Substituted 4,5,6,7-tetrahydro-pyrazolo 1,5-a pyrazine derivatives and 5,6,7,8-tetrahydro-4h-pyrazolo 1,5-a 1,4 diazepine as ros1 inhibitors

摘要

A compound of Formula (I) ** Formula ** one of its tautomers or stereoisomeric forms, where y1 is CR7a or N; y2 is CH or N; R7a is hydrogen, halo, trifluoromethyl or cyano; R7 is hydrogen, -NH2, -NHCH3, -NH (CH2CH3), methyl, -CH2OH, halo or cyano; or when y1 represents CR7a, this R7a can be taken together with an R7 in an adjacent carbon atom to form -CH = CH-NH- or -N = CH-NH-; X is -CR1R1a-, -CH2-CHR1-; R1 is hydrogen or C1-6 alkyl; R1a is hydrogen; C1-6 alkyl; mono- or C1-6 polyhaloalkyl; C1-6 alkyl substituted with one or two hydroxyl groups; C1-6 alkyl substituted with a -NR9aR9b; or -C (= O) -NR9aR9b; R2a is hydrogen; C1-6 alkyl; mono- or C1-6 polyhaloalkyl; C1-6 alkyl substituted with one or two hydroxyl groups; or C1-6 alkyl substituted with a substituent selected from the group consisting of -NR9aR9b, cyano and C1-4 alkyloxy; R2b is hydrogen or C1-6 alkyl; or R2a and R2b are taken together to form -CH2-CH2-, -CH2-NR2c-CH2-, -CH2-CH2-CH2-, -CH2-O-CH2-, -CH2-CH2-CH2- CH2-, - CH2-CH2-NR2c-CH2- o = O; R2c is hydrogen; C1-4 alkyl optionally substituted with one or two hydroxyl groups; mono- or C1-6 polyhaloalkyl; C1-6 alkyloxy; C1-6 alkyl substituted with a cyano group; or C1-6 alkyl substituted with a -NR9aR9b; R3 is hydrogen; C1-6 alkyl; mono- or C1-6 polyhaloalkyl; C1-6 alkyl substituted with one or two hydroxyl groups; C1-6 alkyl substituted with one or two hydroxyl groups and a C1-6 alkyloxy; C 1-6 alkylcarbonyl optionally substituted with one or two hydroxyl groups; mono- or polyhaloalkylcarbonyl C1-6-; R10aR10bN-C 1-6 alkylcarbonyl; C1-6 alkyl-Ocarbonyl-; C1-6 alkylcarbonyloxy; C1-6 alkyl substituted with an R11; C1-6 alkyloxy optionally substituted with a - NR10aR10b; C2-6 alkenyl; C2-6 alkynyl; C2-6 hydroxyalkenyl; C2-6 hydroxyalkynyl; C1-6 alkyloxyC2-6 alkenyl; C1-6 alkyloxyC2-6 alkynyl; C2-6 alkenyl substituted with a -NR10aR10b; C2-6 alkynyl substituted with a -NR10aR10b; C1-6 alkyl substituted with one or two hydroxyl groups and a -NR10aR10b; -C1-6-C alkyl (R13) = N-O-R13; -S (= O) 2-C 1-6 alkyl; -S (= O) 2-NR9aR9b; C1-6 alkyl substituted with a - (C = O) -R14; C1-6 alkyl substituted with one or two hydroxyl groups and an R14; C1-6 alkyl substituted with an R14; C2-6 alkenyl substituted with an R14; C2-6 alkynyl substituted with an R14; or R14; R4a is hydrogen; R4b is hydrogen; or R4a and R4b are taken together to form = O; Y is -O- or -C (= O) -; Z is -CHR6- or -CH2-C-; R6 is hydrogen; C1-4-O-carbonyl- alkyl; C1-4 alkyl; C1-4 alkyl substituted with one or two hydroxyl groups; C1-4 alkyl substituted with a -NR9aR9b; or -C (= O) -NR9aR9b; Ring A is phenyl or a saturated, partially saturated or aromatic 6-membered heterocyclyl, said heterocyclyl containing one or two nitrogen atoms; wherein the phenyl or heterocyclyl is optionally substituted with one or two R8 substituents; each R8 is independently hydrogen; C1-4 alkyloxy; hydroxyl; cyano; C1-4 alkyl or halo; or a substituent R8 in an atom adjacent to the atom carrying the substituent YZ can be taken together with the substituent R6 of Z, whereby the ring A together with YZ forms a bicycle of formula (a-1), (a-2) , (a-3) or (a-4): ** Formula ** R9a and R9b each independently represent hydrogen; mono- or C1-4 polyhaloalkyl; C 1-4 alkylcarbonyl; C1-4-O-carbonyl- alkyl; C1-4 alkyl substituted with one or