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, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, NH2, N(H)\u2014C1-6 alkyl, N(C1-6 alkyl)2, -L-P(O)R\u2032R\u2033, C1-6 alkylene-5-10 membered heterocycle and C0-3 alkylene-O\u2014C0-6 alkylene-5-10 membered heterocycle;
L is a direct bond or C1-2 alkylene;
R\u2032 represents C1-4 alkyl;
R\u2033 represents C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy or hydroxy;
or R\u2032 and R\u2033 together combine to form C3-6 n-alkylene, wherein one CH2 of said n-alkylene group is optionally replaced by O, N(H) or N(C1-4 alkyl);
X represents CH or N,
Y represents NR2R3;
R is
C1-6 alkyl,
C2-6 alkenyl,
C1-6 hydroxyalkyl,
C1-6 haloalkyl,
C1-6 alkyl substituted by C2-3 alkynyl, C1-3 alkoxy or cyano,
C0-2 alkylene-C3-8 cycloalkyl optionally substituted with C1-3 alkyl, a 4-5 membered heterocycle optionally substituted with C1-3 alkyl or
Si(R1a)(R1b)(R1c);
R1a and R1b independently represent C1-4 alkyl or C3-6 cycloalkyl, or R1a and R1b together combine to form C2-6 alkylene;
R1c represents C1-2 alkyl;
Ra and Rb, 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 C1-3 alkyl, C1-3 haloalkyl, cyano and halo,
or one of Ra and Rb represents H, halo, cyano, C1-3 alkyl or C1-3 haloalkyl and the other independently represents halo, cyano, C1-3 alkyl or C1-3 haloalkyl
or Ra and Rb together represent C3-5 n-alkylene, which alkylene group is optionally substituted by one or more methyl substituents andor which alkylene group optionally contains one C\u2014C double bond between two C-atoms of the n-alkylene chain;
R1 is selected from hydrogen, OH, halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C0-3 alkylene-C3-6 cycloalkyl, C0-3 alkylene-O\u2014C1-3 alkylene-C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C0-3 alkylene-SO2C1-3alkyl, C0-3 alkylene-SO2NR4R5, and C0-3 alkylene-NR6R7 and C0-3 alkylene-NCOR6R7;
one of R2 and R3 represents \u2014C2-4 alkylene-O1-12\u2014C2-4 alkylene-R2a and the other of R2 and R3 is selected from H, C1-8 alkyl, C0-6 alkylene aryl, C0-6 alkylene heteroaryl, \u2014C2-4 alkylene-O0-12\u2014C2-4 alkylene-R2a, C0-6 alkylene-4-10 membered heterocycle, and C0-3 alkylene-O\u2014C0-6 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, C1-6 alkyl, C1-4 haloalkyl, C0-3 alkylene-O\u2014C0-6 alkyl, C0-3 alkylene-O\u2014C1-3 haloalkyl, C0-6 alkylene aryl, C0-3 alkylene-O\u2014C0-3 alkylene aryl, C0-6 alkylene heteroaryl, C0-3 alkylene-O\u2014C0-3 alkylene heteroaryl, C(O)C1-6 alkyl, SO2NR8R9, and C0-3 alkylene-NR8R9, C0-3 alkylene-NR8SO2R9 and C0-3 alkylene-NR8C(O)R9;
R2a represents OR2b or N(R2c) R2d;
R2b to R2d independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms, or R2C and R2d together represent
C3-6 n-alkylene,
C4-5 n-alkylene interrupted between C2 and C3 by \u2014O\u2014 or \u2014N(R2e)\u2014 or
C6 n-alkylene interrupted between C2 and C3, or between C3 and C4, by \u2014O\u2014 or \u2014N(R2e)\u2014,
any of which n-alkylene groups are optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C1-4 alkyl and C1-4 alkoxy;
R2e represents H or C1-6 alkyl optionally substituted by one or more substituents selected from halo and hydroxy;
R4 is H or C1-4 alkyl;
R5 is H or C1-4 alkyl,
R6 is H or C1-4 alkyl, C(O)C1-3alkyl and SO2C1-3 alkyl;
R7 is H or C1-4 alkyl, C(O)C1-3alkyl and SO2C1-3 alkyl;
R8 is H or C1-4 alkyl, and
R9 is H or C1-4 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, Ra, Rb, R1, Q and Y are as defined in claim 1.
3. A compound according to claim 1 of formula (If1) or formula (If2):
wherein R, Ra, Rb, R1, Q and Y are as defined in claim 1.
4. A compound according to claim 1 of formula (Ig1) or formula (Ig2):
wherein R, Ra, Rb, R1, X, Q and Y are as defined in claim 1.
