WORTMANN LARS (DE)
MOWAT JEFFREY (BE)
KUHNKE LARA (DE)
GÜNTHER JUDITH (DE)
MÜLLER STEFFEN (DE)
LEDER GABRIELE (DE)
CARRETERO RAFAEL (DE)
FRIBERG ANDERS (DE)
STÖCKIGT DETLEF (DE)
BÖMER ULF (DE)
OFFRINGA RIENK (DE)
CHENG PENG (CN)
WANG XUEWEI (CN)
YAN YUANYUAN (CN)
DEUTSCHES KREBSFORSCH (DE)
CLAIMS 1. Compounds of formula (I) in which both A represent either ‐CH2‐ or ‐CH2‐CH2‐, R3 represents ‐H or ‐CH3, X represents either a direct bond, ‐CH2‐ or ‐O‐, Y represents ‐H, ‐Cl, ‐F, ‐Br, ‐CN, ‐CF3, C1‐C4‐alkyl, C3‐C7‐cycloalkyl, R1 represents a group *‐A'‐B, in which *‐A'‐ represents • a direct bond and in which B represents • hydrogen or • phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) or in which *‐A'‐ represents a group *‐CRaH‐, in which Ra represents • hydrogen, • C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4‐ to 7 membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐ CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)) and in which B represents • hydrogen, • ‐CN, • C1‐C6‐alkyl, C3‐C7‐cycloalkyl or a 4‐ to 7 membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, ‐ S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • ‐phenyl, C3‐6‐cycloalkyl, • ‐C(=O)‐NHRb, in which Rb represents •• hydrogen, •• C1‐C4‐alkoxy, •• C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4‐ to 7 membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐ CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or •• phenyl or a 5‐ or 6‐ membered heteroaryl or a 9‐ or 10‐membered bicyclic heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐ OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl (optionally ‐OCH3 substituiert), C3‐C7‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or • in which R6 and R7 are independently of each other hydrogen, ‐CH3 or bridged by C1‐C4‐alkyl in which one ‐CH2‐group can be replaced by oxygen, • or ; or in which A' represents a group • *‐C(=O)‐ or *‐SO2‐ and in which B represents • C1‐C6‐alkyl, C3‐C7‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, C1‐C4‐alkoxy, an oxo‐group (=O),‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3, or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, ‐C(=O)‐NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)) or 5‐ to 6‐ membered heteroaryl, • C2‐C4‐alkenyl, • , • phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • ‐NRxRy, in which Rx and Ry represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or in which A' represents a group • *‐C(=O)‐O‐, • , in which Rc represents ‐H or C1‐C4‐alkyl, • *‐C(=O)‐NRc‐, in which Rc represents ‐H or C1‐C4‐alkyl, • *‐C(=S)‐NRc‐, in which Rc represents ‐H or C1‐C4‐alkyl, • *‐C(=N‐CN)‐O‐ or • *‐C(=N‐CN)‐NRc, in which Rc represents ‐H or C1‐C4‐alkyl and in which B represents • ‐H, • C1‐C6‐alkyl, C1‐C4‐alkoxy, C3‐C7‐cycloalkyl, 4‐ to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted with ‐F or ‐Cl; • C2‐C6‐alkenyl, • phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • ‐SO2‐(C1‐C4‐alkyl), • a group –C(=O)‐Rd, in which Rd represents •• ‐CF3, •• C1‐C4‐alkoxy or •• C3‐C7‐cycloalkyl, • a group ‐(CH2)n‐Re in which n is 1 or 2 and in which Re represents •• 4 to 7‐membered heterocycloalkyl, optionally substituted with an oxo‐group (=O), •• ‐phenyl, optionally substituted with C1‐C4‐alkyl, or •• 5‐ or 6‐ membered heteroaryl, optionally substituted with C1‐C4‐alkyl, • or in which N, Rc and B together form a 4‐ to 7‐membered heterocycloalkyl, optionally substituted with C1‐C4‐alkyl or ‐NRxRy, in which Rx and Ry represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or • a group –C(=O)‐Rf, in which Rf represents C1‐C4‐alkyl or C3‐C7‐cycloalkyl, R2 represents , , , , or , R4 represents • ‐H, • ‐NO2, • ‐CN, • ‐OH, • ‐P(=O)(C1‐C4‐alkyl)2, • ‐S(=O)2‐(C1‐C4‐alkyl), • ‐N=S(=NH)(C1‐C4‐alkyl)2, • ‐N=S(=O)(C1‐C4‐alkyl)2, • halogen • ‐C(=O)‐O‐ C1‐C4‐alkyl, • ‐C(=O)‐ C1‐C4‐alkyl, • ‐O‐CH3, • ‐C2‐C6‐alkoxy, optionally substituted with •• ‐F, ‐OH, ‐O‐CH3, ‐S‐CH3, ‐NRxRy, in which Rx and Ry represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo‐group (=O), •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐ fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), •• C3‐C7‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐ OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐ S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), •• ‐C(=O)‐NRvRw or ‐C(=O)‐O‐Rv, in which Rv represents ‐H or C1‐C4‐alkyl, Rw represents ‐H, C1‐C4‐alkyl or ‐CH2‐CF3 or in which N, Rv and Rw together form a 4‐ to 7‐membered heterocycloalkyl • C3‐C6‐cycloalkoxy, • C3‐C6‐alkenyloxy, • C1‐C6‐alkyl, C3‐C7‐cycloalkyl, 4‐ to 7‐membered heterocycloalkyl or 4 to 7‐membered heterocycloalkenyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐ CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐C(=O)‐O‐CH3, phenyl or 5‐ or 6‐membered heteroaryl, • C2‐C4‐alkynyl, optionally substituted with 5‐ to 6‐membered heteroaryl, this heteroaryl again optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐ cycloalkyl, 4‐ to 7 membered heterocycloalkyl, C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐ NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐phenyl, ‐CN, C1‐C4‐fluoroalkyl, ‐ OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐ C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • phenyl, optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐ S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐ C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • ‐NRiRj, in which Ri represents ‐H, C1‐C4‐alkyl and Rj represents ‐H, C1‐C4‐alkyl, a 5‐ to 6 membered heteroaryl or in which N, Ri and Rj together form a 4‐ to 7‐membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo‐group (=O) or C1‐C4‐alkyl • ‐NRi‐S(=O)2‐Rp, in which Ri represents ‐H, C1‐C4‐alkyl and Rp represents 5‐ or 6‐membered heteroaryl, • ‐NH‐C(=O)‐NRkRl, in which Rk represents ‐H or C1‐C4‐alkyl and Rl represents •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐ fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or •• C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐ alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)) • ‐NH‐C(=O)‐Rm, in which Rm represents •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐ fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or •• C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐ alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • ‐(C=O)‐NRnRo, in which Rn represents ‐H or C1‐C4‐alkyl, Ro represents C1‐C6‐hydroxyalkyl, 5‐ or 6‐ membered heteroaryl (N), or or in which N, Rn and Ro together form a 3‐ to 7‐membered heterocycloalkyl, optionally substituted with ‐CN, R5 represents ‐H, C1‐C4‐alkyl, ‐F or ‐Cl, R15 represents ‐H, C1‐C4‐alkyl, ‐CF3, ‐F, ‐Cl,‐O‐CH3 or ‐CN or a stereoisomer, a tautomer, an N‐oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. Compounds of formula (I) according to claim 1 in which both A represent ‐CH2‐, R3 represents ‐H, X represents either a direct bond, ‐CH2‐ or ‐O‐, Y represents ‐H, ‐Cl, ‐Br, ‐CN, ‐CF3, C1‐C4‐alkyl, C3‐C7‐cycloalkyl, R1 represents a group *‐A'‐B, in which *‐A'‐ represents a direct bond and in which B represents ‐H or in which *‐A'‐ represents a group *‐CRaH‐, in which Ra represents ‐H, C1‐C4‐alkyl or C3‐C7‐cycloalkyl all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)) and in which B represents ‐H, ‐CN, C1‐C6‐alkyl, C3‐C7‐cycloalkyl or a 4‐ to 7 membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, ‐ S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐C(=O)‐NHRb, in which Rb represents ‐H, C1‐C4‐alkoxy, C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4‐ to 7 membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐ CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or phenyl or a 5‐ or 6‐ membered heteroaryl or a 9‐ or 10‐membered bicyclic heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl (optionally ‐OCH3 substituiert), C3‐ C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or in which R6 and R7 are hydrogen or bridged by C1‐C4‐alkyl in which one ‐CH2‐group can be replaced by oxygen, in which A' represents a group *‐C(=O)‐ and in which B represents C1‐C6‐alkyl, C3‐C7‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, C1‐C4‐alkoxy, an oxo‐group (=O),‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3, or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, ‐C(=O)‐NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)) or 5‐ to 6‐ membered heteroaryl, C2‐C4‐alkenyl, , phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐NRxRy, in which Rx and Ry represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), in which A' represents a group *‐C(=O)‐O‐, *‐C(=O)‐NRc‐, in which Rc represents ‐H or C1‐C4‐alkyl, *‐C(=S)‐NRc‐, in which Rc represents ‐H or C1‐C4‐alkyl, in which B represents ‐H, C1‐C6‐alkyl, C1‐C4‐alkoxy, C3‐C7‐cycloalkyl, 4‐ to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted with ‐F or ‐Cl; C2‐C6‐alkenyl, phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐SO2‐(C1‐C4‐alkyl), a group –C(=O)‐Rd, in which Rd represents ‐CF3, C1‐C4‐alkoxy or C3‐C7‐cycloalkyl, a group ‐(CH2)n‐Re in which n is 1 or 2 and in which Re represents 4 to 7‐membered heterocycloalkyl, optionally substituted with an oxo‐group (=O), ‐phenyl or 5‐ or 6‐ membered heteroaryl, optionally substituted with C1‐ C4‐alkyl; or N, Rc und B together form a 4‐ to 7‐membered heterocycloalkyl, optionally substituted with C1‐C4‐alkyl or ‐NRxRy, in which Rx and Ry represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), a group –C(=O)‐Rf, in which Rf represents C1‐C4‐alkyl or C3‐C7‐cycloalkyl, R2 represents or , R4 represents ‐H, ‐NO2, ‐CN, ‐OH, ‐P(=O)(C1‐C4‐alkyl)2, ‐S(=O)2‐(C1‐C4‐alkyl), halogen ‐C(=O)‐ C1‐C4‐alkyl, ‐O‐CH3, ‐C2‐C6‐alkoxy, optionally substituted with ‐F, ‐OH, ‐O‐CH3, ‐S‐CH3, ‐NRxRy, in which Rx and Ry represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo‐group (=O), phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C3‐C7‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐C(=O)‐NRvRw or ‐C(=O)‐O‐Rv, in which Rv represents ‐H or C1‐C4‐alkyl, Rw represents ‐H, C1‐C4‐alkyl or ‐CH2‐CF3 or in which N, Rv and Rw together form a 4‐ to 7‐membered heterocycloalkyl ‐ C3‐C6‐alkenyloxy, C1‐C6‐alkyl, C3‐C7‐cycloalkyl, 4‐ to 7‐membered heterocycloalkyl or 4 to 7‐membered heterocycloalkenyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐ S(O)2‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐C(=O)‐O‐CH3, phenyl or 5‐ or 6‐membered heteroaryl, C2‐C4‐alkynyl, optionally substituted with 5‐ to 6‐membered heteroaryl, this heteroaryl again optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐ alkyl, C3‐C7‐cycloalkyl, 4‐ to 7 membered heterocycloalkyl, C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐ S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐phenyl, ‐CN, C1‐C4‐ fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), phenyl, optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐ C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐ alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐NRiRj, in which Ri represents ‐H, C1‐C4‐alkyl and Rj represents ‐H, C1‐C4‐alkyl, a 5‐ to 6 membered heteroaryl or in which N, Ri and Rj together form a 4‐ to 7‐ membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo‐group (=O) or C1‐C4‐alkyl ‐NRi‐S(=O)2‐Rp, in which Ri represents ‐H, C1‐C4‐alkyl and Rp represents 5‐ or 6‐membered heteroaryl, ‐NH‐C(=O)‐NRkRl, in which Rk represents ‐H or C1‐C4‐alkyl and Rl represents phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), or C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐ CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)) ‐NH‐C(=O)‐Rm, in which Rm represents phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C1‐C4‐fluoroalkyl, ‐OCF3, ‐OCF2H, halogen, C1‐C4‐alkyl, C3‐C7‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C1‐C4‐alkoxy, ‐ S(O)2‐CH3, ‐S(O)(NRz)‐CH3 or ‐NRxRy, in which Rx,Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or C1‐C4‐alkyl, C3‐C7‐cycloalkyl or 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF3, C1‐C4‐alkyl, ‐CN, ‐S(O)2‐CH3, ‐S(O)(NRz)‐CH3, C1‐C4‐alkoxy, an oxo‐group (=O), ‐NRxRy, in which Rx, Ry and Rz represent independently of each other ‐H or C1‐C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) ‐(C=O)‐NRnRo, in which Rn represents ‐H or C1‐C4‐alkyl, Ro represents C1‐C6‐hydroxyalkyl, 5‐ or 6‐membered heteroaryl (N), or or in which N, Rn and Ro together form a 3‐ to 7‐membered heterocycloalkyl, optionally substituted with ‐CN, R5 represents ‐H, ‐F or ‐Cl, R15 represents ‐H, or a stereoisomer, a tautomer, an N‐oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 3. Compounds according to claim 1 or 2 in which R2 is selected from or . 4. Compounds according to claim 1 or 2 wherein R2 is 5. Compounds according to claim 1 or 2 wherein R2 is and wherein R4 is selected from hydrogen, ‐F, ‐Cl, methyl, ethyl and isopropyl. 6. Compounds according to claim 1 or 2 wherein R1 is selected from ‐C(=O)‐O‐tBu, ‐C(=O)‐NH‐Et, ‐C(=O)‐NH‐C(=O)‐O‐Et, , or . 7. Compounds according to claim 1 or 2 wherein X is a direct bond. 8. Compounds according to claim 1 or 2 wherein Y is hydrogen or ‐Cl. 9. Compound according to claim 1, which is selected from tert‐butyl 2'‐(2‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐[5‐(trifluoromethyl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (pyrimidin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (1‐methyl‐1H‐pyrazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone 4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanenitrile 3‐methoxy‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]propan‐1‐ one 3‐(1H‐pyrazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one 2‐(morpholin‐4‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one 2‐(pyrimidin‐5‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one (3‐chlorophenyl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (pyridin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]methanone 2‐ethyl‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butan‐1‐one 1‐{2‐oxo‐2‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethyl}pyrrolidin‐2‐one (pyridin‐3‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]methanone 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]cyclopropane‐ 1‐carbonitrile 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one (1‐methyl‐1H‐imidazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone 2‐methoxyethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate 2‐methoxyethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyrimidin‐4‐ yl)methanone (1‐methyl‐1H‐pyrazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐3‐(1H‐ pyrazol‐1‐yl)propan‐1‐one 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (morpholin‐4‐yl)ethan‐1‐one 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (pyrimidin‐5‐yl)ethan‐1‐one (3‐chlorophenyl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐4‐ yl)methanone 2‐ethyl‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]butan‐1‐one 1‐{2‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ oxoethyl}pyrrolidin‐2‐one [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐3‐ yl)methanone 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one (1‐methyl‐1H‐imidazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone 3‐methoxy‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one 4‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐4‐ oxobutanenitrile 1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] N,N‐dimethyl‐5‐{[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine 1‐[(1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐indazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐(cyclohexylmethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 6'‐methyl‐1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] N,N‐dimethyl‐5‐{[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine 6'‐methyl‐1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐indazol‐3‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐(cyclohexylmethyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐(cyclopropanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐(cyclopropanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 6'‐methyl‐N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide 1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 6'‐methyl‐1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] N‐(2‐chloroethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide 2'‐(quinolin‐3‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐cyclopentyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐tert‐butyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide methyl [2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]carbamate N‐[(furan‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐(2‐methoxyethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐phenyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbothioamide 1‐(methanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐(methanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] ethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate 1‐[(4‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(imidazo[1,5‐a]pyridin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐{[1‐(propan‐2‐yl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(quinolin‐3‐yl)‐1‐{[4‐(trifluoromethyl)‐1H‐imidazol‐2‐yl]methyl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐(2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐{[1‐(2‐methoxyethyl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(quinolin‐3‐yl)‐1‐[(1,4,5‐trimethyl‐1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐benzimidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(1H‐pyrazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐[(4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(2‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐[(5‐methyl‐1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 3‐(ethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione 3‐(dimethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione 2‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one 3‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one 4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one 2‐(1H‐imidazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one 4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanamide 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐(4H‐1,2,4‐triazol‐4‐ yl)ethan‐1‐one 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]prop‐2‐en‐1‐one 3‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one N'‐cyano‐N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide N'‐cyano‐N,N‐dimethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide N‐[3‐(dimethylamino)propyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐(oxan‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐{[‐oxolan‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide (4‐methylpiperazin‐1‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone N‐[2‐oxopyrrolidin‐3‐yl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]azetidine‐3‐ carboxamide N‐[(1H‐pyrazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide (morpholin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone N‐(3‐hydroxypropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐(2‐hydroxyethyl)‐N‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐(2‐oxopiperidin‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐(6‐oxopiperidin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐[2‐(1H‐imidazol‐1‐yl)ethyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐benzyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐(2‐hydroxy‐2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐[(1‐methyl‐1H‐imidazol‐4‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐{[‐5‐oxopyrrolidin‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide [‐3‐(dimethylamino)pyrrolidin‐1‐yl][2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone N‐{2‐[oxolan‐3‐yl]ethyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide 2'‐(2‐aminopyrimidin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide 2'‐(6‐aminopyridin‐3‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide ethyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate ethyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate ethyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]ethan‐1‐one 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐methylpropan‐1‐one 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carbonyl]cyclopropane‐1‐carbonitrile [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](phenyl)methanone [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](oxan‐4‐yl)methanone tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (rac)‐6'‐methyl‐N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (rac)‐N‐tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide N‐ethyl‐2'‐(6‐methoxyquinolin‐3‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1‐ carboxamide N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐yl}‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐phenyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(quinolin‐3‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1‐ carboxamide N‐ethyl‐2'‐[6‐(trifluoromethyl)quinolin‐3‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐[3‐(propan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐yl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide 2'‐[6‐(cyclohexyloxy)quinolin‐3‐yl]‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide cyclopentyl (rac)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(5‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐ dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐c][1,4]oxazine] 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (rac)‐1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydrospiro[azetidine‐ 3,4'‐pyrazolo[5,1‐c][1,4]oxazine] (rac)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(3,3,3‐trifluoropropyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole] 1‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(cyclohexylmethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1‐methyl‐1H‐pyrazol‐4‐yl)methyl]‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole] [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridin]‐1‐yl](4‐fluorophenyl)methanone [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridin]‐1‐yl](oxan‐4‐yl)methanone 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(methanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐sulfonamide 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](morpholin‐4‐yl)methanone 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2‐hydroxy‐2‐methylpropyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐methyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐hydroxyethan‐1‐one 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐(pyridin‐3‐yl)ethan‐1‐one 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(phenylmethanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propane‐1‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐sulfonamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(pyridine‐3‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(morpholine‐4‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts. 10. A compound of general formula (I) according to any one of claims 1 to 9 for the use as a medicament. 11. A compound of general formula (I) according to any one of claims 1 to 9 for use in the treatment or prophylaxis of a disease. 12. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients. 13. A pharmaceutical combination comprising: one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 9, and one or more pharmaceutical active anti cancer compounds or one or more pharmaceutical active immune checkpoint inhibitors. 14. A pharmaceutical combination according to claim 13, characterized in that the pharmaceutical active immune checkpoint inhibitor is an antibody. 15. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the treatment or prophylaxis of a disease. 16. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease. 17. Use according to claim 15 or 16, wherein the disease is cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, such as liquid and solid tumours. 18. Use according to claim 15 or 16, wherein the diseases, respectively the disorders are benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, neurodegenerative disorders, in inflammatory disorders, and male fertility control. 19. The intermediates for the synthesis of compounds of claim 1 or 2 , , or wherein R1, R3, A, X and Y have the same meaning in claim 1 or 2. |
The present invention relates to MAP4K1 inhibitors, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients.
