US2009221612A1PendingUtilityA1
Certain substituted amides, method of making, and method of use thereof
Est. expiryFeb 13, 2028(~1.6 yrs left)· nominal 20-yr term from priority
A61P 37/08A61P 35/02A61P 35/00A61P 43/00A61P 37/06A61P 37/00A61P 25/28A61P 29/00A61P 25/00A61P 11/08C07D 487/04A61P 11/06A61P 11/00A61P 19/02
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Claims
Abstract
Certain chemical entities chosen from compounds represented by Formula I and pharmaceutically acceptable salts and mixtures thereof, are provided herein. Pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer (e.g., B-cell lymphoma and leukemia), autoimmune diseases, inflammatory diseases, acute inflammatory reactions, and allergic disorders. Methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for determining the presence or absence of Syk kinase in a sample.
Claims
exact text as granted — not AI-modified1 . At least one chemical entity chosen from compounds of Formula I
and pharmaceutically acceptable salts thereof, wherein:
W is selected from optionally substituted aryl and optionally substituted heteroaryl;
A is selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, carboxy, cyano, halo, hydrogen, hydroxy and nitro;
X is selected from CH and N;
Q is selected from CO and SO 2 ;
Y is selected from hydrogen, optionally substituted alkyl; optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
Z is selected from hydrogen, optionally substituted alkyl; optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; or
Z taken together with Y, and the nitrogen to which they are bound, form an optionally substituted 5- to 13-membered nitrogen-containing ring which optionally includes one or two additional heteroatoms chosen from O and S;
provided that if W is 4-(morpholino)phenyl, A is hydrogen, X is CH, Q is CO and Y is hydrogen, then Z is not hydroxyethyl;
provided that if W is p-chlorophenyl or 4-(p-tolylsulfonamido)phenyl, A is hydrogen, X is CH, Q is CO and Y is hydrogen, then Z is not N,N-dimethylaminoethyl; and
provided that if W is 4-(morpholinecarbonyl)phenyl, A is hydrogen, X is CH, Q is CO and Y is hydrogen, then Z is not 3-chlorobenzyl or 4-t-butylphenyl.
2 . At least one chemical entity of claim 1 wherein Z taken together with Y, and the nitrogen to which they are bound, form a 5- to 13-membered nitrogen-containing ring.
3 . At least one chemical entity according to claim 1 wherein Q is SO 2 .
4 . At least one chemical entity according to claim 1 wherein Q is CO.
5 . At least one chemical entity according to claim 1 wherein W is optionally substituted aryl.
6 . At least one chemical entity according to claim 5 wherein W is aryl.
7 . At least one chemical entity according to claim 1 wherein W is optionally substituted heteroaryl.
8 . At least one chemical entity according to claim 7 wherein W is heteroaryl.
9 . At least one chemical entity according to claim 1 wherein the compound of Formula I is chosen from compounds of Formula II:
wherein
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from optionally substituted acyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, carboxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, halo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, hydrogen, hydroxy, nitro, phosphono, sulfanyl, sulfinyl, sulfonyl, and optionally substituted thiocarbonyl; or
two adjacent substituents selected from R 1 , R 2 , R 3 , R 4 and R 5 are taken together with the carbons to which they are bound to form a fused 5 to 7-membered ring chosen from optionally substituted cycloalkyl rings, optionally substituted aryl rings, optionally substituted heteroaryl rings and optionally substituted heterocyclic rings.
10 . At least one chemical entity according to claim 1 wherein the compound of Formula I is chosen from compounds of Formula III:
wherein
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from optionally substituted acyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, carboxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, halo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, hydrogen, hydroxy, nitro, phosphono, sulfanyl, sulfinyl, sulfonyl, and optionally substituted thiocarbonyl; or
two adjacent substituents selected from R 1 , R 2 , R 3 , R 4 and R 5 are taken together with the carbons to which they are bound to form a fused 5 to 7-membered ring chosen from optionally substituted cycloalkyl rings, optionally substituted aryl rings, optionally substituted heteroaryl rings and optionally substituted heterocyclic rings.
11 . At least one chemical entity according to claim 9 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl and hydrogen.
12 . At least one chemical entity according to claim 11 , wherein R 1 , R 2 and R 5 are hydrogen.