two hydroxyl groups; or C1-4 alkyl optionally substituted with a substituent selected from the group consisting of C1-4 alkyloxy, cyano, amino and mono- or di (C1-4 alkyl) amino; R10a and R10b each independently represent hydrogen; C1-4 alkyl; C1-6 cyanoalkyl; C1-6 alkyl substituted with an NR9aR9b; C1-6 alkyl substituted with a -C (= O) -NR9aR9b; C1-6 alkyloxy optionally substituted with one or two hydroxyl groups; C1-6 alkyloxy C1-6 alkyl wherein each C1-6 alkyl is optionally substituted with one or two hydroxyl groups; R14; C1-6 alkyl substituted with an R14; - (C = O) -R14; C1-6 alkylcarbonyl; C1-6-O-carbonyl- alkyl; mono- or polyhaloalkylcarbonyl C1-6- substituted with one or two hydroxyl groups; mono- or polyhaloalkyl C1-6 substituted with one or two hydroxyl groups; mono- or polyhaloalkylcarbonyl C1-6-; C1-6 alkyl substituted with a -Si (CH3) 3; -S (= O) 2-C 1-6 alkyl optionally substituted with one or more halo substituents; -S (= O) 2-NR9aR9b; C1-6 alkyl substituted with a -S (= O) 2-C1-6 alkyl wherein -S (= O) 2-C1-6 alkyl is optionally substituted with one or more halo substituents; C1-6 alkyl substituted with a -S (= O) 2-NR9aR9b; C1-6 alkyl substituted with a -NH-S (= O) 2-C1-6 alkyl wherein -NH-S (= O) 2-C1-6 alkyl is optionally substituted on a carbon atom with one or more substituents halo; C1-6 alkyl substituted with a -NH-S (= O) 2-NR9aR9b; mono- or C1-4 polyhaloalkyl; or C1-4 alkyl substituted with one or two hydroxyl groups; R11 is cyano; -NR10aR10b; C1-6 alkyloxy optionally substituted with one or two hydroxyl groups; -S (= O) 2-C 1-6 alkyl; -S (= O) 2-NR9aR9b; -NR13-S (= O) 2-C1-6 alkyl; -NR13-S (= O) 2-NR9aR9b; C1-6 alkylcarbonyloxy; -C (= O) -NR10aR10b; -OC (= O) -NR10aR10b; -COOH; -P (= O) (OH) 2; or -P (= O) (O-C1-4 alkyl) 2; R12 is -NR9aR9b, C1-6 alkyloxy or cyano; R13 is hydrogen or C1-4 alkyl; R14 is a C3-8 cycloalkyl; or a saturated 4, 5 or 6 membered heterocyclyl which is optionally substituted with one, two or three substituents selected from the group consisting of oxo, C1-4 alkyl, halogen, cyano, hydroxyl, C1-6 alkyloxy and NR9aR9b; x1 is CR5a or N; x2 is CR5b or N; x3 is CR5c or N; each R15 is independently selected from the group consisting of hydrogen, methyl, halo, C1-4 alkyloxy and hydroxyl; R5a and R5c are each independently selected from the group consisting of hydrogen; hydroxyl; cyano; halo; C1-6 alkyl; C1-6 alkyl substituted with one or two hydroxyl groups; mono- or C1-6 polyhaloalkyl; mono- or C1-6 polyhaloalkyloxy; C1-6 alkyl substituted with a -NR9aR9b; C1-6 alkyl substituted with a cyano; C1-6 alkyloxy C1-6 alkyl wherein each of the C1-6 alkyl groups are optionally substituted with one or two hydroxyl groups; C2-6 alkenyl; C1-6alkyl-O-carbonyl-; C1-6 alkyloxy; C1-6 alkyloxy substituted with one or two hydroxyl groups; C 1-6 alkyloxyC 1-6 alkyloxy wherein each of the C 1-6 alkyl groups are optionally substituted with one or two hydroxyl groups; C1-6 alkyloxy substituted with a cyano; and C1-6 alkyloxy substituted with a -NR9aR9b; R5b is hydrogen; C1-6 alkyl; C3-6 cycloalkyl optionally substituted with a cyano; hydroxyl; cyano; mono- or C1-6 polyhaloalkyloxy; mono- or C1-6 polyhaloalkyl; C1-4 alkyl substituted with one or two hydroxyl groups; C2-6 alkenyl; C1-4 alkyloxy; -Yes (CH3) 3; C1-6 alkyl substituted with an R12; C1-6-O-carbonyl- alkyl; or C1-6 alkyloxy substituted with an R12; or an N-oxide, a pharmaceutically acceptable addition salt or a solvate thereof.