The present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control. Background
Although cancer cell commonly can be recognized by the adaptive immune system, the response generated is evidently not capable of eliminating the tumor. A major reason for this is the presence of immunosuppressive mechanisms in the tumor microenvironment. In this respect, inhibitors of T-cell immune checkpoint such as CTLA-4, PD-1 or PD-L1 were recently shown to result in a remarkable clinical efficacy in subsets of cancer patients. Besides cell surface receptors that act as negative immune regulators, several mediators of intracellular signaling have been identified that also represent potential immunoevasive mechanisms utilized by the tumor.
One of these is MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1). MAP4K1 (GenelD11184) is a serine/threonine kinase and member of the Germinal Center Kinase family. In the adult organism MAP4K1 expression is restricted to hematopoietic cell types. The MAP4K1 protein consist of a N-terminal kinase domain, followed by a proline-rich domain that can interact with adaptor molecules through SH2 and SH3 domains, and a C-terminal citron homology domain of which the exact function remains to be identified. Through its proline-rich domain, MAP4K1 is capable of binding to a diversity of adaptors in hematopoietic cells, including those involved in T-cell receptor (TCR), B-cell receptor (BCR) and cytokine signaling (Hu et al., Genes Dev. 1996 Sep 15;10(18):2251-64, 2.; Ling et al.,.
J Biol Chem. 2001 Jun 1;276(22), Sauer et al., J Biol Chem. 2001 Nov 30;276(48):45207-16., Tsuji et al., J Exp Med. 2001 Aug 20;194(4):529-39, Boomer et al., J Cell Biochem. 2005 May l;95(l):34-44).
The function of MAP4K1 has been studied in greatest detail in the context of TCR signaling. Upon TCR stimulation, MAP4K1 is phosphorylated on tyrosine 381 (Y-381; Y-379 in mouse) (Di Bartolo et al., J Exp Med. 2007 Mar 19;204(3):681-91). Consequently, MAP4K1 is recruited to the TCR-signaling complex MAP4K1 phosphorylates the SLP‐76 adaptor protein at Serine‐376, resulting in downregulation of AP‐1 and Erk2 pathways. As, such, MAPK1 acts as a negati ve feedback on TCR‐signaling (Liou et al., Immunity . 2000 Apr;12(4):399‐408; Lasserre et al., J Cell Bio l. 2011 Nov 28;195(5):839‐53.). Alternatively, MAP4K1 can be triggered to suppress T cell function by pro staglandin E2 (PGE2), and possibly also by transformi ng growth factor beta (TGF‐beta), factors that are commonly found in the tumor microenvironment. Notably, MAP4K1 activation by these mediators involves protein kinase A (PKA)‐dependent phosphorylation of Serine 171 (S‐171; also in mouse ) (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419‐29; Sawasdikosol et al., J Biol Chem. 2007 Nov 30;282(48):34693‐9.). Further important insights into the function of MAP4K 1 in the regulation of T cell immunity stem from in vivo and in vitro experiments respectively with M AP4K1 deficient mice produced by two laboratories and with immune cells isolated from these mice (Shui et al., Nat Immunol. 2007 Jan;8(1):84‐91; Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419 29). MAP4K1‐deficient mice show an apparent normal phenotype, are fertile and exhibit normal lymp hocyte development. These animals are prone to develop T‐cell dependent autoimmune reactivity as in dicated by development of a more severe disease score in the EAE (experimental autoimmune encephalomye litis) model of multiple sclerosis (Shui et al., Nat Immunol. 2007 Jan;8(1):84‐91). In case of the second strain, a dysregulation of immune function was observed when, at the age of approximately 6 months, MAP4K1‐deficient mice develop a spontaneous autoimmune phenotype (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419‐29). In vitro studies showed that MAP4K1‐/‐ T‐cells display hy per‐responsiveness upon TCR‐stimulation. These cells proliferate and secrete pro‐inflammatory cytokines li ke IL‐2 or IFNg to a significantly greater extent than their wild‐type counterparts (Shui et al., Nat Immu nol. 2007 Jan;8(1):84‐91). Furthermore, MAP4K1‐/‐ T‐ cells are resistant to PGE2‐mediated suppression of T cell proliferation, suppression of IL‐2 productio n and induction of apoptosis (Alzabin et al., Cancer I mmunol Immunother. 2010 Mar;59(3):419‐29). In the context of tumor immunology, in vivo experi ments revealed that MAP4K1‐/‐ mice are much more resistant to tumorigenesis by PGE2‐producing Lewis lung carcinoma than wild type mice, which correlated with increased T‐lymphocyte infiltration i n the tumor areas. The crucial role of T‐cells in tumor rejection was supported by experiments in which MAP4K 1‐/‐ T‐cells adoptively transferred into T‐cell ‐ deficient mice were able to eradicate tumors more efficiently than wild‐type T‐cells (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419‐29). The important role of the kinase enzymatic activity was demonstrated by studies were only wild type MAP4K1, but not the MAP4K1 kinase‐dead mutant, could mediate serine‐phosphorylation of the TCR‐signaling complex component SLP‐76 and subsequent binding of SLP‐76 to the negative regulator of TCR‐signaling 14‐3‐3‐t (Shui et al., Nat Immunol. 2007 Jan;8(1):84‐91). MAP4K1 also regulates the stimulation and activation of dendritic cells. MAP4K1 deficient Bone marrow derived cells (BMDC) exp ress after maturation and stimulation higher level of costimulatory molecules and produce more proinflammatory cytokines. Also elimination of
tumors was observed to be more efficient by MAP4K 1 ‐/‐ BMDC compared to their wildtype counterpart s (Alzabin et al., J Immunol. 2009 May 15;182(10):6187 94). Prior art In WO2019164846A1 HPK1 inhibitors and methods for the ir use in various forms of cancer are described. These compounds differ from the instant compounds in their chemical structure. In US20190256500A1 HPK1 inhibitors and methods for th eir use in treating, preventing or ameliorating diseases or disorders associated with HPK1 such as c ancer are described. These compounds differ from the instant compounds in their chemical structure. In US20190256520A1 HPK1 inhibitors and methods for th eir use in treating, preventing or ameliorating diseases or disorders associated with HPK1 such as c ancer are described. These compounds differ from the instant compounds in their chemical structure. In CN109721620A HPK1 inhibitors and their uses are d escribed. These compounds differ from the instant compounds in their chemical structure. In WO2019090198A1, compounds used to modulate or inhi bit the activity of HPK1 and methods for their use in treatment of viral infections and proliferative disorders, such as cancer are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/215668, MAP4K1 (HPK1) inhibitors and methods for their use in diseases including hyperproliferative diseases, diseases of immune system dysfunction, intlammatory disorders, neurological diseases, and cardiovascular diseases are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049214, HPK1 modulators and methods for t heir use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049200, HPK1 modulators and methods for t heir use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049152, HPK1 modulators and methods for t heir use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
In WO 2018/049119, HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/102366, HPK1 inhibitors and methods for t heir use in the treatment of cancer are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/183956, HPK1 inhibitors and use of such compounds in treating HPK1‐dependent disorders and enhancing immune response are described. These co mpounds differ from the instant compounds in their chemical structure. In WO 2018/183964, HPK1 inhibitors and use of such compounds in treating HPK1‐dependent disorders and enhancing immune response are described. These co mpounds differ from the instant compounds in their chemical structure. In WO 2018/167147, HPK1 inhibitors and use of such compounds in treating HPK1‐dependent disorders and enhancing immune response are described. These co mpounds differ from the instant compounds in their chemical structure.In WO In WO2016/205942 HPK1, respectively inhibitors and methods of their use in cancer treatment are described. Specifically, the application concerns thieno‐pyridinones that can be used in anti‐cancer therapy. These compounds differ from the instant comp ounds in their chemical structure. In WO 2016/195776 inhibitors and methods for leukemia , cancer and diabetes treatment dependent on inhibition the interaction of menin with of MLL1, MLL2 and MLL‐fu sion oncoproteins are described. These compounds differ from the instant compounds in their chemical structure. In WO 2006/014325 C‐MET modulators and their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2005/058891 Rho kinase inhibitors and their use in cardiovascular and cancer treatment are described. These compounds differ from the instant co mpounds in their chemical structure. In WO 2015/089479 several inhibitors are described th at show inhibition of several kinases (e.g., BTK, HCK, TAK1 and HPK1). These compounds differ from the instant compounds in their chemical structure.
In WO2016/004272 BTK inhibitors and methods of their use in cancer treatment are described. No specific example is disclosed which falls in the gro up of compounds as defined according to the present invention. In WO 2011/090738 Type II RAF kinase inhibitors and their use in various diseases are described. No specific example is disclosed which falls in the gro up of compounds as defined according to the present invention. In CN102086211 and WO2006116713 protein kinase inhibitors and their use in prophylaxis and treatment of diseases including cancer are described. No specific example is disclosed which falls in the group of compounds as defined according to the prese nt invention. In WO 2010/045095 protein tyrosin kinase modulators and their use in the treatment of hyperproliferative disorders are described. No specific example is disclosed which falls in the group of compounds as defined according to the present inventi on. In WO 2008/089307 compounds and methods of their use in the treatment of pain, inflammation and cancer are described. No specific example is disclose d which falls in the group of compounds as defined according to the present invention. In WO 2006/114180 kinase inhibitors for treating dise ases, particularly tumors are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2006/014325 c‐Met modulators and their method s of use to treat kinase‐dependent diseases and conditions are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In US 2003/0055049 compounds for treating disorders with abnormal cell growth in mammals are described. No specific example is disclosed which fal ls in the group of compounds as defined according to the present invention. In WO 2001/23389 antagonists of NPY receptors compositions and methods of the treatment of physiological disorders associated with an excess of neuropeptide Y are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
In WO 2019/149738 protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death are described. It would therefore be desirable to provide novel MAP 4K1 inhibitors having prophylactic and therapeutic properties. Accordingly, it is an object of the present invention to provide compounds and pharmaceutical compositions comprising these compounds used for prophylactic and therapeutic applications for hyperproliferative disorders, in particular for cancer, respectively tumour disorders, and conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients. A further object of the present invention is to provide compounds and pharmaceutical composition s comprising these compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of benign hyperplasias, atherosclerotic dis orders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disor ders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control. Surprisingly, the compounds according to the invention inhibit the MAP4K1 protein and thereby enhance tumor immunogenicity leading to inhibition of cancer cells growth by the immune response. Accordingly, they provide novel structures for the th erapy of human and animal disorders, in particular of cancers. A) The present invention relates to compounds of for mula (I) in which both A represent either ‐CH 2 ‐ or ‐CH 2 ‐CH 2 ‐, R3 represents ‐H or ‐CH 3 , X represents either a direct bond, ‐CH 2 ‐ or ‐O‐,
Y represents ‐H, ‐Cl, ‐F, ‐Br, ‐CN, ‐CF 3 , C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, R 1 represents a group *‐A'‐B, in which *‐A'‐ represents • a direct bond and in which B represents • hydrogen or • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) or in which *‐A'‐ represents a group *‐CR a H‐, in which R a represents • hydrogen, • C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4‐ to 7 membered heterocycloa lkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)) and in which B represents • hydrogen, • ‐CN,
• C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or a 4‐ to 7 membered heterocyc loalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), • ‐C(=O)‐NHR b , in which R b represents •• hydrogen, •• C 1 ‐C 4 ‐alkoxy, •• C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4‐ to 7 membered heterocycloa lkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or •• phenyl or a 5‐ or 6‐ membered heteroaryl or a 9‐ or 10‐membered bicyclic heteroaryl, all optionally substituted with CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl (optionally ‐OCH 3 substituiert), C 3 ‐ C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or • in which R 6 and R 7 are hydrogen or bridged by C 1 ‐C 4 ‐alkyl in which one ‐CH 2 ‐group can be replaced by oxygen, or in which A' represents a group • *‐C(=O)‐ or *‐SO 2 ‐ and in which B represents • C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O),‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together
form a 4 to 7 membered heterocycloalkyl, ‐C(=O) NH 2 , 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) or 5‐ to 6‐ membered heteroaryl, • C 2 ‐C 4 ‐alkenyl, • , • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or in which A' represents a group • *‐C(=O)‐O‐, • , in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, • *‐C(=O)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, • *‐C(=S)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, • *‐C(=N‐CN)‐O‐ or • *‐C(=N‐CN)‐NR c , in which R c represents ‐H or C 1 ‐C 4 ‐alkyl and in which B represents • ‐H, • C 1 ‐C 6 ‐alkyl, C 1 ‐C 4 ‐alkoxy, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)),
• ‐CR 20 R 21 ‐R 22 in which R 20 is ‐CH 3 , R 21 is ‐H, ‐CH 3 or R 20 and R 21 together are ‐ CH 2 ‐CH 2 ‐CH 2 ‐ and in which R 22 is phenyl or pyridyl, both optionally substitu ted with ‐F or ‐Cl; • C 2 ‐C 6 ‐alkenyl, • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • ‐SO 2 ‐(C 1 ‐C 4 ‐alkyl), • a group –C(=O)‐R d , in which R d represents •• ‐CF 3 , •• C 1 ‐C 4 ‐alkoxy or •• C 3 ‐C 7 ‐cycloalkyl, • a group ‐(CH 2 ) n ‐R e in which n is 1 or 2 and in which R e represents •• 4 to 7‐membered heterocycloalkyl, optionally substituted with an oxo‐group (=O), •• ‐phenyl, optionally substituted with C 1 ‐C 4 ‐alkyl, or •• 5‐ or 6‐ membered heteroaryl, optionally s ubstituted with C 1 ‐C 4 ‐alkyl, • or in which N, R c and B together form a 4‐ to 7‐membered h eterocycloalkyl, optionally substituted with C 1 ‐C 4 ‐alkyl or ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or • a group –C(=O)‐R f , in which R f represents C 1 ‐C 4 ‐alkyl or C 3 ‐C 7 ‐cycloalkyl, R 2 represents , , ,
, or , R 4 represents • ‐H, • ‐NO 2 , • ‐CN, • ‐OH, • ‐P(=O)(C 1 ‐C 4 ‐alkyl) 2 , • ‐S(=O) 2 ‐(C 1 ‐C 4 ‐alkyl), • ‐N=S(=NH)(C 1 ‐C 4 ‐alkyl) 2 , • ‐N=S(=O)(C 1 ‐C 4 ‐alkyl) 2 , • halogen • ‐C(=O)‐O‐ C 1 ‐C 4 ‐alkyl, • ‐C(=O)‐ C 1 ‐C 4 ‐alkyl, • ‐O‐CH 3 , • ‐C 2 ‐C 6 ‐alkoxy, optionally substituted with •• ‐F, ‐OH, ‐O‐CH 3 , ‐S‐CH 3 , ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl optionally substituted with a n oxo‐group (=O), •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐ CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), •• C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), •• ‐C(=O)‐NR v R w or ‐C(=O)‐O‐R v ,
in which R v represents ‐H or C 1 ‐C 4 ‐alkyl, R w represents ‐H, C 1 ‐C 4 ‐alkyl or ‐CH 2 ‐CF 3 or in which N, R v and R w together form a 4‐ to 7‐membered heterocycloalkyl • C 3 ‐C 6 ‐alkenyloxy, • C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl or 4 to 7‐membered heterocycloalkenyl, all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐ S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐ group (=O)), ‐C(=O)‐O‐CH 3 , phenyl or 5‐ or 6‐membered heteroaryl, • C 2 ‐C 4 ‐alkynyl, optionally substituted with 5‐ to 6‐membered heteroaryl, this heteroaryl again optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7 membered heterocycloalky l, C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐phenyl, ‐CN, C 1 ‐C 4 ‐ fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered hetero cycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), • phenyl, optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐ C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐ alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), • ‐NR i R j , in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R j represents ‐H, C 1 ‐C 4 ‐alkyl, a 5‐ to 6 membered heteroaryl or in which N, R i and R j together form a 4‐ to 7‐ membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo‐group (=O) or C 1 ‐C 4 ‐alkyl • ‐NR i ‐S(=O) 2 ‐R p ,
in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R p represents 5‐ or 6‐membered heteroaryl, • ‐NH‐C(=O)‐NR k R l , in which R k represents ‐H or C 1 ‐C 4 ‐alkyl and R l represents •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or •• C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) • ‐NH‐C(=O)‐R m , in which R m represents •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐ CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or •• C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), • ‐(C=O)‐NR n R o ,