13 . At least one chemical entity according to claim 9 , wherein R 3 and R 4 are each independently selected from optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, and optionally substituted heterocycloalkyl.
14 . At least one chemical entity according to claim 13 , wherein R 3 and R 4 are both independently optionally substituted C 1 -C 6 alkoxy.
15 . At least one chemical entity according to claim 14 , wherein R 3 and R 4 are both methoxy.
16 . At least one chemical entity according to claim 1 , wherein A is selected from halo, optionally substituted lower alkyl, and hydrogen.
17 . At least one chemical entity according to claim 16 , wherein A is selected from halo, lower alkyl, and hydrogen.
18 . At least one chemical entity according to claim 17 , wherein A is hydrogen.
19 . At least one chemical entity according to claim 1 , wherein X is CH.
20 . At least one chemical entity according to claim 1 , wherein X is N.
21 . At least one chemical entity according to claim 1 , wherein Y is selected from optionally substituted lower alkyl and hydrogen.
22 . At least one chemical entity according to claim 21 , wherein Y is selected from lower alkyl and hydrogen.
23 . At least one chemical entity according to claim 22 , wherein Y is hydrogen.
24 . At least one chemical entity according to claim 1 , wherein Z is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.
25 . At least one chemical entity according to claim 24 wherein Z is selected from optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted benzodiazolyl, optionally substituted pyridinyl and optionally substituted cyclohexyl.
26 . At least one chemical entity according to claim 1 , wherein Z is selected from hydrogen and lower alkyl that is optionally substituted with a group chosen from amino, (lower alkyl)amino, di-(lower alkyl)amino, hydroxy, and lower alkoxy.
27 . At least one chemical entity according to claim 26 wherein Z is selected from hydrogen.
28 . At least one chemical entity according to claim 1 , wherein Y and Z are taken together with the nitrogen to which they are bound to form a 5- to 13-membered nitrogen-containing ring.
29 . At least one chemical entity according to claim 27 , wherein Y and Z are taken together with the nitrogen to which they are bound to form a 5- to 13-membered nitrogen-containing ring selected from optionally substituted piperazinyl, optionally substituted piperidinyl and optionally substituted diazepanyl.
30 . At least one chemical entity according to claim 27 , wherein Y and Z are taken together with the nitrogen to which they are bound to form an optionally substituted morpholinyl.
31 . At least one chemical entity according to claim 24 , wherein Z is represented by the following structure:
wherein
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from optionally substituted acyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, carboxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, halo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, hydrogen, hydroxy, nitro, phosphono, sulfanyl, sulfinyl, sulfonyl, and optionally substituted thiocarbonyl; or
two adjacent substituents selected from R 6 , R 7 , R 8 , R 9 and R 10 are taken together with the carbons to which they are bound to form a fused 5 to 7-membered ring chosen from optionally substituted cycloalkyl rings, optionally substituted aryl rings, optionally substituted heteroaryl rings and optionally substituted heterocyclic rings; and
V is selected from C and N, wherein if V is N, then R 9 is absent.
32 . At least one chemical entity according to claim 31 , wherein V is N.
33 . At least one chemical entity according to claim 31 , wherein V is C.
34 . At least one chemical entity according to claim 31 , wherein R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkylcarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, carboxy, cyano, optionally substituted C 1 -C 6 alkoxycarbonyl, halo, optionally substituted heteroaryl, hydrogen, hydroxy, and sulfonyl.
35 . At least one chemical entity according to claim 34 , wherein R 6 , R 7 , R 9 and R 10 are each hydrogen.
36 . At least one chemical entity according to claim 34 , wherein R 8 is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted aminocarbonyl, carboxy, cyano, halo, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, hydroxyl and sulfonyl.
37 . At least one chemical entity according to claim 36 , wherein R 8 is carboxy.
38 . At least one chemical entity according to claim 36 , wherein R 8 is —C(O)—NH(lower alkyl).
