TRICYCLIC INHIBITORS OF GYRASE Russian patent published in 2017 - IPC C07D487/04 A61P31/04 

FIELD: pharmacology.

SUBSTANCE: invention relates to new tricyclic compounds of formula I having an activity of inhibitors of gyrase B (GyrB) and topoisomerase IV (ParE) enzyme. The compounds may find application in bacterial infections treatment. The invention also relates to a method for preparation of compounds of formula I and formula (1) intermediates for their preparation. In formula I:

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L is O or S; R⁸ is H, Cl, F, Br, OH, NH₂, C_1-3alkyl, amino-C_1-3alkyl, aminocyclopropyl, OCH₃, OCH₂CH₃, cyclopropyl, CH₂cyclopropyl, CH₂Cl, CHCl₂, CCl₃, CH₂CH₂Cl, CH₂Br, CHBr₂, CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, NHNH₂, NHOH, NHNHCH₃, NHOCH₃, NHCD₃, SCH₃ or NHCOH; X, Y and Z are independently selected from the group consisting of N, CR^X, CR^Y and CR^Z, provided that no more than two of X, Y and Z are N. At that, R^X is H, CH₃, Cl, Br or F. At that, R^Y is H, CH₃, CHF₂, CF₃, CN, CH₂CH₃, Cl, Br or F. At that, R^Z is H, CH₃, Cl, Br or F; R² is a 6-membered monocyclic aryl or 6-membered mono- or 9-10 membered bicyclic heteroaryl ring, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from O, S and N. The said 6-membered monocyclic aryl ring, 6- Membered monocyclic heteroaryl ring and a 9-10 membered bicyclic heteroaryl ring may be optionally substituted with 0-3 substituents selected from OH, CO₂H, CO₂CH₃, C(O)NH₂, C(O)CH₃, =O, CN, NH₂, Br, Cl, F, SO₃H, SO₂NH₂, SO₂CH₃, SOCH₃, NHOH, C(O)NHOCH₃, CH(OH)CH₃, C(OH)(CH₃)₂, SCH₃, or C₁-C₆alkyl or C₃-C₆cycloalkyl having 0-2 heteroatoms selected from O, S or N, optionally substituted with C₁-C₄alkyl, OH, CN, =O, NH₂, Br, F, Cl. The bicyclic heteroaryl ring can be spiro-fused with cyclopropyl; or R² is or ; R⁴ is: H; optionally substituted with OR^a, where R^a is pyridyl, pyrimidinyl, optionally substituted with CH₃ and NH₂; optionally substituted saturated secondary or tertiary amine selected from a 4-6 membered aliphatic amine, a 4-6 membered monocyclic amine, a 5-10 membered bicyclic amine with 1 to 3 heteroatoms selected from N, O or S. The said optionally substituted saturated 5-10 membered bicyclic amine may be a spiro- or orthocondensed bicyclic amine, or optionally substituted 5-6-membered unsaturated cyclic residue containing 0-2 N heteroatoms. The optionally substituted saturated secondary or tertiary amine is attached to ring C via N of the secondary or tertiary amine, and the optional substituent is selected from OH, halogen, NH₂, C(O)CH₂NH₂, C(O)NH₂, CH₂NHC(O), C_5-6heterocyclyl, optionally substituted with CH₃ and CF₃, CH₂OH, -C_3-6cycloalkyl, optionally substituted with NH₂, -C_3-6heterocyclyl containing 0-2 N atoms, optionally substituted with NH₂, -CH₃, -C(O)CH₃, -C(O)C_3-6heterocyclyl containing 1 to 3 O atoms, -CH(OH)C_3-6heterocyclyl containing 1 to 3 S atoms, -NHCOCH₃, -NHCH₂CH₂CN, -NHCH₂C_3-6cycloalkyl, -C_1-4alkylC_3-6heterocyclyl containing 0-2 heteroatoms selected from O and N, -C_1-4alkylNH₂, =NOCH₃, -NHC(O)CH₂NH₂, -NHCH₂CH₂OH, -NHCH₂CH₂NH₂, -NHC(O)CH(NH₂)CH₂OH, -NHC(O)CH₂NHC(O)CH(NH₂)CH₂OH, -C(O)OCH₂CH₃, -OC_1-4alkyl. In the intermediates of formula (1), G¹ and G² are leaving groups independently selected from the group consisting of SH, OH, Cl, Br, F, I, SR, SOR, SO₂R, OSO₂ R and OBt; R is C_1-8alkyl, Ar, wherein Ar is phenyl, optionally substituted with C_1-4alkyl, C₁-₄alkoxy_, halogen or NO₂; Bt is benzotriazole; R⁸ is H, Cl, F, Br, OH, NH₂, C_1-3alkyl, amino-C₁-₃alkyl, aminocyclopropyl, OCH₃, OCH₂CH₃, cyclopropyl, CH₂cyclopropyl, CH₂Cl, CHCl_2,CCl₃, CH₂CH₂Cl, CH₂Br, CHBr₂, CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CHF_2,CH₂CF₃, NHNH₂, NHOH, NHNHCH₃, NHOCH₃, NHCD_3, SCH₃ or NHCOH; and X, Y and Z are independently selected from the group consisting of N, CR^X, CR^Y and CR^Z respectively, provided that no more than two of X, Y and Z are N.

EFFECT: improved compounds properties.

35 cl, 3 dwg, 11 tbl, 7 ex