in which R n represents ‐H or C 1 ‐C 4 ‐alkyl, R o represents C 1 ‐C 6 ‐hydroxyalkyl, 5‐ or 6‐membered heteroaryl (N), or or in which N, R n and R o together form a 3‐ to 7‐membered heterocyc loalkyl, optionally substituted with ‐CN, R 5 represents ‐H, C 1 ‐C 4 ‐alkyl, ‐F or ‐Cl, R 15 represents ‐H, C 1 ‐C 4 ‐alkyl, ‐CF 3 , ‐F, ‐Cl,‐O‐CH 3 or ‐CN or a stereoisomer, a tautomer, an N‐oxide, a hydra te, a solvate, or a salt thereof, or a mixture of same. A) The present invention also relates to compounds o f formula (I) (I) in which both A represent either ‐CH 2 ‐ or ‐CH 2 ‐CH 2 ‐, R 3 represents ‐H or ‐CH 3 , X represents either a direct bond, ‐CH 2 ‐ or ‐O‐, Y represents ‐H, ‐Cl, ‐F, ‐Br, ‐CN, ‐CF 3 , C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, R 1 represents a group *‐A'‐B, in which *‐A'‐ represents • a direct bond and in which B represents • hydrogen or • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together
form a 4 to 7 membered heterocycloalkyl (optionall y substituted with an oxo‐ group (=O)) or in which *‐A'‐ represents a group *‐CR a H‐, in which R a represents • hydrogen, • C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4‐ to 7 membered heterocycloa lkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)) and in which B represents • hydrogen, • ‐CN, • C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or a 4‐ to 7 membered heterocyc loalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), • ‐phenyl, C 3‐6 ‐cycloalkyl, • ‐C(=O)‐NHR b , in which R b represents •• hydrogen, •• C 1 ‐C 4 ‐alkoxy, •• C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4‐ to 7 membered heterocycloa lkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x ,
R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or •• phenyl or a 5‐ or 6‐ membered heteroaryl or a 9‐ or 10‐membered bicyclic heteroaryl, all optionally substituted with CN, C 1 ‐C 4 ‐fluoroalkyl, ‐ OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl (optionally ‐OCH 3 substituiert), C 3 ‐C 7 ‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or • in which R 6 and R 7 are independently of each other hydrogen, ‐C H 3 or bridged by C 1 ‐C 4 ‐alkyl in which one ‐CH 2 ‐group can be replaced by oxygen, • or ; or in which A' represents a group • *‐C(=O)‐ or *‐SO 2 ‐ and in which B represents • C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O),‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl, ‐C(=O)‐N H 2 , 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) or 5‐ to 6‐ membered heteroaryl, • C 2 ‐C 4 ‐alkenyl, • , • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐
S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or in which A' represents a group • *‐C(=O)‐O‐, • , in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, • *‐C(=O)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, • *‐C(=S)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, • *‐C(=N‐CN)‐O‐ or • *‐C(=N‐CN)‐NR c , in which R c represents ‐H or C 1 ‐C 4 ‐alkyl and in which B represents • ‐H, • C 1 ‐C 6 ‐alkyl, C 1 ‐C 4 ‐alkoxy, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), • ‐CR 20 R 21 ‐R 22 in which R 20 is ‐CH 3 , R 21 is ‐H, ‐CH 3 or R 20 and R 21 together are ‐ CH 2 ‐CH 2 ‐CH 2 ‐ and in which R 22 is phenyl or pyridyl, both optionally substitu ted with ‐F or ‐Cl; • C 2 ‐C 6 ‐alkenyl, • phenyl or a 5‐ or 6‐ membered heteroaryl, a ll optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together
form a 4 to 7 membered heterocycloalkyl (optionall y substituted with an oxo‐ group (=O)), • ‐SO 2 ‐(C 1 ‐C 4 ‐alkyl), • a group –C(=O)‐R d , in which R d represents •• ‐CF 3 , •• C 1 ‐C 4 ‐alkoxy or •• C 3 ‐C 7 ‐cycloalkyl, • a group ‐(CH 2 ) n ‐R e in which n is 1 or 2 and in which R e represents •• 4 to 7‐membered heterocycloalkyl, optionally substituted with an oxo‐group (=O), •• ‐phenyl, optionally substituted with C 1 ‐C 4 ‐alkyl, or •• 5‐ or 6‐ membered heteroaryl, optionally s ubstituted with C 1 ‐C 4 ‐alkyl, • or in which N, R c and B together form a 4‐ to 7‐membered h eterocycloalkyl, optionally substituted with C 1 ‐C 4 ‐alkyl or ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or • a group –C(=O)‐R f , in which R f represents C 1 ‐C 4 ‐alkyl or C 3 ‐C 7 ‐cycloalkyl, R 2 represents , , , , or , R 4 represents • ‐H, • ‐NO 2 , • ‐CN, • ‐OH, • ‐P(=O)(C 1 ‐C 4 ‐alkyl) 2 , • ‐S(=O) 2 ‐(C 1 ‐C 4 ‐alkyl), • ‐N=S(=NH)(C 1 ‐C 4 ‐alkyl) 2 ,
• ‐N=S(=O)(C 1 ‐C 4 ‐alkyl) 2 , • halogen • ‐C(=O)‐O‐ C 1 ‐C 4 ‐alkyl, • ‐C(=O)‐ C 1 ‐C 4 ‐alkyl, • ‐O‐CH 3 , • ‐C 2 ‐C 6 ‐alkoxy, optionally substituted with •• ‐F, ‐OH, ‐O‐CH 3 , ‐S‐CH 3 , ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo‐g roup (=O), •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C 1 ‐C 4 ‐ fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered hetero cycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), •• C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐ S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), •• ‐C(=O)‐NR v R w or ‐C(=O)‐O‐R v , in which R v represents ‐H or C 1 ‐C 4 ‐alkyl, R w represents ‐H, C 1 ‐C 4 ‐alkyl or ‐CH 2 ‐CF 3 or in which N, R v and R w together form a 4‐ to 7‐membered heterocyc loalkyl • C 3 ‐C 6 ‐cycloalkoxy, • C 3 ‐C 6 ‐alkenyloxy, • C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl or 4 to 7‐membered heterocycloalkenyl, all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐C(=O)‐O‐CH 3 , phenyl or 5‐ or 6‐membered heteroaryl, • C 2 ‐C 4 ‐alkynyl, optionally substituted with 5‐ to 6‐membered heteroaryl, this heteroaryl again optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐ cycloalkyl, 4‐ to 7 membered heterocycloalkyl, C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐ NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which
N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), • 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐phenyl, ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐ OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐ C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • phenyl, optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐ C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), • ‐NR i R j , in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R j represents ‐H, C 1 ‐C 4 ‐alkyl, a 5‐ to 6 membered heteroaryl or in which N, R i and R j together form a 4‐ to 7‐membered heterocyc loalkyl, optionally substituted (1 or more times) with an oxo ‐group (=O) or C 1 ‐C 4 ‐alkyl • ‐NR i ‐S(=O) 2 ‐R p , in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R p represents 5‐ or 6‐membered heteroaryl, • ‐NH‐C(=O)‐NR k R l , in which R k represents ‐H or C 1 ‐C 4 ‐alkyl and R l represents •• phenyl or a 5‐ or 6‐ membered heteroaryl, all optionally substituted with ‐CN, C 1 ‐C 4 ‐ fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered hetero cycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or •• C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐ alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) • ‐NH‐C(=O)‐R m , in which R m represents
•• phenyl or a 5‐ or 6‐ membered heteroar yl, all optionally substituted with ‐CN, C 1 ‐C 4 ‐ fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered hetero cycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or •• C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐ alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), • ‐(C=O)‐NR n R o , in which R n represents ‐H or C 1 ‐C 4 ‐alkyl, R o represents C 1 ‐C 6 ‐hydroxyalkyl, 5‐ or 6‐ membered heteroaryl (N), or or in which N, R n and R o together form a 3‐ to 7‐membered heterocycloalkyl, optionally substituted with ‐CN, R 5 represents ‐H, C 1 ‐C 4 ‐alkyl, ‐F or ‐Cl, R 15 represents ‐H, C 1 ‐C 4 ‐alkyl, ‐CF 3 , ‐F, ‐Cl,‐O‐CH 3 or ‐CN or a stereoisomer, a tautomer, an N‐oxide, a hydra te, a solvate, or a salt thereof, or a mixture of same. The compounds of formula (I) are particularly suitabl e for a large number of prophylactic and therapeutic applications, in particular for hyperproliferative disorders, for tumour disorders and as proteine inhibitors and further for viral infections, for neur odegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for male fertility control. Further, it covers their use in combination with other anti cancer medications such as immunotherapeutics, targeted anti cancer agents, radiat ion or chemotherapy. DEFINITIONS In case an asterix is used in a formula, like for instance in *‐A‐B or *‐A‐, this asterix indi cates the bond towards the core of the compound.
The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible. The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommo dated by replacing a hydrogen atom with a non‐ hydrogen substituent on any available carbon or nitro gen or … atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3. As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, m ore particularly 1, 2 or 3, even more particularly 1 or 2”. When groups in the compounds according to the invent ion are substituted, it is possible for said groups to be mono‐substituted or poly‐substituted with su bstituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the comp ounds according to the invention are substituted with one, two or three identical or different substituents , particularly with one substituent. As used herein, an oxo substituent represents an oxy gen atom, which is bound to a carbon atom or to a sulfur atom via a double bond. The term “ring substituent” means a substituent attach ed to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring. The term “comprising” when used in the specificat ion includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text. The terms as mentioned in the present text have the following meanings: The term “halogen atom” means a fluorine, chlorin e, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
The term “C 1 ‐C 6 ‐alkyl” means a linear or branched, saturate d, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethy l, propyl, isopropyl, butyl, sec‐butyl, isobutyl, te rt‐butyl, pentyl, isopentyl, 2‐methylbutyl, 1‐methylbutyl, 1‐ethylpropyl, 1,2‐dimethylpropyl, neo‐pentyl, 1,1‐dimethylpropyl, hexyl, 1‐methylpentyl, 2‐methylpentyl, 3‐methylpentyl, 4‐methylpentyl, 1‐ethylbutyl, 2‐ethylbutyl, 1,1‐dimethylbutyl, 2,2 dimethylbutyl, 3,3‐dimethylbutyl, 2,3‐dimethylbutyl, 1,2‐dimethylbutyl or 1,3‐dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C 1 ‐C 4 ‐alkyl”), e.g. a methyl, ethyl, propyl, isop ropyl, butyl, sec‐butyl isobutyl, or tert‐ butyl group, more particularly 1, 2 or 3 carbon ato ms (“C 1 ‐C 3 ‐alkyl”), e.g. a methyl, ethyl, n‐propyl o r isopropyl group. The term “C 1 ‐C 6 ‐hydroxyalkyl” means a linear or branched, s aturated, monovalent hydrocarbon group in which the term “C 1 ‐C 6 ‐alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1‐hydroxyethyl, 2‐hydroxyethyl, 1,2‐dihydroxyethyl, 3‐hydroxypropyl, 2‐hydroxypropyl, 1‐hydroxypropyl, 1‐hydroxypropan‐2‐yl, 2‐hydroxypropan‐2‐yl, 2,3‐dihydroxypropyl, 1,3‐dihydroxypropan‐2‐yl, 3 hydroxy‐2‐methyl‐propyl, 2‐hydroxy‐2‐methyl‐ propyl, 1‐hydroxy‐2‐methyl‐propyl group. The term “C 1 ‐C 6 ‐haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 ‐C 6 ‐alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Part icularly, said halogen atom is a fluorine atom. Said C 1 ‐C 6 ‐haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2‐fluoroethyl, 2,2‐difluoroethyl, 2,2,2‐trifluoroethyl, pentafluoroethyl, 3,3,3‐trifluoropropyl or 1,3‐difluoropropan‐2‐yl. Preference is given to perfluorinated alkyl radicals which are named as “perfluoro‐C 1 ‐C x ‐alkyl‐“ wherein x is the maximum number of carbon atoms such as tr ifluoromethyl or 2,2,2‐trifluoroethyl. The term “C 1 ‐C 6 ‐cyanoalkyl” means a linear or branched, sat urated, monovalent hydrocarbon group in which the term “C 1 ‐C 6 ‐alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a cyano gr oup. The term “C 1 ‐C 6 ‐alkoxy” means a linear or branched, saturated, monovalent group of formula (C 1 ‐C 6 ‐alkyl)‐O‐, in which the term “C 1 ‐C 6 ‐alkyl” is as defined supra, e.g. a methoxy , ethoxy, n‐propoxy, isopropoxy, n‐butoxy, sec‐butoxy, isobutoxy, tert‐ butoxy, pentyloxy, isopentyloxy or n‐hexyloxy group, or an isomer thereof.
The term “C 1 ‐C 6 ‐haloalkoxy” means a linear or branched, sat urated, monovalent C 1 ‐C 6 ‐alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C 1 ‐C 6 ‐haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2‐trifluoroethoxy or pentafluoroethoxy. Preference is given to perfluorinated alkyl radicals which are named as “perfluoro‐C 1 ‐C x ‐alkoxy‐“ wherein x is the maximum number of carbon atoms suc h as trifluoromethoxy and 2,2,2‐trifluoroethoxy radicals. The term “C 1 ‐C 6 ‐cyanoalkoxy” means a linear or branched, sa turated, monovalent C 1 ‐C 6 ‐alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a cyano group. Mono‐(C 1 ‐C 4 )‐alkylamino in the context of the invention means an amino group with one straight‐chain or branched alkyl substituent which contains 1, 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n‐propylamino, isopropylamino, n‐butylami no, and tert‐butylamino, for example. Di‐(C 1 ‐C 4 )‐alkylamino in the context of the invention means an amino group with two identical or different straight‐chain or branched alkyl substituen ts which each contain 1, 2, 3 or 4 carbon atoms, such as: N,N‐dimethylamino, N,N‐diethylamino, N‐ethyl‐N‐methylamino, N‐methyl‐N‐n‐propylamino, N‐ isopropyl‐N‐methylamino, N‐isopropyl‐N‐n‐propylamino, N,N‐diisopropylamino, N‐n‐butyl‐N‐methyl‐ amino, and N‐tert‐butyl‐N‐methylamino, for examp le. (C 1 ‐C 4 )‐Alkylcarbonyl in the context of the invention means a straight‐chain or branched alkyl group having having 1, 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carbonyl g roup [‐C(=O)‐], such as: acetyl, propionyl, n‐butyryl, isobutyryl, n‐pentanoyl, and pivaloyl, for example. (C 1 ‐C 4 )‐Alkylcarbonyloxy in the context of the inven tion means a straight‐chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms which is bound t o the rest of the molecule via a carboxy group [ C(=O)‐ O‐], such as: acetoxy (=acyloxy), propionyloxy, n‐butyryloxy, isobutyryloxy, n‐pentanoyloxy, and pivaloyloxy, for example. Mono‐(C 1 ‐C 4 )‐alkylaminocarbonyl in the context of the inv ention means an amino group which is bound to the rest of the molecule via a carbonyl group [ ‐C(=O)‐] and which has one straight‐chain or br anched alkyl substituent having 1, 2, 3 or 4 carbon atoms, such as: methylaminocarbonyl, ethylaminocarbonyl,
n‐propylaminocarbonyl, isopropylaminocarbonyl, n‐butylaminocarbonyl, and tert butylaminocarbonyl, for example. Di‐(C 1 ‐C 4 )‐alkylaminocarbonyl in the context of the inv ention means an amino group which is bound to the rest of the molecule via a carbonyl group [‐C (=O)‐] and which has two identical or different st raight‐ chain or branched alkyl substituents having in each case 1, 2, 3 or 4 carbon atoms, such as: N,N‐ dimethylaminocarbonyl, N,N‐diethylaminocarbonyl, N‐ethyl‐N‐methylaminocarbonyl, N‐methyl‐N‐n‐ propylaminocarbonyl, N‐isopropyl‐N‐methylaminocarbony l, N,N‐diisopropylaminocarbonyl, N‐n‐butyl‐ N‐methylaminocarbonyl, and N‐tert‐butyl‐N‐methyl aminocarbonyl, for example. Mono‐(C 1 ‐C 4 )‐alkylaminosulfonyl in the context of the inv ention means an amino group which is bound to the rest of the molecule via a sulfonyl group [ ‐S(=O) 2 ‐] and which has one straight‐chain or bran ched alkyl substituent having 1, 2, 3 or 4 carbon atoms, such as: methylaminosulfonyl, ethylaminosulfonyl, n‐ propylaminosulfonyl, isopropylaminosulfonyl, n‐butylamino sulfonyl, and tert‐butylaminosulfonyl, for example. Di‐(C 1 ‐C 4 )‐alkylaminosulfonyl in the context of the inv ention means an amino group which is bound to the rest of the molecule via a sulfonyl group [‐S (=O) 2 ‐] and which has two identical or different straight‐ chain or branched alkyl substituents having in each case 1, 2, 3 or 4 carbon atoms, such as: N,N‐ dimethylaminosulfonyl, N,N‐diethylaminosulfonyl, N‐ethyl‐N‐methylaminosulfonyl, N‐methyl‐N‐n‐ propylaminosulfonyl, N‐isopropyl‐N‐methylaminosulfonyl, N,N‐diisopropylaminosulfonyl, N‐n‐butyl‐ N‐methylaminosulfonyl, and N‐tert‐butyl‐N‐methyl aminosulfonyl, for example. The term “C 3 ‐C 8 ‐cycloalkyl” means a saturated, monovalent, m ono‐ or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms (“C 3 ‐C 8 ‐cycloalkyl”). Said C 3 ‐C 8 ‐cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g . a bicyclo[4.2.0]octyl or octahydropentalenyl. The term “C 3 ‐C 8 ‐cycloalkoxy” means a saturated, monovalent, mono‐ or bicyclic group of formula (C 3 ‐C 8 ‐cycloalkyl)‐O‐, which contains 3, 4, 5, 6 , 7 or 8 carbon atoms, in which the term “C 3 ‐C 8 ‐cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy , cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group. The terms “4‐ to 7‐membered heterocycloalkyl” and “4‐ to 6‐membered heterocycloalkyl” mean a monocyclic, saturated or unsaturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring at oms in total, which contains one or two identical or di fferent ring heteroatoms from the series N, O and S , it
being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any on e of the carbon atoms or, if present, a nitrogen atom. A carbon atom may be substituted with an oxo group or or the sulphur atom with one or two oxo groups to form a –C=O, –S(=O)‐ or –S(=O) 2 ‐group in the ring. Said heterocycloalkyl group, without being limited the reto, can be a 4‐membered ring, such as azetidinyl , oxetanyl or thietanyl, for example; or a 5‐membered ring, such as tetrahydrofuranyl, 1,3‐dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1‐dioxidothiolanyl, 1,2‐oxazolidinyl, 1,3‐oxazolidinyl or 1,3‐thiazolidinyl, for example; or a 6‐membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3‐dioxanyl, 1,4‐dioxanyl or 1,2‐oxazinanyl, for example, or a 7‐membered ring, such as azepanyl, 1,4‐diazepanyl or 1,4‐oxazepanyl, for example. Particularly, “4‐ to 6‐membered heterocycloalkyl” means a 4‐ to 6‐membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5‐ or 6‐m embered heterocycloalkyl” means a monocyclic, saturat ed heterocycle with 5 or 6 ring atoms in total, contai ning one ring nitrogen atom and optionally one furth er ring heteroatom from the series: N, O. The term “bridged heterocycloalkyl” means a bicycl ic, saturated or unsaturated heterocycle with 7, 8, 9 or 10 ring atoms in total (= “bridged bicyclic 7‐ to 10‐membered heterocycloalkyl”), in which the two rings share two common ring atoms which are not adj acent, which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom. A carbon atom may be substituted with an oxo group or or the sulphur atom with one or two oxo groups to form a –C=O, –S(=O)‐ or –S(=O) 2 ‐ group in the ring. Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or az abicyclo[4.2.2]decyl.
