Purine and imidazopyridine derivatives for immunosuppression
The present invention provides novel purine and imidazopyridine derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formulas:
1 . A compound of formula I
wherein
Q 1 and Q 2 are independently selected from the group consisting of CX 1 , CX 2 , and nitrogen;
Q 3 is N or CH;
X 1 and X 2 are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, cyano, halo, halo(C 1 -C 6 )alkyl, hydroxyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, nitro, carboxamido, and methylsulfonyl;
V 1 and V 2 are independently selected from CH and N;
R 1 is selected from the group consisting of hydrogen and methyl;
y is zero or an integer selected from 1, 2 and 3;
R 2 and R 3 are selected independently for each occurrence of (CR 2 R 3 ) from the group consisting of hydrogen and (C 1 -C 6 )alkyl; and
R 4 is selected from a group consisting of alkyl, heterocyclyl, aryl, substituted alkyl, substituted heterocyclyl, and substituted aryl.
2 . A compound according to claim 1 of formula:
3 . A compound according to claim 2 of formula:
4 . A compound according to claim 2 of formula:
5 . A compound according to claim 1 of formula:
6 . A compound according to claim 5 of formula:
7 . A compound according to claim 5 of formula:
8 . A compound according to claim 1 of formula:
9 . A compound according to claim 8 of formula:
10 . A compound according to claim 1 of formula:
11 . A compound according to claim 1 of formula:
12 . A compound according to claim 11 of formula:
13 . A compound according to claim 11 of formula:
14 . A compound according to claim 1 of formula:
15 . A compound according to claim 14 of formula:
16 . A compound according to claim 14 of formula:
17 . A compound according to claim 1 wherein X 1 and X 2 are independently selected from hydrogen, cyano, chloro, fluoro, methyl, trifluoromethyl and trifluoromethoxy, carboxamido.
18 . A compound according to claim 8 wherein X 1 is hydrogen and X 2 is chosen from hydrogen, cyano, chloro, fluoro, methyl, carboxamido, and trifluoromethyl.
19 . A compound according to claim 1 wherein R 1 is H.
20 . A compound according to claim 1 wherein, y is 1 or 2 and R 2 and R 3 are hydrogen or methyl.
21 . A compound according to claim 20 , wherein R 4 is selected from phenyl, quinoline, pyridine, pyrazine and their substituted counterparts.
22 . A compound according to claim 1 wherein y is zero.
23 . A compound according to claim 22 , wherein R 4 is selected from a monocycle, bicycle, or substituted monocycle or substituted bicycle containing at least one oxygen atom or nitrogen atom.
24 . A compound according to claim 22 , wherein R 4 is chosen from cyclopentyl, cyclohexyl, phenyl, tetralin, piperidine, oxepane, benzoxepane, tetrahydropyran, tetrahydrofuran, tetrahydroindole, tetrahydroisoquinoline, quinoline, tetrahydroquinoline, chroman, pyridine, dihydrocyclopenta[b]pyridine, dihydrobenzofuran, tetrahydrobenzofuran, tetrahydrobenzothiophene, dihydrobenzothiophene, dihydropyrano[2,3-b]pyridine, tetrahydroquinoxaline, tetrahydrothiopyran (thiane), thiochroman (dihydrobenzothiin), thiochroman-1,1-dioxide, tetrahydronaphthalene, oxa-bicyclooctane, oxocane, tetrathiohydropryan-1,1-dioxide, tetrathiohydropryanoxide, and their substituted counterparts.
25 . A compound according to claim 22 , wherein R 4 is cycloalkyl substituted with OH, alkoxy, hydroxyalkyl, oxo, carboxamido, carboxy, or alkoxycarbonyl.
26 . A compound according to claim 22 wherein R 4 is selected from cyclopentyl, cyclohexyl, phenyl, indane, tetralin, piperidine, oxepane, benzoxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydrofuran, tetrahydroindole, isoquinoline, tetrahydroisoquinoline, quinoline, tetrahydroquinoline, chroman, isochroman, pyridine, dihydrocyclopental[b]pyridine, pyrimidine, dihydropyran, dihydrobenzofuran, tetrahydrobenzofuran, tetrahydrobenzothiophene, dihydrobenzothiophene, furan, dihydropyrano[2,3-b]pyridine, tetrahydroquinoxaline, tetrahydrothiopyran (thiane), thiochroman (dihydrobenzothiin), thiochroman-1,1-dioxide, tetrahydronaphthalene, oxa-bicyclooctane, oxocane, tetrahydrothiopyran-1,1-dioxide, tetrahydrothiopyran oxide, and their substituted counterparts.
27 . A compound according to claim 1 wherein,
(a) y is zero and R 4 is selected from cyclohexyl, tetralin, indane, oxepane, benzoxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano[2,3-b]pyridine and tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo, or halogen; or
(b) y is 1 or 2, R 2 and R 3 are hydrogen or methyl and R 4 is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen.
28 . A compound according to claim 27 wherein y is 0 and R 4 is chosen from chroman-4-yl; 3,4-dihydronaphthalen-1(2H)-on-4-yl; 2,3-dihydroinden-1-on-4-yl and their fluoro substituted counterparts.
29 . A compound according to claim 28 wherein R 4 is chroman-4-yl and the carbon at 4 of the chroman is of the (R) configuration.
30 . A compound according to claim 27 wherein y is 0 and R 4 is
wherein
W is CH 2 , C═O, O, and CHOH;
p is 1, 2 or 3;
A is a six-membered heteroaromatic ring containing 1 or 2 nitrogens, a benzene ring optionally substituted with one or two fluorines, or a five-membered heterocyclic ring; and the wavy line is the point of attachment to the purinone.
31 . A compound according to claim 30 wherein the carbon marked with an asterisk
is of the (R) configuration.
32 . A compound according to claim 1 , wherein Y is 0 and R 4 is a monocyclic carbocycle or bridged bicyclic carbocycle optionally substituted with one or more OH, alkoxy, hydroxyalkyl, oxo, carboxamido, carboxy, and alkoxycarbonyl.
33 . A compound according to claim 1 , wherein Y is 0 and R 4 is a heterocycle containing at least one nitrogen atom and optionally substituted with OH, alkoxy, hydroxyalkyl, oxo, acyl, carboxamido, carboxy, and alkoxycarbonyl.
34 . A compound according to claim 33 , wherein R 4 is a monocyclic heterocycle.
35 . A compound according to claim 27 wherein y is 1 and R 4 is selected from difluorophenyl, fluorophenyl, chlorophenyl, chlorofluorophenyl, pyridin-3-yl and pyrazin-3-yl.
36 . A compound according to claim 27 wherein y is zero and R 4 is selected from tetrahydropyran-4-yl, 4-hydroxycyclohexyl, 4-loweralkoxycyclohexyl, 4-oxocyclohexyl and oxepan-4-yl.
37 - 63 . (canceled)
64 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 1 .
65 . (canceled)
66 . A method of treating a disorder selected from an autoimmune disease, an inflammatory disease, a mast cell mediated disease, cancer, hematological malignancy, organ transplant rejection, and cardiovascular disease which is dependent upon inhibition of Janus kinase 3, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 .
67 . (canceled)
68 . The method according to claim 66 wherein said disorder is organ transplant rejection.
69 - 76 . (canceled)