39 . At least one chemical entity according to claim 1 wherein the compound of Formula I is selected from:
3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-N-(piperidin-4-yl)benzamide;
6-[3-(2,3-Dihydro-1H-indol-1-ylcarbonyl)phenyl]-N-(3,4-Dimethoxyphenyl)-imidazo[1,2-a]pyrazin-8-amine;
4-({3-[8-(1H-Indazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]benzene}amido)benzoic acid;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)-amido]cyclohexane-1-carboxylic acid;
4-{1-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-phenyl)formamido]-2-methylpropan-2-yl}benzoic acid;
2-(Morpholin-4-yl)ethyl 4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzene)amido]benzoate;
2-{4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-phenyl)carbonyl]piperazin-1-yl}ethan-1-ol;
N-(3,4-Dimethoxyphenyl)-6-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-imidazo[1,2-a]pyrazin-8-amine;
N-(3,4-Dimethoxyphenyl)-6-[3-(piperazin-1-ylcarbonyl)phenyl]-imidazo[1,2-a]pyrazin-8-amine;
1-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}phenyl)-carbonyl]piperidine-4-carboxylic acid;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N,N-dimethylbenzamide;
N-(3,4-Dimethoxyphenyl)-6-[3-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)-phenyl]imidazo[1,2-a]pyrazin-8-amine;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(1-methylpiperidin-4-yl)benzamide;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}phenyl)-carbonyl]piperazin-2-one;
4-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[2-(pyridin-4-yl)ethyl]benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-methylbenzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-(pyridin-4-ylmethyl)-benzamide;
4-{[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}phenyl)-formamido]methyl}benzoic acid;
6-[3-(1,4-Diazepan-1-ylcarbonyl)-phenyl]-N-(3,4-dimethoxyphenyl)-imidazo[1,2-a]pyrazin-8-amine;
3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[(6-hydroxypyridin-3-yl)methyl]benzamide;
2-{4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-phenyl)carbonyl]piperazin-1-yl}acetic acid;
1-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}phenyl)-carbonyl]piperidin-4-ol;
5-{8-[(3,4-dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-pyrazol-4-yl)phenyl]pyridine-3-carboxamide;
N-(1H-1,3-Benzodiazol-6-yl)-3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}benzene)amido]-2-methoxybenzoic acid;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzene)amido]-2-fluorobenzoic acid;
Benzyl 4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-benzene)amido]benzoate;
N-(1H-1,2,3-Benzotriazol-5-yl)-3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzamide;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-benzene)amido]benzoic acid;
3-[(4-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)-amido]benzoic acid;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)-amido]-3-methylbenzoic acid;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[3-(methylsulfamoyl)phenyl]benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-phenylbenzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(1H-indazol-5-yl)benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(1H-indazol-6-yl)-benzamide;
3-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)-amido]benzoic acid;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)amido]-2-methylbenzoic acid;
N-(1H-1,3-benzodiazol-5-yl)-3-(8-{[4-(morpholin-4-yl)phenyl]amino}-imidazo[1,2-a]pyrazin-6-yl)benzamide;
3-{8-[(3,4-dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]benzamide;
3-{8-[(3,4-dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[2-methyl-4-(1H-pyrazol-4-yl)phenyl]benzamide.