The term “heteroaryl” means a monovalent, monoc yclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5‐ to 14‐membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroa tom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and whi ch is bound via a ring carbon atom or optionally v ia a ring nitrogen atom (if allowed by valency). Said heteroaryl group can be a 5‐membered heteroary l group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6‐membered heteroar yl group, such as, for example, pyridinyl, pyridaziny l, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9‐membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10‐membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, pht halazinyl, quinoxalinyl or pteridinyl. In general, and unless otherwise mentioned, the heter oaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to t he rest of the molecule. Thus, for some illustrative non‐restricting examples, the term pyrid inyl includes pyridin‐2‐yl, pyridin‐3‐yl and pyridin‐4‐yl; or the term thienyl includes thien‐2‐yl and thie n‐3‐yl. Particularly, the heteroaryl group is a 5‐membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6‐membered heteroaryl group group such as, for example, pyridinyl (=pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl or tria zinyl. The term “C 1 ‐C 6 ”, as used in the present text, e.g. in the context of the definition of “C 1 ‐C 6 ‐alkyl”, “C 1 ‐C 6 ‐haloalkyl”, “C 1 ‐C 6 ‐hydroxyalkyl”, “C 1 ‐C 6 ‐alkoxy” or “C 1 ‐C 6 ‐haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms. Further, as used herein, the term “C 3 ‐C 8 ”, as used in the present text, e.g. in the context of the definition of “C 3 ‐C 8 ‐cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompa sses each value and sub‐range within said range. For example: "C 1 ‐C 6 " encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 ‐C 6 , C 1 ‐C 5 , C 1 ‐C 4 , C 1 ‐C 3 , C 1 ‐C 2 , C 2 ‐C 6 , C 2 ‐C 5 , C 2 ‐C 4 , C 2 ‐C 3 , C 3 ‐C 6 , C 3 ‐C 5 , C 3 ‐C 4 , C 4 ‐C 6 , C 4 ‐C 5 , and C 5 ‐C 6 ;
"C 2 ‐C 6 " encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 ‐C 6 , C 2 ‐C 5 , C 2 ‐C 4 , C 2 ‐C 3 , C 3 ‐C 6 , C 3 ‐C 5 , C 3 ‐C 4 , C 4 ‐C 6 , C 4 ‐C 5 , and C 5 ‐C 6 ; "C 3 ‐C 10 " encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 3 ‐C 10 , C 3 ‐C 9 , C 3 ‐C 8 , C 3 ‐C 7 , C 3 ‐C 6 , C 3 ‐C 5 , C 3 ‐C 4 , C 4 ‐C 10 , C 4 ‐C 9 , C 4 ‐C 8 , C 4 ‐C 7 , C 4 ‐C 6 , C 4 ‐C 5 , C 5 ‐C 10 , C 5 ‐C 9 , C 5 ‐C 8 , C 5 ‐C 7 , C 5 ‐C 6 , C 6 ‐C 10 , C 6 ‐C 9 , C 6 ‐C 8 , C 6 ‐C 7 , C 7 ‐C 10 , C 7 ‐C 9 , C 7 ‐C 8 , C 8 ‐C 10 , C 8 ‐C 9 and C 9 ‐C 10 ; "C 3 ‐C 8 " encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 3 ‐C 8 , C 3 ‐C 7 , C 3 ‐C 6 , C 3 ‐C 5 , C 3 ‐C 4 , C 4 ‐C 8 , C 4 ‐C 7 , C 4 ‐C 6 , C 4 ‐C 5 , C 5 ‐C 8 , C 5 ‐C 7 , C 5 ‐C 6 , C 6 ‐C 8 , C 6 ‐C 7 and C 7 ‐C 8 ; "C 3 ‐C 6 " encompasses C 3 , C 4 , C 5 , C 6 , C 3 ‐C 6 , C 3 ‐C 5 , C 3 ‐C 4 , C 4 ‐C 6 , C 4 ‐C 5 , and C 5 ‐C 6 ; "C 4 ‐C 8 " encompasses C 4 , C 5 , C 6 , C 7 , C 8 , C 4 ‐C 8 , C 4 ‐C 7 , C 4 ‐C 6 , C 4 ‐C 5 , C 5 ‐C 8 , C 5 ‐C 7 , C 5 ‐C 6 , C 6 ‐C 8 , C 6 ‐C 7 and C 7 ‐C 8 ; "C 4 ‐C 7 " encompasses C 4 , C 5 , C 6 , C 7 , C 4 ‐C 7 , C 4 ‐C 6 , C 4 ‐C 5 , C 5 ‐C 7 , C 5 ‐C 6 and C 6 ‐C 7 ; "C 4 ‐C 6 " encompasses C 4 , C 5 , C 6 , C 4 ‐C 6 , C 4 ‐C 5 and C 5 ‐C 6 ; "C 5 ‐C 10 " encompasses C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 5 ‐C 10 , C 5 ‐C 9 , C 5 ‐C 8 , C 5 ‐C 7 , C 5 ‐C 6 , C 6 ‐C 10 , C 6 ‐C 9 , C 6 ‐C 8 , C 6 ‐C 7 , C 7 ‐ C 10 , C 7 ‐C 9 , C 7 ‐C 8 , C 8 ‐C 10 , C 8 ‐C 9 and C 9 ‐C 10 ; "C 6 ‐C 10 " encompasses C 6 , C 7 , C 8 , C 9 , C 10 , C 6 ‐C 10 , C 6 ‐C 9 , C 6 ‐C 8 , C 6 ‐C 7 , C 7 ‐C 10 , C 7 ‐C 9 , C 7 ‐C 8 , C 8 ‐C 10 , C 8 ‐C 9 and C 9 ‐ C 10 . As used herein, the term “leaving group” means an atom or a group o f atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(non afluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4‐methylphenyl)sulfonyl]oxy, [(4‐bromophenyl)sulfonyl]oxy, [(4‐nitrophenyl)sulfonyl]oxy, [(2‐nitrophenyl)sulfonyl]oxy, [(4‐isopropylphenyl)sulfonyl]oxy, [(2,4,6‐triisopropylphenyl)sulfonyl]oxy, [(2,4,6‐trimethylphenyl)sulfonyl]oxy, [(4‐tert‐butylphenyl)sulfonyl]oxy and [(4‐methoxyphenyl)sulfonyl]oxy. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single c ompound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of the present invention optionally con tain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more
asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixt ures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possi ble that asymmetry also be present due to restricted rotation about a given bond, for example, the centra l bond adjoining two substituted aromatic rings of the specified compounds. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or ra cemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accompli shed by standard techniques known in the art. Preferred isomers are those which produce the more d esirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purif ication and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereo isomeric salts using an optically active acid or bas e or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physic al and/or chemical differences by methods known in the art, for example, by chromatography or fracti onal crystallisation. The optically active bases or a cids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen t o maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are comme rcially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without der ivatisation, are also useful. The optically active compounds of the present invention can likewise be o btained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11‐30, 1976). The present invention includes all possible stereoisom ers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)‐ or (S)‐ isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single en antiomer or a single diastereomer, of a compound of
the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomer s, in any ratio. Further, the compounds of the present invention can exist as N‐oxides, which are defined in that at l east one nitrogen of the compounds of the present inventi on is oxidised. The present invention includes all such possible N‐oxides. The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in p articular pharmaceutically acceptable salts, and/or co‐precipitates. The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the com pounds. It is possible for the amount of polar solv ents, in particular water, to exist in a stoichiometric or non‐stoichiometric ratio. In the case of stoichiom etric solvates, e.g. a hydrate, hemi‐, (semi‐), mono‐, sesqui‐, di‐, tri‐, tetra‐, penta‐ etc. so lvates or hydrates, respectively, are possible. The present invention incl udes all such hydrates or solvates. Further, it is possible for the compounds of the pr esent invention to exist in free form, e.g. as a f ree base, or as a free acid, or as a zwitterion, or to exis t in the form of a salt. Said salt may be any sa lt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention. The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. P harm. Sci. 1977, 66, 1‐19. A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid‐addition salt of a compound of th e present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficien tly basic, such as an acid‐addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2
(4‐hydroxybenzoyl)‐benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3‐hydroxy‐2‐ naphthoic, nicotinic, pamoic, pectinic, 3‐phenylpropionic, pivalic, 2‐hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para‐toluenesulfonic, methanesulfonic, 2‐naphthalenesulfonic, naphthalinedisulfonic, camphorsul fonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D‐gluconic, mandelic, ascorbic, glucoheptanoic, glycer ophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example. Further, another suitably pharmaceutically acceptable s alt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or p otassium salt, an alkaline earth metal salt, for example a calcium, magnesium or stro ntium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organi c primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N‐ methylmorpholine, arginine, lysine, 1,2‐ethylenediamine, N‐methylpiperidine, N‐methyl‐glucamine, N,N‐dimethyl‐glucamine, N‐ethyl‐glucamine, 1,6‐hexanediamine, glucosamine, sarcosine, serinol, 2‐ amino‐1,3‐propanediol, 3‐amino‐1,2‐propanediol, 4‐amino‐1,2,3‐butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n‐propyl)ammonium, tetra(n‐butyl)ammonium, N‐benzyl‐N,N,N‐ trimethylammonium, choline or benzalkonium. Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compound s with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by r eacting the compounds of the present invention with the appropriate base via a variety of known me thods. The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any rat io. In the present text, in particular in the Experiment al Section, for the synthesis of intermediates and o f examples of the present invention, when a compound i s mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical na mes or structural formulae relating to salts, such a s "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF 3 COOH", "x Na + ", for example, mean a salt form, the stoichiometry of which salt form n ot being specified. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiom etric composition. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio. Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds whic h themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body. The invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations. The invention further includes all possible cyclodextrin clathrates, i.e alpha‐, beta‐, or gamma‐ cyclodextrins, hydroxypropyl‐beta‐cyclodextrins, methy lbetacyclodextrins. B) Of selected interest are those compounds of formu la (I) in which both A represent ‐CH 2 ‐, R 3 represents ‐H, X represents either a direct bond, ‐CH 2 ‐ or ‐O‐, Y represents ‐H, ‐Cl, ‐Br, ‐CN, ‐CF 3 , C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, R 1 represents a group *‐A'‐B, in which *‐A'‐ represents a direct bond and in which B represents ‐H or in which *‐A'‐ represents a group *‐CR a H‐, in which R a represents ‐H, C 1 ‐C 4 ‐alkyl or C 3 ‐C 7 ‐cycloalkyl all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and R z represent
independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)) and in which B represents ‐H, ‐CN, C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or a 4‐ to 7 membered heterocyc loalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), ‐C(=O)‐NHR b , in which R b represents ‐H, C 1 ‐C 4 ‐alkoxy, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4‐ to 7 membered heterocycloa lkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or phenyl or a 5‐ or 6‐ membered heteroaryl or a 9‐ or 10‐membered bicyclic heteroaryl, all optionally substituted with CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl (optionally ‐OCH 3 substituiert), C 3 ‐ C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or in which R 6 and R 7 are hydrogen or bridged by C 1 ‐C 4 ‐alkyl in which one ‐CH 2 ‐group can be replaced by oxygen, in which A' represents a group *‐C(=O)‐ and in which B represents
C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O),‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl, ‐C(=O)‐N H 2 , 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) or 5‐ to 6‐ membered heteroaryl, C 2 ‐C 4 ‐alkenyl, , phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), in which A' represents a group *‐C(=O)‐O‐, *‐C(=O)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, *‐C(=S)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, in which B represents ‐H, C 1 ‐C 6 ‐alkyl, C 1 ‐C 4 ‐alkoxy, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), • ‐CR 20 R 21 ‐R 22 in which R 20 is ‐CH 3 , R 21 is ‐H, ‐CH 3 or R 20 and R 21 together are ‐ CH 2 ‐CH 2 ‐CH 2 ‐ and in which R 22 is phenyl or pyridyl, both optionally substitu ted with ‐F or ‐Cl;
C 2 ‐C 6 ‐alkenyl, phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐SO 2 ‐(C 1 ‐C 4 ‐alkyl), a group –C(=O)‐R d , in which R d represents ‐CF 3 , C 1 ‐C 4 ‐alkoxy or C 3 ‐C 7 ‐cycloalkyl, a group ‐(CH 2 ) n ‐R e in which n is 1 or 2 and in which R e represents 4 to 7‐membered heterocycloalkyl, optionally substitu ted with an oxo‐group (=O), ‐phenyl or 5‐ or 6‐ membered heteroaryl, optionally substitut ed with C 1 ‐ C 4 ‐alkyl; or N, R c und B together form a 4‐ to 7‐membered h eterocycloalkyl, optionally substituted with C 1 ‐C 4 ‐alkyl or ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), a group –C(=O)‐R f , in which R f represents C 1 ‐C 4 ‐alkyl or C 3 ‐C 7 ‐cycloalkyl, R 2 represents or , R 4 represents ‐H, ‐NO 2 ,
‐CN, ‐OH, ‐P(=O)(C 1 ‐C 4 ‐alkyl) 2 , ‐S(=O) 2 ‐(C 1 ‐C 4 ‐alkyl), halogen ‐C(=O)‐ C 1 ‐C 4 ‐alkyl, ‐O‐CH 3 , ‐C 2 ‐C 6 ‐alkoxy, optionally substituted with ‐F, ‐OH, ‐O‐CH 3 , ‐S‐CH 3 , ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl optionally substituted with a n oxo‐group (=O), phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐C(=O)‐NR v R w or ‐C(=O)‐O‐R v , in which R v represents ‐H or C 1 ‐C 4 ‐alkyl, R w represents ‐H, C 1 ‐C 4 ‐alkyl or ‐CH 2 ‐CF 3 or in which N, R v and R w together form a 4‐ to 7‐membered heterocycloalkyl ‐ C 3 ‐C 6 ‐alkenyloxy, C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl or 4 to 7‐membered heterocycloalkenyl, all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐ S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐ group (=O)), ‐C(=O)‐O‐CH 3 , phenyl or 5‐ or 6‐membered heteroaryl,
C 2 ‐C 4 ‐alkynyl, optionally substituted with 5‐ to 6‐membered heteroaryl, this heteroaryl again optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐ alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7 membered heterocycloalky l, C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), 5‐ or 6‐ membered heteroaryl, all optionally subs tituted with ‐phenyl, ‐CN, C 1 ‐C 4 ‐ fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered hetero cycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), phenyl, optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐ C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐ alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐NR i R j , in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R j represents ‐H, C 1 ‐C 4 ‐alkyl, a 5‐ to 6 membered heteroaryl or in which N, R i and R j together form a 4‐ to 7‐ membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo‐group (=O) or C 1 ‐C 4 ‐alkyl ‐NR i ‐S(=O) 2 ‐R p , in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R p represents 5‐ or 6‐membered heteroaryl, ‐NH‐C(=O)‐NR k R l , in which R k represents ‐H or C 1 ‐C 4 ‐alkyl and R l represents phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in
which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) ‐NH‐C(=O)‐R m , in which R m represents phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) ‐(C=O)‐NR n R o , in which R n represents ‐H or C 1 ‐C 4 ‐alkyl, R o represents C 1 ‐C 6 ‐hydroxyalkyl, 5‐ or 6‐membered heteroaryl (N), or or in which N, R n and R o together form a 3‐ to 7‐membered heterocyc loalkyl, optionally substituted with ‐CN, R 5 represents ‐H, ‐F or ‐Cl, R 15 represents ‐H, or a stereoisomer, a tautomer, an N‐oxide, a hydra te, a solvate, or a salt thereof, or a mixture of same. B) Of selected interest are also those compounds of formula (I) in which both A represent ‐CH 2 ‐,
R 3 represents ‐H, X represents either a direct bond, ‐CH 2 ‐ or ‐O‐, Y represents ‐H, ‐Cl, ‐Br, ‐CN, ‐CF 3 , C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, R 1 represents a group *‐A'‐B, in which *‐A'‐ represents a direct bond and in which B represents ‐H or in which *‐A'‐ represents a group *‐CR a H‐, in which R a represents ‐H, C 1 ‐C 4 ‐alkyl or C 3 ‐C 7 ‐cycloalkyl all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)) and in which B represents ‐H, ‐CN, C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or a 4‐ to 7 membered heterocyc loalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), ‐C(=O)‐NHR b , in which R b represents ‐H, C 1 ‐C 4 ‐alkoxy, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4‐ to 7 membered heterocycloa lkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or phenyl or a 5‐ or 6‐ membered heteroaryl or a 9‐ or 10‐membered bicyclic heteroaryl, all optionally substituted with CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl (optionally ‐OCH 3 substituiert), C 3 ‐
C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or in which R 6 and R 7 are hydrogen or bridged by C 1 ‐C 4 ‐alkyl in which one ‐CH 2 ‐group can be replaced by oxygen, in which A' represents a group *‐C(=O)‐ and in which B represents C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O),‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl, ‐C(=O)‐N H 2 , 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) or 5‐ to 6‐ membered heteroaryl, C 2 ‐C 4 ‐alkenyl, , phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), in which A' represents a group *‐C(=O)‐O‐, *‐C(=O)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl,
*‐C(=S)‐NR c ‐, in which R c represents ‐H or C 1 ‐C 4 ‐alkyl, in which B represents ‐H, C 1 ‐C 6 ‐alkyl, C 1 ‐C 4 ‐alkoxy, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐group (=O)), • ‐CR 20 R 21 ‐R 22 in which R 20 is ‐CH 3 , R 21 is ‐H, ‐CH 3 or R 20 and R 21 together are ‐ CH 2 ‐CH 2 ‐CH 2 ‐ and in which R 22 is phenyl or pyridyl, both optionally substitu ted with ‐F or ‐Cl; C 2 ‐C 6 ‐alkenyl, phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), ‐SO 2 ‐(C 1 ‐C 4 ‐alkyl), a group –C(=O)‐R d , in which R d represents ‐CF 3 , C 1 ‐C 4 ‐alkoxy or C 3 ‐C 7 ‐cycloalkyl, a group ‐(CH 2 ) n ‐R e in which n is 1 or 2 and in which R e represents 4 to 7‐membered heterocycloalkyl, optionally substitu ted with an oxo‐group (=O), ‐phenyl or 5‐ or 6‐ membered heteroaryl, optionally substitut ed with C 1 ‐ C 4 ‐alkyl; or N, R c und B together form a 4‐ to 7‐membered h eterocycloalkyl, optionally substituted with C 1 ‐C 4 ‐alkyl or ‐NR x R y , in which R x and R y represent
independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), a group –C(=O)‐R f , in which R f represents C 1 ‐C 4 ‐alkyl or C 3 ‐C 7 ‐cycloalkyl, R 2 represents or , R 4 represents ‐H, ‐NO 2 , ‐CN, ‐OH, ‐P(=O)(C 1 ‐C 4 ‐alkyl) 2 , ‐S(=O) 2 ‐(C 1 ‐C 4 ‐alkyl), halogen ‐C(=O)‐ C 1 ‐C 4 ‐alkyl, ‐O‐CH 3 , ‐C 2 ‐C 6 ‐alkoxy, optionally substituted with ‐F, ‐OH, ‐O‐CH 3 , ‐S‐CH 3 , ‐NR x R y , in which R x and R y represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl optionally substituted with a n oxo‐group (=O), phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 3 ‐C 7 ‐cycloalkyl, 4 to 7‐membered heterocycloalkyl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)),
‐C(=O)‐NR v R w or ‐C(=O)‐O‐R v , in which R v represents ‐H or C 1 ‐C 4 ‐alkyl, R w represents ‐H, C 1 ‐C 4 ‐alkyl or ‐CH 2 ‐CF 3 or in which N, R v and R w together form a 4‐ to 7‐membered heterocycloalkyl ‐ C 3 ‐C 6 ‐alkenyloxy, C 1 ‐C 6 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7‐membered heterocycloalk yl or 4 to 7‐membered heterocycloalkenyl, all optionally substituted with ‐ OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐ S(O) 2 ‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (op tionally substituted with an oxo‐ group (=O)), ‐C(=O)‐O‐CH 3 , phenyl or 5‐ or 6‐membered heteroaryl, C 2 ‐C 4 ‐alkynyl, optionally substituted with 5‐ to 6‐membered heteroaryl, this heteroaryl again optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐ alkyl, C 3 ‐C 7 ‐cycloalkyl, 4‐ to 7 membered heterocycloalky l, C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐ S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), 5‐ or 6‐ membered heteroaryl, all optionally subs tituted with ‐phenyl, ‐CN, C 1 ‐C 4 ‐ fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered hetero cycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), phenyl, optionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐ C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo ‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐ alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x , R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), ‐NR i R j , in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R j represents ‐H, C 1 ‐C 4 ‐alkyl, a 5‐ to 6 membered heteroaryl or in which N, R i and R j together form a 4‐ to 7‐ membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo‐group (=O) or C 1 ‐C 4 ‐alkyl ‐NR i ‐S(=O) 2 ‐R p ,
in which R i represents ‐H, C 1 ‐C 4 ‐alkyl and R p represents 5‐ or 6‐membered heteroaryl, ‐NH‐C(=O)‐NR k R l , in which R k represents ‐H or C 1 ‐C 4 ‐alkyl and R l represents phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐ cycloalkyl (optionally substituted with an oxo‐group (=O)), 4‐ to 7 membered heterocycloalkyl (optionally substituted with an oxo‐group (=O)), C 1 ‐C 4 ‐alkoxy, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloal kyl (optionally substituted with an oxo‐group (=O)), or C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐ CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) ‐NH‐C(=O)‐R m , in which R m represents phenyl or a 5‐ or 6‐ membered heteroaryl, all o ptionally substituted with ‐CN, C 1 ‐C 4 ‐fluoroalkyl, ‐OCF 3 , ‐OCF 2 H, halogen, C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl (optionally substituted with an oxo‐group (=O)), 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), C 1 ‐C 4 ‐alkoxy, ‐ S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 or ‐NR x R y , in which R x ,R y and R z represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)), or C 1 ‐C 4 ‐alkyl, C 3 ‐C 7 ‐cycloalkyl or 4 to 7‐membered heterocycloalk yl, all optionally substituted with ‐OH, halogen, ‐CF 3 , C 1 ‐C 4 ‐alkyl, ‐CN, ‐S(O) 2 ‐CH 3 , ‐S(O)(NR z )‐CH 3 , C 1 ‐C 4 ‐alkoxy, an oxo‐group (=O), ‐NR x R y , in which R x , R y and Rz represent independently of each other ‐H or C 1 ‐C 4 alkyl or in which N, R x and R y together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo‐ group (=O)) ‐(C=O)‐NR n R o ,
in which R n represents ‐H or C 1 ‐C 4 ‐alkyl, R o represents C 1 ‐C 6 ‐hydroxyalkyl, 5‐ or 6‐membered heteroaryl (N), or or in which N, R n and R o together form a 3‐ to 7‐membered heterocyc loalkyl, optionally substituted with ‐CN, R 5 represents ‐H, ‐F or ‐Cl, R 15 represents ‐H, or a stereoisomer, a tautomer, an N‐oxide, a hydra te, a solvate, or a salt thereof, or a mixture of same. C) Of selected interest are those compounds defined under A) (page 6) or B (page 25) in which R 2 is selected from or . D) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 2 is E) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 2 is and wherein R 4 is selected from hydrogen, ‐F, ‐Cl, methyl , ethyl and isopropyl. F) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 1 is selected from ‐C(=O)‐O‐ t Bu, ‐C(=O)‐NH‐Et, ‐C(=O)‐NH‐C(=O)‐O‐ Et, , or . G) Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is a direct bond. G 1 ) Of selected interest are those compounds defi ned under A) (page 6) or B) (page 25) wherein X i s oxygen. G 2 ) Of selected interest are those compounds defi nded under A) (page 6) or B) (page 25) in which R 1 represents a group *‐A'‐B, in which A' represents a group *‐C(=O)‐NR c ‐ and in which R c represents ‐H or C 1 ‐C 4 ‐alkyl.
