Pyrazolyl-ureas as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9701670-B2
Application number	US-201314422158-A
Country	US
Kind code	B2
Filing date	Aug 16, 2013
Priority date	Aug 17, 2012
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

There are provided compounds of formula I,

wherein R, R 1 , 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

The invention 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 the group consisting of 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 , C 1-6 alkylene-5-10 membered heterocycle and C 0-3 alkylene-O—O 0-6 alkylene-5-10 membered heterocycle;
X represents CH or N,
Y represents NR 2 R 3 , or a 4-10 heterocycle optionally linked through a heteroatom, wherein said heterocycle bears 0 or 1 substituents selected from the group consisting of halo, OH, C 1-6 alkyl, C 1-4 haloalkyl, C 0-3 alkylene-O—O 0-6 alkyl, C 0-3 alkylene-O—C 1-3 haloalkyl, C 0-6 alkylene aryl, C 0-3 alkylene-O—O 0-3 alkylene aryl, C 0-6 alkylene heteroaryl, C 0-3 alkylene-O—O 0-3 alkylene heteroaryl, C(O)C 1-6 alkyl, SO 2 NR 4 R 5 , C 0-3 alkylene-NR 4 R 5 , C 0-3 alkylene-NR 4 SO 2 R 5 and C 0-3 alkylene-NR 4 C(O)R 5 ;
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 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;

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 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;
R 1 is selected from the group consisting of 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 ;
R 2 and R 3 are each independently selected from the group consisting of H, C 1-8 alkyl, C 0-6 alkylene aryl, C 0-6 alkylene heteroaryl, and C 0-6 alkylene-4-10 membered heterocycle, wherein independently each alkyl or alkylene group optionally bears 1 oxo substituent, and optionally one carbon atom in the alkyl 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 the group consisting of 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—O 0-3 alkylene aryl, C 0-6 alkyleneheteroaryl, 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 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 (Ia2)

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

3. A compound according to claim 1 of formula (Ib2)

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

4. A compound according to claim 1 of formula (Ic):

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

5. A compound according to claim 1 of formula (Id2):

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

6. A compound according to claim 1 of formula (Ie2):

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

7. A compound according to claim 1 of formula (If2):

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

8. A compound according to claim 1 of formula (Ig2):

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

9. A compound or salt according to claim 1 , wherein R represents:
C 1-6 n-alkyl,
C 4-6 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.

10. A compound according to claim 1 selected from the group consisting of:
3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)benzamide;
3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide;
4-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide;
N-(2-(dimethylamino)ethyl)-3-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamide;
N-(2-(dimethylamino)ethyl)-3-((4-((4-(3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamide;
3-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide;
3-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) pyrimidin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-methoxy-N-(2-morpholinoethyl)-5-((4-((4-(3-(3-(perfluoroethyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)benzamide;
3-((4-((4-(3-(3-isopropyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-methoxyethyl)benzamide;
1-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-methoxy-5-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
5-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(2-morpholinoethyl)benzamide;
3-((6-((4-(3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-4-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)naphth

Assignees

• Respivert Ltd
• Topivert Pharma Ltd

Inventors

• Cariou Claire Anne Marie
• Charron Catherine Elisabeth
• Fordyce Euan Alexander Fraser
• Hamza Daniel
• Fyfe Matthew Colin Thor
• Ito Kazuhiro
• King-Underwood John
• Murray Peter John
• Onions Stuart Thomas
• Thom Stephen Malcolm
• Watson Hayley Tegan Angela
• Williams Jonathan Gareth

Classifications

• A61P37/06

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/08

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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/00

  Antineoplastic agents · CPC title