Dihydroquinone and dihydronaphthyridine inhibitors of jnk kinase

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

in which
X represents a group CR11or N;
Y represents a group-C(O)R3, oxazolyl or isoxazolyl;
Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and substituted groups R1and R2;
R1and R2each independently represents H, halogen, the group CN, C1-6alkyl or the group-Y1-Y2-Y3-R8or R1and R2together form a group-O(CH2)nO-, where n represents 1 or 2;
Y1represents a group-O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -S-, -SO2or communication;
Y2is heterocyclochain,1-6alkylen or connection, where heteroseksualci the means cycloalkenyl group, in which one, two carbon atoms are replaced by heteroatoms O or N, where literoticalolita group still contains at least two carbon atoms and cycloalkyl is a;
Y3represents a group-O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2or communication;
R8represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, tetrahydropyranyl, or the group-NR9R10where R8different from H, optionally substituted C1-6by alkyl, halogen, the group-CF3or the group-HE;
R9and R10each independently represents N or C1-6alkyl;
R3represents a group HE1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy;
R4represents a C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1-dioxide, and optionally substituted C1-6the alkyl, a hydroxy group, a C1-6alkoxy, halogen, nitro group, amino group, cyano group or a halo-lower alkyl;
R5and R6each independently represents H, halogen, C1-6alkyl, a group-CF3With1-6alkoxy;
R7represents H;
R11is Soboh is N;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which Y represents a group-C(O)R3and R3represents a methoxy group.

3. The compound according to claim 2, in which R7represents N.

4. The compound according to claim 3, in which Z represents a phenyl, and R2represents N.

5. The compound according to claim 4, in which R6represents N.

6. The compound according to claim 5, in which R5selected from the group consisting of H, F, Cl, Me, or CF3.

7. The connection according to claim 6, in which X represents a group CH or N.

8. The connection according to claim 7, in which R1is a group-Y1-Y2-Y3-R8and Y1represents the SO2.

9. Pharmaceutical composition for treating diseases mediated by kinase JNK, comprising a compound of formula I according to claim 1, and pharmaceutically acceptable inert carrier.



 

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