Kinase inhibitors

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.

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-methoxyethoxy)ethoxy)ethyl)-benzamide; 
 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-(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-methoxyethoxy)ethyl)benzamide; 
 3-((4-((4-(3-(3-(tert-butyl)-1-(2,3,5,6-tetradeutero-4-(trideuteromethyl)phenyl)-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-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-ethynyl-N-(2,5,8,11-tetraoxatridecan-13-yl)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-methoxyethoxy)ethyl)benzamide; 
 3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-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-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)-ethoxy)ethyl)benzamide; 
 3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)-ethoxy)ethyl)benzamide; 
 3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)-5,6,7,8-tetrahydronaphthalen-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-(2,4-dimethoxyphenyl)-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-(3-((dimethylphosphoryl)methyl)phenyl)-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-(3-((dimethylphosphoryl)methyl)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 
 3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 
 3-((4-((4-((3-(3-(tert-butyl)-1-(4-methoxy-2-methylphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide, 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         11 . (canceled) 
     
     
         12 . A compound according to  claim 1  that is 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, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A pharmaceutical composition comprising a compound according to  claim 1 , in combination with one or more pharmaceutically acceptable diluents or carriers 
     
     
         14 . A combination product comprising:
 (A) a compound according to  claim 1 ; and   (B) another therapeutic agent,   wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.   
     
     
         15 . A medicament comprising a compound according to  claim 1 . 
     
     
         16 . A method of treating a disease or condition in a subject comprising administering to the subject a compound according to  claim 1 , wherein the disease or condition is selected from the group consisting of COPD, chronic bronchitis, emphysema, asthma, pediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis, keratoconjunctivitis sicca (dry eye), glaucoma, diabetic retinopathy, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, uveitis, posterior uveitis, anterior uveitis, pan uveitis, corneal graft and limbal cell transplant rejection, gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis and osteoarthritis. 
     
     
         17 . The method of  claim 16 , wherein the disease or condition is selected from the group consisting of COPD, asthma, keratoconjunctivitis sicca (dry eye), uveitis, posterior uveitis, anterior uveitis, pan uveitis, Crohn's disease and ulcerative colitis. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A process for the preparation of a compound of formula (I), as defined in  claim 1 , which process comprises:
 (a) reacting a compound of formula (II), with a compound of formula (III)
 wherein LG II  represents a leaving group and one of Z 1  and Z 2  is a structural fragment of formula (IV) 
 wherein R and Q are as defined in  claim 1 , and the other of Z 1  and Z 2  is a structural fragment of formula (V) 
 wherein R 1 , R a , R b , X and Y are as defined in  claim 1 ; 
   (b) reacting a compound of formula (VI),
 wherein R, R a , R b , Q and X are as defined in  claim 1  and LG VI  represents a leaving group, with a compound of formula (VII), 
 wherein R 1  and Y are as defined in  claim 1 ; 
   (c) reacting a compound of formula (VIII), with a compound of formula (III), wherein the compound of formula (III) and Z 1  and Z 2  are as defined above;   (d) reacting a compound of formula (IX),   wherein Z 1  is as defined above, with an azide-forming agent, which reaction is followed, without isolation, by thermal rearrangement of the intermediate acyl azide (of formula Z 1 —C(O)—N 3 ) to provide, in situ, a compound of formula (VIII), which compound is then reacted with a compound of formula (III), as defined above, to provide the compound of formula (I);   (e) reacting a compound of formula (X)   wherein R, R 1 , R a , R b , Q and X are as defined in  claim 1  and R X  represents H or C 1-4  alkyl, with a compound of formula (XI)   wherein R 2  and R 3  are as hereinbefore defined; or   (f) deprotecting a protected derivative of a compound of formula (I).   
     
     
         21 . A compound of formula (III), as defined in  claim 20 , or a salt or protected derivative thereof, wherein Z 2  represents a structural fragment of formula (V), as defined in  claim 20 . 
     
     
         22 . A compound of formula (VII), as defined in  claim 20 , or a salt or protected derivative thereof.