5. A compound or salt according to claim 1, wherein R represents:
C1-6 n-alkyl,
C3-6 branched alkyl,
C2-6 alkenyl,
C1-6 hydroxyalkyl,
C1-6 haloalkyl,
C1-6 alkyl substituted by C1-3 alkoxy or cyano,
C0-2 alkylene-C3-8 cycloalkyl optionally substituted with C1-3 alkyl, or
a 4-5 membered heterocycle optionally substituted with C1-3 alkyl.
6. A compound according to claim 1, wherein:
R1 represents ethynyl or OCH3;
R2 represents \u2014(CH2CH2O)2-4CH3; and
R3 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;
R1 represents ethynyl or OCH3;
Y is NR2R3; and
one of R2 and R3 represents \u2014(CH2CH2O)2-3CH3 and the other of R2 and R3 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 andor 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 LGII represents a leaving group and one of Z1 and Z2 is a structural fragment of formula (IV)
wherein R and Q are as defined in claim 1, and the other of Z1 and Z2 is a structural fragment of formula (V)
wherein R1, Ra, Rb, X and Y are as defined in claim 1;
(b) reacting a compound of formula (VI),
wherein R, Ra, Rb, Q and X are as defined in claim 1 and LGVI represents a leaving group, with a compound of formula (VII),
wherein R1 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 Z1 and Z2 are as defined above;
(d) reacting a compound of formula (IX),
wherein Z1 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 Z1\u2014C(O)\u2014N3) 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, R1, Ra, Rb, Q and X are as defined in claim 1 and RX represents H or C1-4 alkyl, with a compound of formula (XI)
wherein R2 and R3 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 Z2 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.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
I claim:
1. In a switching center having input lines and output lines, a switching matrix for coupling the input lines and the output lines of the switching center to a network node in a communications network, the switching matrix comprising:
primary switching elements each having an element input side;
bus structures for respectively connecting one subset of input lines to said primary switching elements; and
at least three assemblies each having a number of said primary switching elements and at least one output interface with an interface input side;
said number of said primary switching elements supported by a common supporting element and connected on said element input side to said one subset of input lines by the same common bus structure;
said interface input side connected to at least one of said primary switching elements of at least two of said assemblies connected to a different one of said one subset of input lines;
said output interfaces respectively disposed at said assemblies between said number of said primary switching elements and a subset of output lines;
each of said assemblies having one of said output interfaces connected on said interface input side to primary switching elements of at least two of said assemblies.
2. The switching matrix according to claim 1, wherein at least one of said output interfaces is formed by a secondary switching element for coupling input lines of different ones of said assemblies.
3. The switching matrix according to claim 1, including base boards, each of said bus structures mounted on one of said base boards.
4. The switching matrix according to claim 3, including plug connectors connecting each of said assemblies to a respective one of said bus structures, each of said plug connectors forming a retaining connection between a respective one of said base boards and said supporting element.
5. The switching matrix according to claim 1, wherein said bus structures have a bus input side and each of said assemblies has a distribution structure connecting at least one line connected on said bus input side of a respective one of said bus structures to each primary switching element in a respective one of said assemblies.
6. The switching matrix according to claim 1, wherein each of said bus structures are identical and a same number of input lines is to be connected by each of said bus structure to a same number of said primary switching elements.
7. The switching matrix according to claim 1, wherein each input line is to be connected through only one of said bus structures to said primary switching elements.
8. The switching matrix according to claim 1, wherein said assemblies are networked to form funnel structures, each of said funnel structures of each of said bus structures has at least one connected assembly, and said output interfaces are distributed and connected within each of said funnel structures to said primary switching elements to couple each of the input lines of the switching matrix to each of the output lines of said funnel structures.
9. In a switching center having input lines and output lines, a switching matrix for coupling the input lines and the output lines of the switching center to an asynchronous transfer mode communications network with primary switching elements and for selecting input signals arriving through the input lines at the respective primary switching element and to output only the selected input signals on the output side with the switching matrix, the switching matrix comprising:
primary switching elements each having an element input side;
bus structures for respectively connecting one subset of input lines to said primary switching elements; and
at least three assemblies each having a number of said primary switching elements and at least one output interface with an interface input side;
said number of said primary switching elements supported by a common supporting element and connected on said element input side to said one subset of input lines by a same common bus structure;
said interface input side connected to at least one of said primary switching elements of at least two of said assemblies connected to a different one of said one subset of input lines;
said output interfaces respectively disposed at said assemblies between said number of said primary switching elements and a subset of output lines;
each of said assemblies having one of said output interfaces connected on said interface input side to primary switching elements of at least two of said assemblies.