H) Of selected interest are those compounds define d under A) (page 6) or B) (page 25) wherein Y is hydrogen or ‐Cl. I) Compounds of most interest are those as follows: tert‐butyl 2'‐(2‐fluoroquinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxylate tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxy late tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐1‐ carboxylate tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxylate tert‐butyl 2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐1‐ carboxylate tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐y l]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazole]‐1‐ carboxylate tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2 ,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐[5‐(trifluoromethyl)pyridin‐3‐yl] 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐ 1‐carboxylate tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐ 1‐carboxylate tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6' ‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] ‐1‐ carboxylate tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxylate tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyrid in‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxylate tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6 '‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole ]‐1‐ carboxylate
(pyrimidin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]methanone (1‐methyl‐1H‐pyrazol‐5‐yl)[2'‐(quinolin‐3‐yl )‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b] pyrazol]‐1‐ yl]methanone 4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]buta nenitrile 3‐methoxy‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] propan‐1‐ one 3‐(1H‐pyrazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razol]‐1‐ yl]propan‐1‐one 2‐(morpholin‐4‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ol]‐1‐ yl]ethan‐1‐one 2‐(pyrimidin‐5‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ol]‐1‐ yl]ethan‐1‐one (3‐chlorophenyl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (pyridin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] methanone 2‐ethyl‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]bu tan‐1‐one 1‐{2‐oxo‐2‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihyd rospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethyl}pyrrolidin‐2‐one (pyridin‐3‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] methanone 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]cyclopr opane‐ 1‐carbonitrile 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐on e (1‐methyl‐1H‐imidazol‐5‐yl)[2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazol]‐1‐ yl]methanone 2‐methoxyethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydro spiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate 2‐methoxyethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ole]‐1‐ carboxylate [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyr imidin‐4‐ yl)methanone (1‐methyl‐1H‐pyrazol‐5‐yl)[6'‐methyl‐2'‐(qui nolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐py rrolo[1,2‐ b]pyrazol]‐1‐yl]methanone 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐3‐(1H‐ pyrazol‐1‐yl)propan‐1‐one
1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]‐2‐ (morpholin‐4‐yl)ethan‐1‐one 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐2‐ (pyrimidin‐5‐yl)ethan‐1‐one (3‐chlorophenyl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zol]‐1‐ yl]methanone [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyr idin‐4‐ yl)methanone 2‐ethyl‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo l]‐1‐ yl]butan‐1‐one 1‐{2‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]‐2‐ oxoethyl}pyrrolidin‐2‐one [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyr idin‐3‐ yl)methanone 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ethan‐1‐one (1‐methyl‐1H‐imidazol‐5‐yl)[6'‐methyl‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone 3‐methoxy‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zol]‐1‐ yl]propan‐1‐one 4‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐4‐ oxobutanenitrile 1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole] N,N‐dimethyl‐5‐{[2'‐(quinolin‐3‐yl)‐5',6'‐di hydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]methyl}‐1,3‐thiazol‐2‐amine 1‐[(1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐indazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazole] 1‐(cyclohexylmethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 6'‐methyl‐1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2 '‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐ pyrrolo[1,2‐b]pyrazole] N,N‐dimethyl‐5‐{[6'‐methyl‐2'‐(quinolin‐3‐yl )‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b] pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine
6'‐methyl‐1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)m ethyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[aze tidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐indazol‐3‐yl)methyl]‐6'‐methyl‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] 1‐(cyclohexylmethyl)‐6'‐methyl‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐(cyclopropanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6 '‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole ] 1‐(cyclopropanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐ 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1, 2‐ b]pyrazole] N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐ carboxamide N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[ azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxami de 6'‐methyl‐N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐ carboxamide N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxamide 1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 6'‐methyl‐1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] N‐(2‐chloroethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxamide N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxamide 2'‐(quinolin‐3‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxamide N‐cyclopentyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydro spiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐tert‐butyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ca rboxamide methyl [2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[aze tidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]carbamate N‐[(furan‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxamide N‐(2‐methoxyethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐ carboxamide N‐phenyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro [azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxam ide N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carbothioamide
1‐(methanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐(methanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] ethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azeti dine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxylate 1‐[(4‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] 1‐[(imidazo[1,5‐a]pyridin‐3‐yl)methyl]‐2'‐(quino lin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrr olo[1,2‐ b]pyrazole] 1‐{[1‐(propan‐2‐yl)‐1H‐imidazol‐2‐yl]methyl} ‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine ‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(quinolin‐3‐yl)‐1‐{[4‐(trifluoromethyl)‐1H imidazol‐2‐yl]methyl}‐5',6'‐dihydrospiro[azetidine ‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐(2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐{[1‐(2‐methoxyethyl)‐1H‐imidazol‐2‐yl]methyl }‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(quinolin‐3‐yl)‐1‐[(1,4,5‐trimethyl‐1H‐im idazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(1H‐benzimidazol‐2‐yl)methyl]‐2'‐(quinolin‐ 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1, 2‐ b]pyrazole] 1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] 1‐[(1H‐pyrazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazole] 1‐[(4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] 1‐[(2‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] 1‐[(1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl )‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b] pyrazole] 1‐[(1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] 1‐[(5‐methyl‐1H‐pyrrol‐2‐yl)methyl]‐2'‐(quin olin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyr rolo[1,2‐ b]pyrazole] 3‐(ethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]cyclobut‐3‐ene‐1,2‐dione 3‐(dimethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol] 1‐ yl]cyclobut‐3‐ene‐1,2‐dione
2‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5', 6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol ]‐1‐ yl]ethan‐1‐one 3‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrroli din‐2‐ one 4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrroli din‐2‐ one 2‐(1H‐imidazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl) ‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]p yrazol]‐1‐ yl]ethan‐1‐one 4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]buta namide 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐(4H‐1 ,2,4‐triazol‐4‐ yl)ethan‐1‐one 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]prop‐2‐en 1‐one 3‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol] 1‐ yl]propan‐1‐one N'‐cyano‐N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐ carboximidamide N'‐cyano‐N,N‐dimethyl‐2'‐(quinolin‐3‐yl)‐5', 6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol e]‐1‐ carboximidamide N‐[3‐(dimethylamino)propyl]‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐(oxan‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxamide N‐{[‐oxolan‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxamide (4‐methylpiperazin‐1‐yl)[2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo l]‐1‐ yl]methanone N‐[2‐oxopyrrolidin‐3‐yl]‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxamide 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]azetidi ne‐3‐ carboxamide N‐[(1H‐pyrazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazole]‐ 1‐carboxamide (morpholin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihy drospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone N‐(3‐hydroxypropyl)‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxamide
N‐(2‐hydroxyethyl)‐N‐methyl‐2'‐(quinolin‐3 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐1‐carboxamide N‐(2‐oxopiperidin‐4‐yl)‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐1‐ carboxamide N‐(6‐oxopiperidin‐3‐yl)‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐1‐ carboxamide N‐[2‐(1H‐imidazol‐1‐yl)ethyl]‐2'‐(quinolin‐3 ‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 ‐ b]pyrazole]‐1‐carboxamide N‐benzyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro [azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxam ide N‐(2‐hydroxy‐2‐methylpropyl)‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐[(1‐methyl‐1H‐imidazol‐4‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐{[‐5‐oxopyrrolidin‐2‐yl]methyl}‐2'‐(quinolin ‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide [‐3‐(dimethylamino)pyrrolidin‐1‐yl][2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1 ,2‐ b]pyrazol]‐1‐yl]methanone N‐{2‐[oxolan‐3‐yl]ethyl}‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxamide N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ole]‐1‐ carboxamide 2'‐(2‐aminopyrimidin‐5‐yl)‐N‐ethyl‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxamide 2'‐(6‐aminopyridin‐3‐yl)‐N‐ethyl‐5',6'‐dihyd rospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxamide N‐ethyl‐2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxamide N‐ethyl‐2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxamide N‐ethyl‐2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl] ‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]p yrazole]‐1‐ carboxamide
N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl) ‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]p yrazole]‐1‐ carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1 ,2‐ b]pyrazole]‐1‐carboxamide 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4 '‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3 ‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3, 4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3, 4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ole]‐1‐ carboxamide ethyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxylate ethyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐1‐carboxylate ethyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐1‐carboxylate 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4 '‐pyrrolo[1,2‐ b]pyrazole] 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razole]‐ 1‐carboxylate tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate
tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐car boxylate tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2 ,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine 4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[ piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxam ide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4 ,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐ 1‐yl]ethan‐1‐one 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐ 1‐yl]‐2‐methylpropan‐1‐one 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐ 1‐carbonyl]cyclopropane‐1‐carbonitrile [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razol]‐1‐ yl](phenyl)methanone [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razol]‐1‐ yl](oxan‐4‐yl)methanone tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxylate tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2, 3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxylate 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4 '‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]p yridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl )‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine 3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3 b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' ‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide
2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]py ridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐py rrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4 '‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]p yridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (rac)‐6'‐methyl‐N‐(propan‐2‐yl)‐2'‐(quinolin ‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide (rac)‐N‐tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐ 1‐carboxamide N‐ethyl‐2'‐(6‐methoxyquinolin‐3‐yl)‐6',7'‐di hydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyr idine]‐1‐ carboxamide N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐y l}‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyraz olo[1,5‐ a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(propan‐2‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperi dine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]p yridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine 4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐phenyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4' ‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(quinolin‐3‐yl)‐6',7'‐dihydro‐5'H ‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1 carboxamide N‐ethyl‐2'‐[6‐(trifluoromethyl)quinolin‐3‐yl]‐ 6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1 ,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐[3‐(propan‐2‐yl)‐1H‐pyrrolo[2,3 b]pyridin‐5‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperid ine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4' pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo [5,1‐ c][1,4]oxazine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo [5,1‐ c][1,4]oxazine]‐1‐carboxamide N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazol o[5,1‐ c][1,4]oxazine]‐1‐carboxamide
N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyrid in‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4, 4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6 ',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1, 5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4' pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐ 6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1 ,5‐ a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4' pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazol o[5,1‐ c][1,4]oxazine]‐1‐carboxamide N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐y l}‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazole]‐ 1‐carboxamide 2'‐[6‐(cyclohexyloxy)quinolin‐3‐yl]‐N‐ethyl‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxamide cyclopentyl (rac)‐6'‐methyl‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐ 1‐carboxylate 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐[(5‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐ dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐c][1,4]oxazin e] 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1 ‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[a zetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐2'‐(3 ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (rac)‐1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐6 '‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro [azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydrospiro[ azetidine‐ 3,4'‐pyrazolo[5,1‐c][1,4]oxazine] (rac)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6'‐methyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine 3,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐ dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H ‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(3,3,3‐trifluoropropyl)‐5',6'‐dihydrospiro[piperid ine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) ‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospi ro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole] 1‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrol o[1,2‐ b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(cyclohexylmethyl)‐5',6'‐dihydrospiro[piperidine‐4 ,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[piperidine‐4, 4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐[(1‐methyl‐1H‐pyrazol‐4‐yl)methyl]‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole] [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[ 1,5‐ a]pyridin]‐1‐yl](4‐fluorophenyl)methanone [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[ 1,5‐ a]pyridin]‐1‐yl](oxan‐4‐yl)methanone 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(methanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐4, 4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N,N‐dimethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐ 4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐sulfonamide 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piper idine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razol]‐1‐ yl](morpholin‐4‐yl)methanone 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐py rrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(2‐hydroxy‐2‐methylpropyl)‐5',6'‐dihydrospiro[ piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐methyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxamide 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐ 1‐yl]‐2‐hydroxyethan‐1‐one
1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2 ‐b]pyrazol]‐ 1‐yl]‐2‐(pyridin‐3‐yl)ethan‐1‐one 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(phenylmethanesulfonyl)‐5',6'‐dihydrospiro[piperidin e‐ 4,4'‐pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(propane‐1‐sulfonyl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐py rrolo[1,2‐ b]pyrazole]‐1‐sulfonamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(pyridine‐3‐sulfonyl)‐5',6'‐dihydrospiro[piperid ine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(morpholine‐4‐sulfonyl)‐5',6'‐dihydrospiro[piper idine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts. J) Also of interest are the intermediates for the s ynthesis of compounds definded under A) (page 6) or B) (page 25), especially , , or . wherein R 1 , R 3 , A and Y have the same meaning as defined u nder A) (page 6) or B) (page 25). The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compou nd of general formula (I) of the present invention can be converted into the free compound, by any method whic h is known to the person skilled in the art. Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predic ted. Compounds of the present invention have surprisingly been found to effectively inhibit MAP4K1 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases , preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, in humans and animals.
Disorders and conditions particularly suitable for treatment with an MAP4K1 inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, e ye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also in clude lymphomas, sarcomas, and leukaemias. Examples of breast cancers include, but are not limi ted to, triple negative breast cancer, invasive ducta l carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to, small‐cell and non‐smal l‐cell lung carcinoma, as well as bronchial adenoma and ple uropulmonary blastoma. Examples of brain cancers include, but are not limit ed to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarc oma of the uterus. Examples of ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Ser toli‐Leydig cell tumour and arrhenoblastoma. Examples of cervical cancer include, but are not lim ited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroend ocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma. Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small‐intest ine, and salivary gland cancers. Examples of esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma. Examples of gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma. Examples of pancreatic cancer include, but are not l imited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours. Tumours of the urinary tract include, but are not l imited to, bladder, penile, kidney, renal pelvis, ure ter, urethral and human papillary renal cancers. Examples of kidney cancer include, but are not limit ed to renal cell carcinoma, urothelial cell carcinoma , juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear‐cell sarcoma of the kidney, mesoblastic nephro ma and Wilms' tumour. Examples of bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carc inoma.
