said amino group is a tertiary amine,
wherein each 4-10 membered heterocycle is optionally substituted by 1 or 2 groups independently selected from halo, OH, C 1-6 alkyl, C 1-4 haloalkyl, C 0-3 alkylene-O—C 0-6 alkyl, C 0-3 alkylene-O—C 1-3 haloalkyl, C 0-6 alkylene aryl, C 0-3 alkylene-O—C 0-3 alkylene aryl, C 0-6 alkylene heteroaryl, C 0-3 alkylene-O—C 0-3 alkylene heteroaryl, C(O)C 1-6 alkyl, SO 2 NR 8 R 9 , and C 0-3 alkylene-NR 8 R 9 , C 0-3 alkylene-NR 8 SO 2 R 9 and C 0-3 alkylene-NR 8 C(O)R 9 ;
R 2a represents OR 2b or N(R 2c )R 2d ;
R 2b to R 2d independently represent H or C 1-4 alkyl optionally substituted by one or more halo atoms, or R 2c and R 2d together represent
C 3-6 n-alkylene,
C 4-5 n-alkylene interrupted between C2 and C3 by —O— or —N(R 2e )— or
C 6 n-alkylene interrupted between C2 and C3, or between C3 and C4, by —O— or —N(R 2e )—,
any of which n-alkylene groups are optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 1-4 alkyl and C 1-4 alkoxy;

R 2e represents H or C 1-6 alkyl optionally substituted by one or more substituents selected from halo and hydroxy;
R 4 is H or C 1-4 alkyl;
R 5 is H or C 1-4 alkyl,
R 6 is H or C 1-4 alkyl, C(O)C 1-3 alkyl and SO 2 C 1-3 alkyl;
R 7 is H or C 1-4 alkyl, C(O)C 1-3 alkyl and SO 2 C 1-3 alkyl;
R 8 is H or C 1-4 alkyl, and
R 9 is H or C 1-4 alkyl,
p is 0, 1 or 2
or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.

2. A compound according to claim 1 of formula (Id1) or formula (Id2):

wherein R, R a , R b , R 1 , Q and Y are as defined in claim 1 .

3. A compound according to claim 1 of formula (If1) or formula (If2):

wherein R, R a , R b , R 1 , Q and Y are as defined in claim 1 .

4. A compound according to claim 1 of formula (Ig1) or formula (Ig2):

wherein R, R a , R b , R 1 , X, Q and Y are as defined in claim 1 .

5. A compound or salt according to claim 1 , wherein R represents:
C 1-6 n-alkyl,
C 3-6 branched alkyl,
C 2-6 alkenyl,
C 1-6 hydroxyalkyl,
C 1-6 haloalkyl,
C 1-6 alkyl substituted by C 1-3 alkoxy or cyano,
C 0-2 alkylene-C 3-8 cycloalkyl optionally substituted with C 1-3 alkyl, or
a 4-5 membered heterocycle optionally substituted with C 1-3 alkyl.

6. A compound according to claim 1 , wherein:
R 1 represents ethynyl or OCH 3 ;
R 2 represents —(CH 2 CH 2 O) 2-4 CH 3 ; and
R 3 is H.

7. A compound of formula (Ig2)

wherein:
R represents isopropyl, 1-methylcyclopropyl, propen-2-yl or tert-butyl;
Q represents phenyl substituted in the para position by methyl, methoxy or dimethylamino;
X represents CH or N;
R 1 represents ethynyl or OCH 3 ;
Y is NR 2 R 3 ; and
one of R 2 and R 3 represents —(CH 2 CH 2 O) 2-3 CH 3 and the other of R 2 and R 3 is H,
or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.

8. A compound according to claim 1 , wherein:
Q represents phenyl substituted in the para position by methyl, methoxy or dimethylamino; and
R represents isopropyl or tert-butyl.

9. A compound according to claim 1 , wherein R represents tert-butyl.

10. A compound according to claim 1 selected from the group comprising or consisting of:
3-ethynyl-5-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3-((4-((4-(3-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxye

Assignees

• Respivert Ltd
• Topivert Pharma Ltd

Inventors

• Fyfe Matthew Colin Thor

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title