4-{3-[8-(3,4-Dimethoxy-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-benzoylamino}-benzoic acid;
3-{8-[(3-Methoxy-4-methylphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
5-(3-(8-(3,4-Dimethoxyphenylamino)-imidazo[1,2-a]pyrazin-6-yl)benzamido)-N-methylpicolinamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(4-acetylphenyl)benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide;
N-(4-Cyanophenyl)-3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
Ethyl 4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}benzene)amido]benzoate;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methanesulfonylcarbamoyl)phenyl]-benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]benzamide;
N-{4-[(Dimethylamino)methyl]phenyl}-3-(8-{[4-(morpholin-4-yl)phenyl]amino}-imidazo[1,2-a]pyrazin-6-yl)benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(piperazin-1-yl)phenyl]benzamide;
3-(8-{[4-(Morpholin-4-yl)phenyl]-amino}imidazo[1,2-a]pyrazin-6-yl)-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1-hydroxyethyl)phenyl]benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-imidazol-2-yl)phenyl]benzamide;
2-{4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}benzene)amido]phenyl}acetic acid;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylsulfamoyl)phenyl]benzamide;
N-{4-[(1R)-1-Aminoethyl]phenyl}-3-{8-[(3,4-dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-[8-({4-[(4-ethylpiperazin-1-yl)methyl]-phenyl}amino)imidazo[1,2-a]pyrazin-6-yl]-N-[4-(1H-pyrazol-4-yl)phenyl]-benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-pyrazol-5-yl)phenyl]benzamide;
5-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)-amido]pyridine-2-carboxylic acid;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-{4-[(methylcarbamoyl)methyl]phenyl}benzamide;
N-(4-Carbamoylphenyl)-3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-(4-fluorophenyl)benzamide;
Methyl 4-[(3-{8-[(3,4-Dimethoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}benzene)amido]benzoate;
N-{4-[(1S)-1-Aminoethyl]phenyl}-3-{8-[(3,4-dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(4-methylphenyl)benzamide;
3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(6-hydroxypyridin-3-yl)benzamide;
N-{4-[(methylamino)methyl]phenyl}-3-(8-{[4-(morpholin-4-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-{[3-(8-{[4-(morpholin-4-yl)phenyl]-amino}imidazo[1,2-a]pyrazin-6-yl)benzene]amido}benzoic acid;
3-[8-({4-[2-(dimethylamino)ethoxy]-3-methoxyphenyl}amino)imidazo[1,2-a]pyrazin-6-yl]-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
N-[4-(hydroxycarbamoyl)phenyl]-3-(8-{[4-(morpholin-4-yl)phenyl]amino}-imidazo[1,2-a]pyrazin-6-yl)benzamide;
3-(8-{[4-(morpholin-4-yl)phenyl]amino}-imidazo[1,2-a]pyrazin-6-yl)-N-[4-(1H-1,2,4-triazol-3-yl)phenyl]benzamide;
3-(8-{[3-methoxy-4-(morpholin-4-yl)-phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)-N-[4-(1H-pyrazol-4-yl)phenyl]-benzamide;
3-(8-{[3-methoxy-4-(morpholin-4-ylcarbonyl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
N-[4-(1H-imidazol-4-yl)phenyl]-3-(8-{[4-(morpholin-4-yl)phenyl]amino}-imidazo[1,2-a]pyrazin-6-yl)benzamide;
3-{8-[(3,4-diethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
3-{8-[(3-ethoxy-4-methoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide;
3-{8-[(4-ethoxy-3-methoxyphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide;
3-{8-[(4-methoxy-3-methylphenyl)-amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide;
4-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[2-(pyridin-4-yl)ethyl]benzamide;
4-[(3-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}benzene)-sulfonamido]benzoic acid;
4-{8-[(3,4-Dimethoxyphenyl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-(pyridin-3-ylmethyl)benzamide;
3-{8-[(6-methoxypyridazin-3-yl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide;
3-{8-[(1-ethyl-1H-pyrazol-4-yl)amino]-imidazo[1,2-a]pyrazin-6-yl}-N-[4-(1H-pyrazol-4-yl)phenyl]benzamide;
3-{8-[(3-fluoro-4-methoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide;
N-[4-(methylcarbamoyl)phenyl]-3-(8-{[4-(piperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
3-(8-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)-N-[4-(methylcarbamoyl)phenyl]benzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]pyridine-2-carboxamide;
3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-N-[4-(methylcarbamoyl)phenyl]benzamide;
4-(8-{[4-(1H-imidazol-2-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
5-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]pyridine-3-carboxamide;
3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-N-[4-(methylcarbamoyl)phenyl]benzamide;
N-[4-(methylcarbamoyl)phenyl]-3-(8-{[4-(3-oxopiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
5-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}pyridine-3-carboxamide;
4-{8-[(4-ethoxy-3-methoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
4-{8-[(3,4,5-trimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-fluorobenzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-methylbenzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N,N-diethylbenzamide;
6-[4-(1,4-diazepan-1-ylcarbonyl)phenyl]-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-fluorobenzamide;
5-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-methylbenzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-ethylbenzamide;
2-chloro-4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-methylbenzamide;