Eye cancers include, but are not limited to, intr aocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limit ed to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcin oma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non‐melanoma skin cancer. Head‐and‐neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to, AIDS‐related lymphoma, non‐Hodgkin’s lymphoma, cutaneous T‐cell lymphoma, Burkitt lymphoma, Hodgkin s disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leuke mia, and hairy cell leukemia. The term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or d isorder, such as a carcinoma. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especial ly in solid tumours of all indications and stages with or without pre‐treatment of the tumour growth. Generally, the use of chemotherapeutic agents and/or anti‐cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated pat ients,
6. provide for a longer survival time among treated pat ients compared to standard chemotherapy treatments, 7. provide a longer time for tumour progression, and/or 8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinati ons produce antagonistic effects. In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervent ion. In a further embodiment of the present invention, th e compounds of general formula (I) of the present invention are used in combination with radiation: i.e. radiation treatment sensitizes cancers to anti‐ tumor immune responses by induction of tumor cell death and subsequent presentation of tumor neoantigens to tumor‐reactive Tcells. As MAP4K1 inhi bition is enhancing the antigen specific activation of T cells, the overall effect results in a much stronger cancer cell attack as compared to irradiation treatment alone. Thus, the present invention also provides a method o f killing a tumor, wherein conventional radiation therapy is employed previous to administering one or more of the compounds of the present invention. The compounds of the present invention can be administered as the sole pharmaceuti cal agent or in combination with one or more other pharmaceutically a ctive ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with: 131 I‐chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado‐trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharain, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, an tithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carm ofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambu cil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, darolutamide, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydroga lactitol, dexrazoxane, dibrospidium chloride,
dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epir ubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gado versetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpid ase, glutoxim, GM‐CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I‐125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, in genol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane ( 123 I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, larotrectinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, mo rphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palo nosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxin e mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplat in, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium 103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pega spargase, PEG‐epoetin beta (methoxy PEG‐ epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa‐2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perf osfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide‐K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarb azine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium‐223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refamet inib , regorafenib, risedronic acid, rhenium‐ 186 etidronate, rituximab, rogaratinib, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium ( 153 Sm) lexidronam, sargramostim, satumomab, secretin, siltuxima b, sipuleucel‐T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin,
talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium ( 99m Tc) nofetumomab merpentan, 99m Tc‐HYNIC‐[Tyr3]‐octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, test osterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorel bine, vismodegib, vorinostat, vorozole, yttrium‐90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. The compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aP D‐1/‐L1 axis antagonists. PD‐1, along with its ligands PD‐L1 and PD‐L2, function as negative regulators of T cell activation. MAP4K1 suppresses immune cell function. PD‐L1 is overexpres sed in many cancers and overexpression of PD‐1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol. 26:677). In accordance with a further aspect, the present inv ention covers combinations comprising one or more of the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly ph armaceutically acceptable salts thereof, or mixtures of same, and one or more immune checkpoint inhibitor s. In a further embodiment the immune checkpoint inhibit or is a aPD‐1/‐L1 axis antagonist. A further use of the compounds of the invention is the combination with chimeric antigen re ceptor T cells (CAR‐T cells) such as Axicabtagen‐Ciloleucel or Tisagenlecleucel. The activity of CAR‐T cells c an be suppressed by the tumor micro environment (TME), which supposedly can be overcome by MAP4K1 inhibition. In accordance with a further aspect, the present inv ention covers compounds of general formula (I), as described herein, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the expansion of T cells including CAR‐T cells, CAR‐NKT cells or CAR‐NK cells and tumor infiltrated lymphocytes ex‐ vivo.
Hence, the present invention also relates to the use of the compounds according to the invention for the expansion of T cells, including CAR‐T cell, CAR‐NKT cells or CAR‐NK cells and tumor infiltrated lymphocytes, ex‐vivo. The present invention also comprises an ex‐vivo method for the expansion of T cells, including CAR‐T cells, CAR‐NKT cells or CAR‐NK cells and tumor infiltrated lymphocytes, contacting said T cells with compounds according to the invention. In addition, the inventive compounds can also be use d as a therapeutic in a variety of other disorders wherein MAP4K1 is involved such as, cardiovascular an d lung diseases. Accordingly, the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammato ry and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure. Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also o f acute and chronic renal failure. For the purpose of the present invention the term r enal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underl ying or related renal disorders such as diabetic and non‐diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides; minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane‐proliferative glomerulonephritis; cres centic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease); post‐infectious glomerulonephritis; secondary glomerulonephritides: diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegener granulomatosi s, Henoch‐Schönlein purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (for example as a result of: urolithiasis, benign prostate hyperplasia, diabetes, malformations, abuse of analgesics, Crohn's disease), glomerulosclerosis, arteriolonecrose of the kidney, tubulointerstitial dise ases, nephropathic disorders such as primary and congenital or aquired renal disorder, Alport syndrome, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex‐induced renal disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agen ts, diabetic and non‐diabetic nephropathy, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which can be characterized diagnostically, for example by abnormally reduced creatinine and/or water excretion,
abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synth etase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or the need for dialysis. The present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart fai lure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbanc es in bone and carbohydrate metabolism. The present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insu fficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism. The compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH secretion (SIADH). Furthermore, the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees I‐III (AB block I‐ III), supraventricular tachyarrhythmia, atrial fibrillat ion, atrial flutter, ventricular fibrillation, ventricular f lutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV‐junctional extrasystoles, sick sinus syndrome, syncopes, AV‐nodal re‐entry tachycardia, Wolff‐Par kinson‐White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endo carditis, valvolitis, aortitis, cardiomyopathies), shock such as cardiogenic shock, septic shock and an aphylactic shock, aneurysms, boxer cardiomyopathy (premature ventricular contraction (PVC)), for treatment and/or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, oedema formation, for example pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, myocardial insufficiency, endothelial dysfunction, to prevent restenoses, for ex ample after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations, and also micro‐ and macrovascular damage (vasculitis), increased levels of fibrinogen
and of low‐density lipoprotein (LDL) and increase d concentrations of plasminogen activator inhibitor 1 (PAI‐1), and also for treatment and/or prophylaxis of erectile dysfunction and female sexual dysfunction. In addition, the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left‐heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis‐associated pulmonary hypertension, chronic‐obstructive pulmonary disease (COPD), acute respiratory distress s yndrome (ARDS), acute lung injury (ALI), alpha‐1‐ antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibr osis (CF). The compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, lea rning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age‐associated learning and memory impair ments, age‐associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occur ring after strokes (post stroke dementia), post‐ traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer s disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick´s s yndrome, Parkinson’s disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld‐ Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff’s psychosis. They are also su itable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS‐related sexual dysfunctions and sleep disturbances, and for controlli ng pathological disturbances of the intake of food, stimulants and addictive substances. The compounds according to the invention are furtherm ore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infar ction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma. The compounds acc ording to the invention can likewise be used for controlling states of pain and tinnitus. In addition, the compounds according to the invention have anti‐inflammatory action and can therefore be used as anti‐inflammatory agents for treatment a nd/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD,
Crohn's disease, UC), pancreatitis, peritonitis, rhe umatoid disorders, inflammatory skin disorders and inflammatory eye disorders. Furthermore, the compounds according to the invention can also be used for treatment and/or prophylaxis of autoimmune diseases. The compounds according to the invention are also su itable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lu ng, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term fibrotic disorders include s in particular the following terms: hepatic fibrosis , cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis). The compounds according to the invention are also su itable for controlling postoperative scarring, for example as a result of glaucoma operations. The compounds according to the invention can also be used cosmetically for ageing and keratinized skin. Moreover, the compounds according to the invention ar e suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastro paresis. The present invention further provides the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above. The present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorder s, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunct ion, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld‐Jakob.
The present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an ef fective amount of at least one of the compounds according to the invention. The present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diab etic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld‐Jakob. In another embodiment, the inventive compounds can al so be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women. Compounds of the present invention can be utilized to inhibit, block, reduce or decrease MAP4K1 activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g. to b lock immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy; This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disor der. The present invention also provides methods of treati ng a variety of other disorders wherein MAP4K1 is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, viral infectio ns, obesity and diet‐induced obesity, adiposity, met abolic disorders, hepatic steatosis and uterine fibroids. These disorders have been well characterized in human s, but also exist with a similar etiology in other mammals, and can be treated by administering pharmace utical compositions of the present invention. The term “treating” or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liq uid and solid tumours. In accordance with a further aspect, the present inv ention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or
prophylaxis of diseases, in particular cancer or c onditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling. The pharmaceutical activity of the compounds according to the invention can be explained by their activity as MAP4K1 inhibitors. In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signal ing, particularly liquid and solid tumours. In accordance with a further aspect, the present inv ention covers the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the use of treatment or prophylaxis of diseases, in particular cancer or cond itions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, p articularly liquid and solid tumours. In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours. In accordance with a further aspect, the present inv ention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N‐oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, fo r the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immu ne responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and sol id tumours. In accordance with a further aspect, the present inv ention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N‐
oxides, hydrates, solvates, and salts thereof, part icularly pharmaceutically acceptable salts thereof, or mixtures of same. In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N‐oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutica lly acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional p rocedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utili zed. The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to th e invention, conventionally together with one or more pharmaceutically suitable excipients, and to thei r use for the above mentioned purposes. It is possible for the compounds according to the i nvention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms. For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds o f the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated ta blets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally‐disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or sof t gelatine capsules), sugar‐coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline a nd/or amorphised and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, sus pensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear‐rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixtura e agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceuti cally suitable excipients. Pharmaceutically suitable excipients include, inter ali a, ^ fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di‐Cafos ® )), ^ ointment bases (for example petroleum jelly, paraffins , triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene g lycols), ^ bases for suppositories (for example polyethylene glyc ols, cacao butter, hard fat), ^ solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain length triglycerides fatty oils, liquid polyethylene g lycols, paraffins), ^ surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ® ), sorbitan fatty acid esters (such as, for example, Span ® ), polyoxyethylene sorbitan fatty acid esters (s uch as, for example, Tween ® ), polyoxyethylene fatty acid glycerides (such as, for e xample, Cremophor ® ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, gly cerol fatty acid esters, poloxamers (such as, for example, Pluronic ® ), ^ buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), ^ isotonicity agents (for example glucose, sodium chlori de), ^ adsorbents (for example highly‐disperse silicas), ^ viscosity‐increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose‐sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ® ); alginates, gelatine), ^ disintegrants (for example modified starch, carboxymethylcellulose‐sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross‐ linked polyvinylpyrrolidone, croscarmellose‐ sodium (such as, for example, AcDiSol ® )),
^ flow regulators, lubricants, glidants and mould releas e agents (for example magnesium stearate, stearic acid, talc, highly‐disperse silicas (such as , for example, Aerosil ® )), ^ coating materials (for example sugar, shellac) and fi lm formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellul ose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, fo r example, Eudragit ® )), ^ capsule materials (for example gelatine, hydroxypropylm ethylcellulose), ^ synthetic polymers (for example polylactides, polyglyco lides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), ^ plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), ^ penetration enhancers, ^ stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluen e, propyl gallate), ^ preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), ^ colourants (for example inorganic pigments such as, f or example, iron oxides, titanium dioxide), ^ flavourings, sweeteners, flavour‐ and/or odour‐maski ng agents. The present invention furthermore relates to a pharma ceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention. In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signalinggeneric name disorders, particularly liquid and solid tumours. The term “combination” in the present invention i s used as known to persons skilled in the art, it being possible for said combination to be a fixed combinat ion, a non‐fixed combination or a kit‐of‐parts. A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a fir st active ingredient, such as one or more compounds
of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formula tion. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture. A non‐fixed combination or “kit‐of‐parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredie nt are present in more than one unit. One example of a non‐fixed combination or kit‐of‐parts is a combination wherein the first active ingredient and t he further active ingredient are present separately. It is possible for the components of the non‐fixed combination or kit‐of‐parts to be administered separately, sequentially, simultaneously, concurrently o r chronologically staggered. Based upon standard laboratory techniques known to ev aluate compounds useful for the treatment of cancer or conditions with dysregulated immune response s or other disorders associated with aberrant MAP4K1 signaling, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identifie d above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of admin istration, the period of treatment, the age and sex of the patient treated, and the nature and exte nt of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a pa tient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance betwee n pharmacological effect and tolerability. It is possibl e for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more time s per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The a verage daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The a verage daily vaginal dosage regimen will preferably
be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will prefer ably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.0 1 to 100 mg/kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined b y the attending diagnostician, the activity of the specific compound employed, the age and general condi tion of the patient, time of administration, route of administration, rate of excretion of the drug, dr ug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. EXPERIMENTAL SECTION NMR peak forms are stated as they appear in the sp ectra, possible higher order effects have not been considered. The multiplicities are stated according to the signal form which appears in the spectrum, NMR‐spectroscopic effects of a higher order were no t taken into consideration. Multiplicity of the NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br = broad signal, m = multiplet. NMR signals: shift in [ppm]. Combinations of multipli city could be e.g. dd = doublet from doublet. In some cases not all H atoms are found as a sign al in the NMR because the signal could overlays wit h a solvent signal or it is a very braod signal depende nt on the NMR solvent used. The 1 H‐NMR data of selected examples / intermediate s are listed in the form of 1 H‐NMR peaklists. For each signal peak the δ value in ppm is given, fol lowed by the signal intensity, reported in round bra ckets. The δ value‐signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ 1 (intensity 1 ), δ 2 (intensity2), ... , δ i (intensity i ), ... , δ n (intensity n ). The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spe ctrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensit ies. In the case of broad signals, more than one peak, or the center of the signal along with their relati ve intensity, compared to the most intense signal displa yed in the spectrum, are shown. A 1 H‐NMR peaklist is similar to a classical 1 H‐NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H‐NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of title compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or pea ks of impurities are typically displayed with a lowe r
intensity compared to the peaks of the title comp ounds (e.g., with a purity of >90%). Such stereoi somers and/or impurities may be typical for the particular manufacturing process, and therefore th eir peaks may help to identify the reproduction of our manufacturing process on the basis of "by‐product fingerprints". An expert who calculates the peaks of the title compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated e xpectation values), can isolate the peaks of title compounds as required, optionally using additional int ensity filters. Such an operation would be similar to peak‐picking in classical 1 H‐NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data wi thin Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching‐disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the p arameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structu re and/or depending on the concentration of the measured compound it may be reasonable to set t he parameter "MinimumHeight" <1%. Chemical names were generated using the ACD/Name soft ware from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names. Table 1 lists the abbreviations used in this paragra ph and in the Examples section as far as they are not explained within the text body. Other abbreviations h ave their meanings customary per se to the skilled person.
Table 1: Abbreviations ACN acetonitrile aq. aqueous AUC Area Under Curve d day(s) DCM dichloromethane DIAD dipropan‐2‐yl (E)‐diazene‐1,2‐dicarboxylate DIPEA N,N‐diisopropylethylamine DMA N,N‐dimethylacetamide DMF N,N‐dimethylformamide DMSO dimethylsulphoxide dppf 1‐(diphenylphosphanyl)cyclopentane‐1,2,3,4,5‐pentayl ‐ iron (2:1) EAE experimental autoimmune encephalomyelitis EDTA Ethylenediaminetetraacetic acid EtOAc ethyl acetate EtOH ethanol Expl. Example h hour(s) FCS fetal calf serum HATU N‐[(dimethylamino)(3H‐[1,2,3]triazolo[4,5‐b]pyridin‐ 3‐yloxy)methylidene]‐N‐ methylmethanaminium hexafluorophosphate HMDS Hexamethyldisilazane IFNg Interferon gamma LiHMDS lithium 1,1,1,3,3,3‐hexamethyldisilazan‐2‐ide LPS lipopolysaccharide MeOH methanol MCPBA 3‐chloroperbenzoic acid mL milliliter µL microliter min. minute(s) MTBE tert‐butyl methyl ether MW microwave NCS 1‐chloropyrrolidine‐2,5‐dione Pd(dppf) 2 Cl 2 *DCM [1,1′‐Bis(diphenylphosphino)ferrocene]dichloropalladium( II), complex with dichloromethane PBMCs peripheral blood mononuclear cells
Pd 2 (dba) 3 (1E,4E)‐1,5‐diphenylpenta‐1,4‐dien‐3‐one ‐ p alladium (3:2) Pd(PPh 3 ) 4 tetrakis(triphenyl‐lambda 5 ‐phosphanyl)palladium PPh 3 triphenylphosphine PyBroP bromo(tripyrrolidin‐1‐yl)phosphonium hexafluorophosphat e RT or rt room temperature sat. saturated SDS Sodium dodecyl sulfate TBAF tetra‐n‐butylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran TNFa tumour necrosis factor alpha uM micromolar Xantphos (9,9‐dimethyl‐9H‐xanthene‐4,5‐diyl)bis(diphenylpho sphane) XPhos Pd G2 2'‐aminobiphenyl‐2‐yl)(chloro)palladium ‐ dicycloh exyl[2',4',6'‐tri(propan‐2‐ yl)biphenyl‐3‐yl]phosphane (1:1) The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. EXPERIMENTAL SECTION – GENERAL PART All reagents, for which the synthesis is not describ ed in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. The compounds and intermediates produced according to the methods of th e invention may require purification. Purification of organic compounds is wel l known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by cry stallization. In some cases, impurities may be stirre d out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for ex ample prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP‐Sil ® or KP‐NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate, DCM/methanol, or DCM/ethanol. In some cases, the compounds may be purified by preparative HPLC us ing for example a Waters autopurifier equipped with a diode array detector and/or on‐line electrospray ionization mass spectrometer in
combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trif luoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described abov e can provide those compounds of the present invention which possess a sufficiently basic or acidi c functionality in the form of a salt, such as, in the case of a compound of the present invention which i s sufficiently basic, a trifluoroacetate or formate s alt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free a cid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biologic al assay in order to quantify the specific biologica l activity. EXPERIMENTAL SECTION – GENERAL SYNTHESIS The following paragraphs outline a variety of synthet ic approaches suitable to prepare compounds of the general formula (Ia), and intermediates useful fo r their synthesis. In addition to the routes described below, also other routes may be used to synthesize the title compounds, in accordance with common general knowledge of a per son skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from va rious schemes can be combined to form additional synthesis sequences. In addition, interconversion of a ny of the substituents, in particular R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b , which are as defined in formula (Ia) supra, can be achieved before and/or after the exemplified transformations. These modifications can be , for example, the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exempl ified by but not limited to e.g. Buchwald, Suzuki, Sonogashira and Ullmann coupling, ester saponifications , amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well known to a person skilled in the art (see for exa mple T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4 th edition, Wiley 2006). Further, it is possible that two or more successive steps may be performed without work‐up being performed between said steps, e.g. a “one‐pot” reaction, as it is well‐known to a person skilled in the art. EXPERIMENTAL SECTION ‐ METHODS
Analytical LC‐MS methods: Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.2 vol % aq. ammonia (32%), elu ent B: acetonitrile; gradient: 0‐1.6 min 1‐99% B, 1.6‐ 2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C ; DAD scan: 210‐400 nm. Method 2: Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 µm, 50x2.1mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0‐1.7 2‐90% B, 1.7‐ 2.0 90% B; flow 1.2 ml/min; temperature: 60°C; DAD scan: 190‐400 nm. Method 3: Instrument: Waters Acquity UPLCMS SingleQuad; Colum: A cquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2 vol % aq. ammonia (32%), eluent B: acetonitrile; gradient: 0‐1.6 min 1‐99% B, 1.6‐ 2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD sc an: 210‐400 nm. Syntheses of Compounds (Overview): The compounds of the present invention can be prepared as described in the following section. The schemes and the procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not in tended to be limiting. It is clear to the person s killed in the art that the order of transformations as exempli fied in the schemes can be modified in various ways . The order of transformations exemplified in the schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents can be achieved before and/or after the exemplified transformations. These modifications can be such as t he introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction a nd cleavage are well‐known to the person skilled in the art (see for example P.G.M. Wuts and T.W. G reene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006). Specific examples are de scribed in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work‐up being performed between said steps, e.g. a “one‐pot” reaction, as is well‐known to the person skilled in the art . The syntheses of the derivatives according to the pr esent invention are preferably carried out according to the general synthetic sequence, shown in schemes 1‐3.
