6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
View Patent ↗The present invention provides novel purinones and purines useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formulae I and II shown below, in which Q is selected from the group consisting of CX and nitrogen; and A is chosen from the group consisting of H, (C 1 -C 6 ) alkyl, heteroaryl, and aryl:
1. A compound of formula I or II
wherein
Q is selected from the group consisting of CX and nitrogen;
X is selected from the group consisting of hydrogen, halogen, and an electron-withdrawing group;
A is chosen from the group consisting of H, (C 1 -C 6 ) alkyl, heteroaryl, and aryl;
R 1 is selected from the group consisting of halogen, CN, (C 2 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, aryl, substituted aryl, azetidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, indolyl, isoquinolinyl, azepinyl, diazepinyl, cyclobutyl, substituted azetidinyl, substituted piperidinyl, substituted piperazinyl, substituted pyridinyl, substituted pyrimidinyl, substituted morpholinyl, substituted thiomorpholinyl, substituted pyrrolyl, substituted pyrazolyl, substituted indolyl, substituted isoquinolinyl, substituted azepinyl, substituted diazepinyl, substituted cyclobutyl, and —V—R 7 ;
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;
R 4 is selected from a group consisting of alkyl, OH, alkoxy, pyranyl, benzopyranyl, furanyl, pyridinyl, cyclohexyl, aryl, substituted alkyl, substituted pyranyl, substituted benzopyranyl, substituted furanyl, substituted pyridinyl, substituted cyclohexyl, and substituted aryl;
R 7 is chosen from H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, aryl, substituted aryl, pyridinyl, piperidinyl, furanyl, oxadiazolyl, azetidinyl, cyclopropyl, cyclobutyl, cyclopentyl, and substituted pyridinyl, substituted piperidinyl, substituted furanyl, substituted oxadiazolyl, substituted azetidinyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl;
V is chosen from —C(═O)O—, —C(═O)NR 8 —, —O—, and —NR 8 —;
R 8 is chosen from H and (C 1 -C 6 ) alkyl, or, azetidinyl, piperidinyl, oxadiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, substituted azetidinyl, substituted piperidinyl, substituted oxadiazolyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl;
R 9 is chosen from hydrogen, alkyl, and substituted alkyl; and
y is zero or an integer selected from 1, 2, 3, and 4.
2. A compound according to claim 1 , wherein R 9 is hydrogen and R 1 is chosen from aryl, substituted aryl, azetidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, indolyl, isoquinolinyl, azepinyl, diazepinyl, cyclobutyl, and substituted azetidinyl, substituted piperidinyl, substituted piperazinyl, substituted pyridinyl, substituted pyrimidinyl, substituted morpholinyl, substituted thiomorpholinyl, substituted pyrrolyl, substituted pyrazolyl, substituted indolyl, substituted isoquinolinyl, substituted azepinyl, substituted diazepinyl, substituted cyclobutyl.
3. A compound according to claim 2 , wherein R 1 is chosen from pyridinyl, pyrazolyl, pyrimidinyl, isoquinolinyl, azetidinyl, piperidinyl, piperizinyl, pyrrolidinyl, morpholinyl, azepanyl, diazepanyl, and phenyl optionally substituted with hydroxy, halogen, carboxamido, alkyl, carboxy, sulfonyl, alkoxy, and cyano.
4. A compound according to claim 1 , wherein R 1 is chosen from aryl, substituted aryl, (C 1 -C 6 ) alkyl, and substituted (C 1 -C 6 ) alkyl.
5. A compound according to claim 1 , wherein R 1 is V—R 7 .
6. A compound according to claim 5 , wherein V is —C(═O)O— or —C(═O)NR 8 —, and R 7 is chosen from —CH 2 CN 3 (C 1 -C 6 ) alkyl, and H, or VR 7 is
7. A compound according to claim 5 , wherein V is chosen from —O— and —NR 8 —; R 7 is (C 1 -C 6 ) alkyl; and R 8 is H.
8. A compound according to claim 1 , wherein R 9 is hydrogen, y is zero and R 4 is a residue selected from a monocycle, a bicycle, a substituted monocycle, and a substituted bicycle, said residue containing at least one oxygen atom.
9. A compound according to claim 8 , wherein R 4 is chosen from pyranyl, benzopyranyl, furanyl, substituted pyranyl, substituted benzopyranyl, substituted furanyl, a hydroxyl-substituted cycloalkyl, an alkoxy-substituted aryl, and a hydroxyl-substituted aryl.
10. A compound according to claim 9 , wherein R 4 is chosen from
wherein R 6 is hydrogen or fluorine, and the carbon marked with an asterisk is of the R absolute configuration.
11. A compound according to claim 1 , wherein R 9 is hydrogen, y is 1-4, R 2 and R 3 are hydrogen in all occurrences, and R 4 is alkoxy or OH of formula Ib or IIb:
wherein R 5 is hydrogen or (C 1 -C 6 ) alkyl.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 .