4-(8-{[4-(propylcarbamoyl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
5-{8-[(4-ethoxy-3-methoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-methyl-N-[4-(methylcarbamoyl)phenyl]benzamide;
5-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-fluorobenzamide;
N-(3,4-dimethoxyphenyl)-6-[4-(piperazin-1-ylcarbonyl)phenyl]imidazo[1,2-a]pyrazin-8-amine;
4-(8-{[4-(1H-imidazol-2-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-(8-{[3-methoxy-4-(propan-2-yloxy)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-{8-[(3-methoxy-4-propoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-4-fluorobenzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-3-fluorobenzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-3-methylbenzamide;
4-(8-{[4-(2-hydroxyethoxy)-3-methoxyphenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-{8-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]imidazo[1,2-a]pyrazin-6-yl}benzamide;
3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-4-methylbenzamide;
4-[8-({4-[2-(dimethylamino)ethoxy]-3-methoxyphenyl}amino)imidazo[1,2-a]pyrazin-6-yl]benzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-(2-methoxyethyl)benzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-(2-hydroxyethyl)benzamide;
4-(8-{[3-methoxy-4-(2-methoxyethoxy)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[2-(methylamino)ethyl]benzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[2-(dimethylamino)ethyl]benzamide;
N-(3,4-dimethoxyphenyl)-6-[4-(morpholin-4-ylcarbonyl)phenyl]imidazo[1,2-a]pyrazin-8-amine;
4-(8-{[4-(1H-imidazol-2-yl)-3-methylphenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-methoxybenzamide;
4-(8-{[3-methoxy-4-(piperidin-4-yloxy)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-(8-{[4-(hydroxymethyl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-(8-{[4-(cyanomethoxy)-3-methoxyphenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-(8-{[3-(1-hydroxyethyl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
4-(8-{[3-methoxy-4-(1H-pyrazol-5-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide;
5-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-2-methoxybenzamide;
5-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}pyridine-2-carboxamide;
4-(8-{[4-(2-hydroxypropan-2-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)benzamide; and
5-(8-{[4-(2-hydroxypropan-2-yl)phenyl]amino}imidazo[1,2-a]pyrazin-6-yl)-2-methyl-N-[4-(methylcarbamoyl)phenyl]benzamide.
40 . A pharmaceutical composition comprising at least one chemical entity of claim 1 , together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants and excipients.
41 . A method for treating a patient having a disease responsive to the inhibition of Syk activity, comprising administering to the patient an effective amount of at least one chemical entity according to claim 1 .
42 . The method according to claim 41 wherein the patient is human.
43 . A method for treating a patient having a disease chosen from cancer, autoimmune diseases, inflammatory diseases, acute inflammatory reactions, and allergic disorders comprising administering to the patient an effective amount of at least one chemical entity of claim 1 .
44 . The method according to claim 43 wherein the patient is human.
45 . The method according to claim 41 wherein the disease responsive to inhibition of Syk activity is cancer.
46 . The method according to claim 45 wherein the disease responsive to inhibition of Syk activity is B-cell lymphoma and leukemia.
47 . The method according to claim 41 wherein an effective amount of said at least one chemical entity is administered by a method chosen from intravenously, intramuscularly, and parenterally.
48 . The method according to claim 41 wherein an effective amount of said at least one chemical entity is administered orally.
49 . A method for inhibiting ATP hydrolysis, the method comprising contacting cells expressing Syk with at least one chemical entity of claim 1 in an amount sufficient to detectably decrease the level of ATP hydrolysis in vitro.
50 . The method of claim 49 wherein the cells are present in a mammal.
51 . The method of claim 50 wherein the mammal is a human.
52 . A method for determining the presence of Syk in a sample, comprising contacting the sample with at least one chemical entity of claim 1 under conditions that permit detection of Syk activity, detecting a level of Syk activity in the sample, and therefrom determining the presence or absence of Syk in the sample.
53 . A method for inhibiting B-cell activity comprising contacting cells expressing Syk with at least one chemical entity of claim 1 , in an amount sufficient to detectably decrease B-cell activity in vitro.
54 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is rheumatoid arthritis.
55 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is allergic rhinitis.
56 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is chronic obstructive pulmonary disease (COPD).
57 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is adult respiratory distress syndrome (ARDs).
58 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is an allergy-induced inflammatory disease.
59 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is multiple sclerosis.
60 . The method according to claim 41 , wherein the disease responsive to inhibition of Syk activity is asthma.Cited by (0)
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