Scheme 1: Route for the preparation of building blocks of general formula 13 and 15, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 2 represents a suitable alcohol protecting group (e.g. TBDMS), X 1 represents a direct bond or –CH 2 ‐, Z 1 represents a methyl group, an ethyl group or a tert‐butyl group, A, R 1 , R 2 , R 3 and Y have the meaning as given for general f ormula (I). Suitable starting materials 1 are commercially available or described i n the literature. Step 1 ^ 3 (Scheme 1) Alkylation In the first step (scheme 1), ester derivative 1 ca n be alkylated using an alkylbromide or alkyliodide of
formula 2 to give the desired product 3. For example ester 1 can be alkylated using (2‐brom oethoxy)(tert‐butyl)dimethylsilane 2 in an organic solvent such as THF in the presence of a base such as LiHMDS or LDA. Step 3 ^ 4 (Scheme 1) beta‐Keto ester formation Methylester 3 is reacted with a methyl acetate or tert‐butyl acetate to give beta‐keto esters of the general formula 4. Typically the reaction is performe d in the presence of a base like LiHMDS or LDA in an organic solvent like THF at a temperature range betw een ‐78°C and room temperature. Step 4 ^ 5 (Scheme 1) Pyrazol formation beta‐Keto esters of formula 4 can be converted wit h hydrazine to the corresponding pyrazole derivatives of formula 5. Typically the reaction is performed in an organic solvent like ethanol at a temperature between ‐20°C and the boiling point of the select ed solvent. Step 5 ^ 6 (Scheme 1) Deprotection of PG 2 The protecting group PG 2 of pyrazoles of formula 5 can be cleaved to give an alcohol of formula 6. The cleavage of suitable alcohol protecting groups is well‐known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006). For example, when PG2 in compounds of formula 5 is TBDMS, cleavage can be achieved using e.g. HCl in an organic solvent such as methanol or TBAF in an organic solvent such as THF. Step 6 ^ 7 (Scheme 1) Ring closure Alcohols of formula 6 can be converted to spiro com pounds of formula 7 by ring closing reactions. For example, alcohols of formula 6 can be reacted with mesylchloride and DIEA in an organic solvent like DCM to give the corresponding mesylate, which is the n reacted to give spiro compounds of formula 7, e.g. in the presence of a base like NaOH using a solvent mixture like methanol / water. Moreover, ring closure can be achieved using Mitsunobu conditions kn own to the skilled person. For example, DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate), triphenylphosphine in an organic solvent such as for example THF can be used. Step 7 ^ 8 (Scheme 1) Triflate formation Spiro compounds of formula 7 can be converted to triflates of formula 8. Typically the reaction is performed using Tf 2 O in the presence of a base like DIEA in an organic solvent like DCM at a temperature range between ‐78°C and room temperature. Alternatively the reaction is performed using N,N‐bis‐ (trifluormethansulfonyl)‐aniline in the presence of a base like DIEA in an organic solvent like THF at a
temperature range between room temperature and the boiling point of the selected solvent. Step 8 ^ 9 (Scheme 1) Deprotection of PG 1 The protecting group PG 1 of spiro compounds of formula 8 can be cleav ed to give amines of formula 9. The cleavage of suitable amine protecting groups is well‐known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006). For example, when PG 1 in compounds of formula 8 is BOC, cleavage c an be achieved using e.g. TFA in an organic solvent such as DCM. Step 9 ^ 10 (Scheme 1) Amine decoration Amines of formula 9 can be functionalized with a br oad variety of substituents to give compounds of formula 10. For examples, secondary amines of formula 9 can be reacted to give for example tertiary amines, amides, ureas, carbamates or sulphonamides of formula 10. All these transformations are known to the skilled person. Step 10 ^ 13 (Scheme 1) C‐C cross coupling reaction Compounds of general formula 10 can be reacted with a boronic acid derivative R 2 ‐B(OR) 2 to give a compound of formula 13. The boronic acid derivative may be a boronic acid (R = ‐H) or an ester of the boronic acid, e.g. its isopropyl ester (R = ‐CH(CH 3 ) 2 ), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 4,4,5,5‐tetram ethyl‐l,3,2‐dioxaborolane (R‐R = ‐C(CH 3 ) 2 ‐C(CH 3 ) 2 ‐). The coupling reaction is catalyzed by palladium catal ysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di‐palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)‐palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], palladium (ll) acetate and triphenylphosphine, [1,1'‐bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2‐dicyclohexylphosphino‐2′,4′,6′‐triisop ropyl‐1,1′‐biphenyl)[2‐(2′‐amino‐ 1,1′‐biphenyl)]palladium(II), X‐Phos aminobiphenyl palladium chloride precatalyst). The reaction is preferably carried out in a mixture of a solvent li ke 1,2‐dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a bas e like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY‐VCH V erlag GmbH & Co. KGaA, Weinheim, ISBN 3‐527‐30991‐8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 36 hours. Step 8 ^ 11 (Scheme 1) C‐C cross coupling reaction Compounds of general formula 8 can be reacted with a boronic acid derivative R 2 ‐B(OR) 2 to give a
compound of formula 11. The boronic acid derivativ e may be a boronic acid (R = ‐H) or an ester o f the boronic acid, e.g. its isopropyl ester (R = ‐CH(CH 3 ) 2 ), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 4,4,5,5‐tetram ethyl‐l,3,2‐dioxaborolane (R‐R = ‐C(CH 3 ) 2 ‐C(CH 3 ) 2 ‐). The coupling reaction is catalyzed by palladium catal ysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di‐palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)‐palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], palladium (ll) acetate and triphenylphosphine, [1,1'‐bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2‐dicyclohexylphosphino‐2′,4′,6′‐triisop ropyl‐1,1′‐biphenyl)[2‐(2′‐amino‐ 1,1′‐biphenyl)]palladium(II), X‐Phos aminobiphenyl palladium chloride precatalyst). The reaction is preferably carried out in a mixture of a solvent li ke 1,2‐dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a bas e like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY‐VCH V erlag GmbH & Co. KGaA, Weinheim, ISBN 3‐527‐30991‐8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 36 hours. Step 11 ^ 12 (Scheme 1) Deprotection of PG 1 The protecting group PG 1 of spiro compounds of formula 11 can be clea ved to give amines of formula 12. The cleavage of suitable amine protecting groups is well‐known to the person skilled in the art ( see for example P.G.M. Wuts and T.W. Greene in “Protec tive Groups in Organic Synthesis”, 4 th edition, Wiley 2006). For example, when PG 1 in compounds of formula 12 is BOC, cleavage can be achieved using e.g. TFA in an organic solvent such as DCM. Step 12 ^ 13 (Scheme 1) Amine decoration Amines of formula 12 can be functionalized with a b road variety of substituents to give compounds of formula 13. For examples, secondary amines of formula 13 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 13. All these tranformations are known to the skilled person. Step 13 ^ 14 (Scheme 1) Bromination Pyrazole compounds of formula 13 can be converted to bromides of formula 14. Typically the reaction is performed using NBS in an organic solvent such a s for example DMF. Step 14 ^ 15 (Scheme 1) Functional group interconversion Bromides 14 can be converted to compounds of the general formula 15 by using functional group interconversion reactions known to the skilled person. Scheme 2: Alternative route for the preparation of b uilding blocks of general formula 7, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), X 1 represents a direct bond or –CH 2 ‐, Z 1 represents a methyl group or a tert‐butyl group an d R 3 represents a methyl group (In this method R 3 can only be a methyl group) and A has the meaning as given for general formula (I). Step 1 ^ 17 (Scheme 2) Alkylation Compounds of the general formula 1 can be converted to compounds of the general formula 17 by alkylation. Typically the reaction is performed with an alkylating agent such as for example 16, a base such as LiHMDS or LDA in an organic solvent such a s THF. Step 17 ^ 18 (Scheme 2) beta‐Keto ester formation Methylester 17 is reacted with a methyl acetate or tert‐butyl acetate to give beta‐keto esters of th e general formula 18. Typically the reaction is perform ed in the presence of a base like LiHMDS or LDA i n an organic solvent like THF at a temperature range between ‐78°C and room temperature. Step 18 ^ 19 (Scheme 2) Pyrazol formation beta‐Keto esters of formula 18 can be converted with hydrazine to the corresponding pyrazole derivatives of formula 19. Typically the reaction is performed in an organic solvent like ethanol at a
temperature between ‐20°C and the boiling point of the selected solvent. Step 19 ^ 7 (Scheme 2) Cyclization Compounds of the general formula 19 can be converted to compounds of formula 7. Reaction conditions are known to the skilled person. Typically the reaction is performed using Hg(OAc) 2 in an organic solvent such as THF followed by addition of sodium hydroxide in water followed by a reducing agent such as for example sodium borohydride.
Scheme 3: Route for the preparation of compounds of general formula 30, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 3 represents a suitable pyrazole protecting group (e.g.
SEM), R represents a lower alkyl group, A, Y, R 1 , R 2 have the meaning as given for general formula (I). Suitable starting materials 20 and 21 are commerciall y available or described in the literature. Step 20 + 21 ^ 22 (Scheme 3) Pyrazole addition to the carbonyl group Ketones of the general formula 21 and pyrazoles of the general formula 20 can be converted to compounds of the general formula 22. The conversion is known to the person skilled in the art. For example, the conversion can be carried out in analogy to a literature procedure described in Tetrahedron, 1983, 39, 2023‐2029. Step 22 ^ 23 (Scheme 3) Protection with PG 3 Compounds of the general formula 22 can be converted to compounds of the general formula 23 using a suitable protecting group to protect the pyrazole NH. Protecting groups for pyrazoles are known to the skilled person (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006). For example, when PG 3 in compounds of formula 23 is SEM, then 2‐ (trimethylsilyl)ethoxymethylchloride, a base such as so dium hydride in an organic solvent such as THF can be used. Step 23 ^ 24 (Scheme 3) Alkylation of the alcohol Alcohols of the general formula 23 can be converted to compounds of the general formula 24 in an alkylation reaction known to the skilled person. For example, bromo ethyl acetate, a base, such as sodium hydride in an organic solvent such as dioxane at elevated temperature can be used. Step 24 ^ 25 (Scheme 3) Deprotection of PG 3 The protecting group PG 3 of pyrazole compounds of general formula 24 can be cleaved to give compounds of formula 25. The cleavage of suitable am ine protecting groups is well‐known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006). For example, when PG 3 in compounds of formula 24 is SEM, cleavage can be achieved using e.g. TFA in an organic solven t such as DCM. Step 25 ^ 26 (Scheme 3) Reduction of the ester Esters of the general formula 25 (R = lower alkyl group) can be converted to the corresponding alcohols of the general formula 26 with hydride reducing agen ts known to the skilled person. For example lithium borohydride in an organic solvent, such as THF can be used. Step 26 ^ 27 (Scheme 3)
Mitsunobu reaction Compounds of the general formula 26 can be converted to the corresponding morpholine derivatives of the general formula 27 using Mitsunobu conditions known to the skilled person. For example, DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate), triphenylphosphine in an organic solvent such as for example THF can be used. Step 27 ^ 28 (Scheme 3) Deprotection of PG 1 The protecting group PG 1 of spiro compounds of formula 27 can be clea ved to give amines of formula 28. The cleavage of suitable amine protecting groups is well‐known to the person skilled in the art ( see for example P.G.M. Wuts and T.W. Greene in “Protec tive Groups in Organic Synthesis”, 4 th edition, Wiley 2006). For example, when PG1 in compounds of formula 27 is BOC, cleavage can be achieved using e.g. TFA in an organic solvent such as DCM. Step 28 ^ 29(Scheme 3) Amine decoration Amines of formula 28 can be functionalized with a b road variety of substituents to give compounds of formula 23. For examples, secondary amines of formula 29 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 29. All these transformations are known to the skilled person. Step 29 ^ 30(Scheme 3) C‐C cross coupling reaction Halogen compounds of general formula 29 can be react ed with a boronic acid derivative R 2 ‐B(OR) 2 to give a compound of formula 30. The boronic acid der ivative may be a boronic acid (R = ‐H) or an es ter of the boronic acid, e.g. its isopropyl ester (R = ‐ CH(CH 3 ) 2 ), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 4,4,5,5‐tetram ethyl‐l,3,2‐dioxaborolane (R‐R = ‐C(CH 3 ) 2 ‐C(CH 3 ) 2 ‐). The coupling reaction is catalyzed by palladium catal ysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di‐palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)‐palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], palladium (ll) acetate and triphenylphosphine, [1,1'‐bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2‐dicyclohexylphosphino‐2′,4′,6′‐triisop ropyl‐1,1′‐biphenyl)[2‐(2′‐amino‐ 1,1′‐biphenyl)]palladium(II), X‐Phos aminobiphenyl palladium chloride precatalyst). The reaction is preferably carried out in a mixture of a solvent li ke 1,2‐dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a bas e like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY‐VCH V erlag GmbH & Co. KGaA, Weinheim, ISBN 3‐527‐30991‐8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is
preferably completed after 1 to 36 hours. The steps for the synthesis sequence giving rise to spiro compounds of formula 7, 15 or 30 may be als o interchanged using similar reaction conditions for eac h step as described above. EXPERIMENTAL SECTION ‐ INTERMEDIATES Intermediate 1 1‐tert‐butyl 3‐methyl 3‐(prop‐2‐en‐1‐yl)az etidine‐1,3‐dicarboxylate To a solution of 1‐tert‐butyl 3‐methyl azetidine ‐1,3‐dicarboxylate (940 g, 4.37 mol, 1.00 equiv, CAS‐RN [610791‐05‐4]) in dry THF(9 L) was added LiHMDS (8.8 L, 8.74 mol, 2.00 equiv) at ‐78°C under nit rogen atmosphere, and the reaction mixture was stirred at this temperature for 30 min. Then a solution of 3 bromoprop‐1‐ene (1058 g, 8.74 mol, 2.00 equiv) in dry THF (5 L) was added and the mixture was left to warm to ambient temperature and stirred overnight (mo nitored by TLC). Sat. aq. solution of NH 4 Cl (15 L) was added and the mixture was extracted with 3 x 10 L of EtOAc, and the combined organic layer wa s washed with 3x15 L of brine, dried over anhydrous N a 2 SO 4 , and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (EtOAc / petroleum ether) to give 832 g (75%) of the title compound as yellow oil. Intermediate 2 tert‐butyl 3‐(3‐methoxy‐3‐oxopropanoyl)‐3‐(pr op‐2‐en‐1‐yl)azetidine‐1‐carboxylate To a solution of methyl acetate (482 g, 6.52 mol, 2.00 equiv) in dry THF(9 L) was added LiHMDS (6.6 L, 6.52 mol, 2.00 equiv) at ‐78°C under nitrogen atm osphere, and the reaction mixture was stirred at thi s temperature for 1 h. Then a solution of 1‐tert‐butyl 3‐methyl 3‐(prop‐2‐en‐1‐yl)azetidine‐1,3‐
dicarboxylate (832 g, 3.26 mol, 1.00 equiv, see intermediate 1) in dry THF( 2 L) was added and the mixture was left to warm to rt and stirred for ano ther 2 h (monitored by TLC). Sat. aq. NH 4 Cl (10 L) was added and the mixture was extracted with 3x10 L of EtOAc, and the combined organic layer was washed with 3x10 L of brine, dried over anhydrous Na 2 SO 4 , and concentrated under vacuum to yield a cru de product which was directly purified by silica gel co lumn (EtOAc/petroleum ether) to give 810 g (84%) of the title compound as yellow oil. Intermediate 3 tert‐butyl 3‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)‐3 (prop‐2‐en‐1‐yl)azetidine‐1‐carboxylate To a stirred solution of tert‐butyl 3‐(3‐methoxy‐3‐oxopropanoyl)‐3‐(prop‐2‐en‐ 1‐yl)azetidine‐1‐ carboxylate (810 g, 2.73 mol, 1.00 equiv, see intermediate 2) in anhydrous EtOH (3 L) was added hydrazine—water (1:1) (280 g, 8.75 mol, 3.00 equiv). This mixture was stirred at an oil bath. The temperature was warmed to 80°C and stirred for anot her 1 h (monitored by LCMS). The solvent was removed in vacuum and the residue was dissolved in 2 L EtOAc and washed with 2x2 L of aq. HCl (1 M) , 1x2 L of brine, dried over anhydrous Na 2 SO 4 to afford 779 g (96%) of the title compound as white solid. LCMS: (ES, m/z):280 [M+H]+ Intermediate 4 tert‐butyl 3‐(prop‐2‐en‐1‐yl)‐3‐[3‐(trifl uoromethanesulfonyloxy)‐1H‐pyrazol‐5‐yl]azetidine‐ 1‐ carboxylate To a stirred solution of tert‐butyl 3‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)‐3‐(prop‐2‐ en‐1‐yl)azetidine‐1‐ carboxylate (779 g, 2.79 mol, 1.00 equiv, see interm ediate 3) in anhydrous THF (10 L) was added DIPEA
(1079 g, 8.37 mol, 3.00 equiv) followed by 1,1,1‐trifluoro‐N‐phenyl‐N‐ trifluoromethanesulfonylmethanesulfonamide (1095 g, 3.07 mol, 1.10 equiv). This mixture was stirred at 60 °C in an oil bath for 2 h, the solvent wa s removed under vacuum and the residue was dissolved in 2 L EtOAc and washed with 3x2 L of aq. HCl (1 M) and 3x2 L of water, dried over anhydrous Na 2 SO 4 , concentrated under vacuum and recrystallization from M TBE to afford 810 g (71%) of the title compound as white solid. LCMS: (ES, m/z):412 [M+H]+ Intermediate 5 tert‐butyl 3‐(2‐hydroxyethyl)‐3‐[3‐(trifluorome thanesulfonyloxy)‐1H‐pyrazol‐5‐yl]azetidine‐1‐ carboxylate To a stirred solution of tert‐butyl 3‐(prop‐2‐en‐1‐yl)‐3‐[3‐(trifl uoromethanesulfonyloxy)‐1H‐pyrazol‐5‐ yl]azetidine‐1‐carboxylate (400 g, 0.97 mol, 1.00 equiv, see intermediate 4) in dioxane/H 2 O (2L, 3/2, v/v) was added 2,6‐Lutidine (207 g, 1.94 mol, 2.00 equi v) followed by K 2 OsO 4 *2H 2 O (7.87 g, 0.02 mol, 0.02 equiv). This mixture was stirred at rt for 40 min before NaIO 4 (888 g, 4.15 mol, 4.00 equiv) was added in batches. The final mixture was stirred for another 2 h at rt. The reaction mixture was filtrated and t he filtrate cake was washed with EtOAc (4 L), the filt rate was separated. The organic layer was concentrate d under vacuum. The residue was dissolved in 2 L MeOH and stirred at 0 °C in an ice‐water bath, then NaBH 4 (19.0 g, 0.51 mol, 0.50 equiv) was added in small portions. The pH value of the reaction mixtur e was adjusted to 7 by 0.1 mol/L HCl aq. solution wh en the addition was completed. The resulting mixture was extracted with 3x5 L of DCM. The organic phase was combined, washed with 3x5 L of brine, dried over anhydrous Na 2 SO 4 , concentrated under vacuum yield a crude produ ct which was directly purified by silica gel column (EtOAc/petroleum ether) to give 360 g (89.4%) of the title compound as yellow oil. LCMS: (ES, m/z):416 [M+H]+ Intermediate 6 tert‐butyl 2'‐(trifluoromethanesulfonyloxy)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxylate
To a solution of tert‐butyl 3‐(2‐hydroxyethyl)‐3‐[3‐(trifluoromethanesulfonylo xy)‐1H‐pyrazol‐5‐ yl]azetidine‐1‐carboxylate (360 g, 0.87 mol, 1.00 equiv, see intermediate 5) and PPh 3 (320 g, 1.22 mol, 1.40 equiv) in dry THF (4 L) was added DIAD (246 g, 1.4 mol, 1.30 equiv) dropwise at rt under nitrog en atmosphere. The reaction mixture was stirred at this temperature for 16 h. The solvent was removed under vacuum and the residue was dissolved in MTBE (2 L) and stirred overnight until white solid was precipitated. The solid was removed by filtration. Th e filtrate was concentrated under vacuum and the crude product was re‐crystallized from MeOH to give 240 g (69.5%) of the title compound as white soli d. LCMS: (ES, m/z):398 [M+H] + , 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.399 (1 6.00), 2.787 (0.67), 2.805 (1.02), 2.822 (0.71), 4.044 (1.70), 4.129 (0.72), 4.1 48 (1.05), 4.165 (0.67), 6.536 (2.35). Intermediate 7 [1‐(tert‐butoxycarbonyl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl]boronic acid tert‐butyl 2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[az etidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (1.00 g, 2.52 mmol, see intermediate 6) was dissolved in 1,4‐dioxane (10 ml), 4,4,4',4',5,5,5',5'‐octamethyl‐2,2'‐bi‐1,3,2‐dioxa borolane (671 mg, 2.64 mmol), KOAc (741 mg, 7.55 mmol; CAS‐RN:[127‐08‐2]), Pd(dppf) 2 Cl 2 complex with DCM (103 mg, 126 µmol; CAS‐RN :[14221‐01‐3]) and dppf (69.8 mg, 126 µmol; CAS‐RN:[12150‐46‐8 ]) were added and the mixture was stirred overnight at 100°C. The mixture was diluted with DCM, filtered and evaporated. The residue was purified by preparative HPLC to yield the title compound (657 mg , 89 % yield). LC‐MS (Method 1): R t = 0.62 min; MS (ESIpos): m/z = 294 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.249 (5.06), 1.399 (7.17), 1.403 (2.56), 2.539 (16.00), 2.862 (0.41), 4.091 (0.41), 6. 466 (0.82).
Intermediate 8/Intermediate 18 trifluoroacetic acid—5',6'‐dihydrospiro[azetidine‐3,4 '‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl trifluoromethanesulfonate (1/1) tert‐butyl 2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[az etidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (1.00 g, 2.52 mmol, see intermediate 6) was dissolved in DCM (60 ml), under argon, TFA (6.3 ml, 82 mmol; CAS‐RN:[76‐05‐1]) was added and th e mixture was stirred for 2 h at rt. The mixture was evaporated to yield the title compound (1,23 g), which was used in the next step without further purification. LC‐MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 298 [M+H] + Intermediate 9 1‐(ethylcarbamoyl)‐5',6'‐dihydrospiro[azetidine‐3,4' ‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl trifluoromethanesulfonate Trifluoroacetic acid—5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazol]‐2'‐yl trifluoro‐ methanesulfonate (1/1) (126 mg, 41 % purity, 126 µm ol, see intermediate 8) was dissolved in DCM (3.0 ml) and DIPEA (220 µl, 1.3 mmol; CAS‐RN:[7087‐68‐5]) under ni trogen, isocyanatoethane (50 µl, 630 µmol) was added and the mixture was stirred overnig ht at rt. The solution was evaporated and purified by preparative HPLC to yield the title compound (37. 8 mg, 82 % yield). LC‐MS (Method 1): R t = 1.01 min; MS (ESIpos): m/z = 369 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.98 3 (7.36), 0.996 (5.33), 1.000 (16.00), 1.014 (2.88), 1.018 (7.47), 1.232 (1.71), 1.906 (0.64), 2.322 (1.07), 2.327 (1.49), 2.331 (1.07), 2.522 (5.23), 2.539 (1.71), 2.649 (0.75), 2.668 (2.45 ), 2.673 (1.39), 2.684 (0.85), 2.770 (2.99), 2.788 ( 4.80), 2.806 (3.20), 2.977 (0.53), 2.986 (1.28), 3.003 (3.63 ), 3.010 (1.81), 3.017 (4.05), 3.021 (3.84), 3.027 ( 1.60), 3.035 (3.41), 3.053 (1.07), 3.861 (0.85), 3.879 (1.49), 3.899 (6.40), 3.934 (2.35), 3.955 (12.05), 3.962 (12.69), 3.982 (2.35), 4.139 (3.41), 4.157 (5.01), 4.174 (3.20), 5.412 (2.88), 6.401 (0.53), 6.445 (1.28), 6.459 (2.45), 6.472 (1.28), 6.495 (10.88), 9.644 (0.5 3).
Intermediate 10 tert‐butyl 2'‐hydroxy‐6'‐methyl‐5',6'‐dihydrosp iro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbo xylate tert‐butyl 3‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)‐3 (prop‐2‐en‐1‐yl)azetidine‐1‐carboxylate (50 g,0.12 mol, 1.00 equiv, see intermediate 3) was gradually added to a stirred solution of Hg(OAc) 2 (77 g, 0.24 mol, 2.00 equiv) in THF (0.3 L)/H 2 O (0.2 L). After stirring for 24 h at rt, th e yellow color disappeared. The reaction mixture was alkalinized with 3 mol/L NaOH aq. Soluti on (0.2 L), then a solution of NaBH 4 (2.4 g, 0.06 mol, 0.50 equiv) in NaOH aq. solution (100 mL, 3 mol/L) was added dropwise. 6 bathes were run at the same time. After 24 h the 6 reactions were mixed and ad ded with sat. aq. NaCl solution. The organic layer was separated and the aq. layer was further extracted with 4x500 mL of EtOAc. The combined organic extracts were then washed with 3x250 mL of water, d ried over anhydrous Na 2 SO 4 . The aq. phase was treated with sulfur powder. The organic phase was ev aporated under vacuum to give 160 g (79.6%) of the title compound as yellow oil in total. LCMS: (E S, m/z):280 [M+H] + . Intermediate 11 tert‐butyl 6'‐methyl‐2'‐(trifluoromethanesulfonylox y)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate To a stirred solution of tert‐butyl 2'‐hydroxy‐6'‐methyl‐5',6'‐dihydrospiro[azetidine 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (160 g, 0.57 mol, 1.00 e quiv, see intermediate 10) in anhydrous THF (2 L) w as
added DIPEA (222 g, 1.72 mol, 3.00 equiv) followed by 1,1,1‐trifluoro‐N‐phenyl‐N‐ trifluoromethanesulfonylmethanesulfonamide (239 g, 0.67 mol, 1.17 equiv). This mixture was stirred at 60 °C in an oil bath for 2 h, the solvent was r emoved under vacuum and the residue was dissolved in 2 L EtOAc and washed with 2 x 2 L of aq. HCl (1 M) and 3x2 L of water, dried over anhydrous Na 2 SO 4 , concentrated under vacuum and recrystallization from M TBE to afford 200 g (81%) of the title compound as white solid. LCMS: (ES, m/z):412 [M+H] + Intermediate 12 1‐tert‐butyl 4‐methyl 4‐(2‐{[tert‐butyl(dimeth yl)silyl]oxy}ethyl)piperidine‐1,4‐dicarboxylate 1‐tert‐butyl 4‐methyl piperidine‐1,4‐dicarboxylate (15.0 g, 61.7 mmol, CAS‐RN [124443‐68‐1]) was dissolved in THF (150 ml) under nitrogen, cooled to ‐78°C, LiHMDS (120 ml, 1.0 M in THF, 120 mmol; CAS‐ RN:[865‐47‐4]) was added dropwise and the mixture was stirred for 1 h at ‐78°C. (2‐bromoethoxy)(t ert‐ butyl)dimethylsilane (29.5 g, 123 mmol) in THF (75 m l) was added dropwise at ‐78°C. The mixture was warmed up to rt overnight. Sat. NH 4 Cl solution was added to the mixture, diluted with EtOAc and the phases were separated. The organic phase was washed with sat. NaCl solution, dried with Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Hex/EtOAc) to yield the title compound (23.1 g, 93 % yield). LC‐MS (Method 2): R t = 1.71 min; MS (ESIpos): m/z = 302 [M+H]‐BOC + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: ‐0.007 (0.53), 0.007 (0.52), 0.067 (4.71), 0.831 (1.01), 0.838 (16.00), 0.845 (0.96), 0.869 (0.42), 0. 876 (6.49), 1.376 (13.87), 1.716 (0.41), 1.732 (0.88) , 1.749 (0.42), 2.519 (0.60), 3.526 (0.70), 3.532 (0.54 ), 3.541 (0.52), 3.548 (1.10), 3.566 (0.48), 3.622 ( 5.65), 3.877 (0.60). Intermediate 13 tert‐butyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}eth yl)‐4‐(3‐methoxy‐3‐oxopropanoyl)piperidine‐1‐ carboxylate
Methyl acetate (14 ml, 170 mmol) was dissolved in T HF (300 ml) with molsieves under nitrogen, cooled to ‐78°C, LiHMDS (170 ml, 1.0 M, 170 mmol; CAS RN:[865‐47‐4]) was added dropwise and the mixture was stirred for 1 h at ‐78°C. 1‐tert‐butyl 4‐methyl 4‐(2‐{[tert‐b utyl(dimethyl)silyl]oxy}ethyl)piperidine‐ 1,4‐dicarboxylate (17.4 g, 43.3 mmol, see intermedia te 12) in THF (100 ml) was added dropwise at ‐78 °C. The mixture was warmed up to rt in 2 h and stirre d overnight at rt. Sat. NH 4 Cl solution was added to the mixture, diluted with EtOAc and the phases were sepa rated. The organic phase was washed with sat. NaCl solution, dried with Na 2 SO 4 and concentrated under reduced pressure. The r esidue was purified by flash chromatography (Hex/EtOAc) to yield the title c ompound (10.8 g, 56 % yield). LC‐MS (Method 2): R t = 1.60 min; MS (ESIpos): m/z = 344 [M+H]‐B OC + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: ‐0 .008 (0.62), 0.007 (0.57), 0.828 (1.30), 0.835 (16.00), 0.842 (1.0 0), 1.382 (13.72), 1.816 (0.85), 1.849 (0.88), 1.865 (0.56), 2.176 (5.75), 2.523 (0.96), 2.528 (0.63), 3.4 79 (1.44), 3.500 (0.66), 3.516 (0.96), 3.533 (0.41), 3.606 (6.20), 3.616 (3.35), 3.628 (7.06), 3.728 (2.24). Intermediate 14 tert‐butyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}eth yl)‐4‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)piperidine‐ 1‐ carboxylate Tert‐butyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)‐4‐(3 methoxy‐3‐oxopropanoyl)piperidine‐1‐ carboxylate (10.8 g, 24.2 mmol, see intermediate 13) was dissolved in EtOH (25 ml) under nitrogen, hydrazine—water (1:1) (3.5 ml, 73 mmol; CAS‐RN:[78 03‐57‐8]) was added and the mixture was stirred for 3 h at 80°C. The mixture was evaporated, dilut ed with DCM/MeOH (9:1), filtered and the filtrate wa s evaporated. The residue was purified by flash chromat ography (DCM/EtOH) to yield the title compound
(7.57 g, 73 % yield). LC‐MS (Method 1): R t = 1.02 min; MS (ESIpos): m/z = 426 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: ‐0.064 (0.51), ‐0.056 (13.74) , ‐0.051 (0.41), ‐0.049 (0.47), ‐0.011 (2.02), 0.000 (2.05), 0.798 (0.95), 0.805 (16.00), 0.813 (0.89), 0.818 (0.4 1), 0.825 (2.78), 0.830 (2.84), 1.367 (13.30), 1.760 (1.10), 1.809 (0.55), 1.819 (0.56), 1.921 (1.31), 2.5 12 (1.14), 2.517 (0.75), 3.342 (0.56), 3.361 (0.61), 3.595 (0.97). Intermediate 15 tert‐butyl 4‐(2‐hydroxyethyl)‐4‐(3‐hydroxy‐1H ‐pyrazol‐5‐yl)piperidine‐1‐carboxylate Tert‐butyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)‐4‐(3 hydroxy‐1H‐pyrazol‐5‐yl)piperidine‐1‐ carboxylate (7.56 g, 17.8 mmol, see intermediate 14) was dissolved in THF (140 ml), TBAF (21 ml, 1.0 M in THF, 21.3 mmol) was added and the mixture was stirred overnight at ambient temperature. The mixture was evaporated. The residue was purified by flash chromatography (DCM/MeOH) to yield the title compound (3.53 g, 64% yield). LC‐MS (Method 1): R t = 0.51 min; MS (ESIpos): m/z = 312 [M+H] + . ¹H‐ NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.375 (16.00), 1. 472 (0.41), 1.609 (0.43), 1.628 (0.66), 1.647 (0.45), 1.914 (0.44), 2.518 (0.78), 2.523 (0.51), 3.159 (1.23 ), 3.172 (1.50), 3.186 (0.48), 3.563 (0.44), 3.596 ( 0.41), 4.252 (0.44), 5.278 (0.78). Intermediate 16 tert‐butyl 2'‐hydroxy‐5',6'‐dihydrospiro[piperidine ‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate Tert‐butyl 4‐(2‐hydroxyethyl)‐4‐(3‐hydroxy‐1H ‐pyrazol‐5‐yl)piperidine‐1‐carboxylate (2.48 g, 7.98 mmol, see intermediate 15) was dissolved in THF (40 ml), PPh3 (2.93 g, 11.2 mmol; CAS‐RN:[ 603‐35‐0]) was added and DIAD (2.0 ml, 10.4 mmol) was added dropwi se. The mixture was stirred overnight at ambient
temperature. The mixture was evaporated and purifie d by flash chromatography (DCM/EtOH) to yield the title compound (2.43 g, 73% yield). LC‐MS (Met hod 1): R t = 0.64 min; MS (ESIpos): m/z = 294 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.406 (16.00), 1.519 (0.41), 1.576 (0.41), 2.235 (0.62), 2.252 (1.00), 2.269 (0.65), 3.876 (0.69), 3.894 (1.05), 3.9 10 (0.65), 5.369 (2.76), 9.531 (0.46). Intermediate 17 tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6' dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole] 1‐carboxylate Tert‐butyl 2'‐hydroxy‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrr olo[1,2‐b]pyrazole]‐1‐carboxylate (2.42 g, 8.25 mmol, see intermediate 16) was dissolved in THF (65 ml), DIPEA (4.3 ml, 25 mmol; CAS‐RN: [7087 68‐5]) and 1,1,1‐trifluoro‐N‐phenyl‐N‐[(trifluoromethyl)sulfo nyl]methanesulfonamide (3.24 g, 9.07 mmol) were added and stirred overnight at 60°C. The mixture was evaporated and purified by flash chromatography (DCM/EtOH) to yield the title compound (2.98 g, 85 % yield). LC‐MS (Method 1): Rt = 1.36 min; MS (ESIpos): m/z = 326 [M+H] + . 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.411 (1 6.00), 1.597 (0.41), 1.612 (0.65), 1.670 (0.68), 2.366 (0.64), 2.3 84 (0.96), 2.402 (0.67), 2.518 (0.99), 2.523 (0.64), 3.408 (0.69), 3.421 (1.14), 3.434 (0.68), 3.566 (6.84), 4.1 65 (0.69), 4.183 (1.05), 4.200 (0.66), 6.476 (2.24). Intermediate 18/Intermediate 8 trifluoroacetic acid—5',6'‐dihydrospiro[azetidine‐3,4 '‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl trifluoromethanesulfonate (1/1) To a solution of tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[ azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (1.00 g, 2.52 mmol, see intermediate 6) in dichloromethane (60 mL) was added under nitrogen at ambient temperature trifluoroacetic acid (6.3 mL, 82 mmol; CAS‐ RN:[76‐05‐1]) and the reaction was stirred at ambient temperature for two hours. The solvent was
evaporated, toluene was added and the reaction was evaporated again (2x). Toluene was added, the organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to yield the crude title compound (1.23 g). The materia l was used withour further purification in the next step. Intermediate 19 ethyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate To a suspension of trifluoroacetic acid—5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazol]‐2'‐yl trifluoromethanesulfonate (1/1) (1.13 g, 84 % purity, 2.31 mmol, see intermediate 18) in dichloromethane (11 mL) was added at ambient temperat ure under argon N,N‐diisopropylethylamine (1.2 ml, 6.9 mmol; CAS‐RN:[7087‐68‐5]). The reac tion was cooled to 0°C and ethyl carbonochloridate (220 µl, 2.3 mmol) was added. The reaction was war med to ambient temperature and stirred at this temperature for three hours. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to yield 92 % (784 mg) of the title compound. 1H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.157 (7.26), 1.175 (16.00), 1.192 (7.45), 1.232 (0.21), 2.065 (0.17), 2.518 (3.52), 2.522 (2.24), 2.803 (2.69), 2.820 (4.09 ), 2.838 (2.87), 4.004 (1.69), 4.022 (5.11), 4.040 ( 5.07), 4.058 (1.80), 4.104 (4.39), 4.134 (3.60), 4.143 (1.16 ), 4.152 (4.46), 4.169 (2.91), 5.759 (0.22), 6.548 ( 9.54). Intermediate 20 3-bromo-6-[(propan-2-yl)oxy]quinoline 3-Bromoquinolin-6-ol (500 mg, 2.23 mmol) was solubilised in DMF (8.6 ml), sodium hydride (179 mg, 60 % purity, 4.46 mmol) was added and the mixture was stirred for 30 min at rt. 2- bromopropane (420 µl, 4.5 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was diluted with sat. NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried with Na2SO4 and concentrated under reduced pressure to give 680 mg of the title compound, which was used without further purification.
LC-MS (Method 1): R t = 1.37 min; MS (ESIpos): m/z = 266 [M+H] + Intermediate 21 3-bromo-6-methoxyquinoline 3-Bromoquinolin-6-ol (25.0 g, 112 mmol) was solubilised in DMF (500 ml), sodium hydride (13.4 g, 60 % purity, 335 mmol) was added and the mixture was stirred for 30 min at rt. iodomethane (14 ml, 220 mmol; CAS-RN:[74-88-4]) was added and the mixture was stirred overnight at 50°C. The mixture was diluted with sat. NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried with Na2SO4 and concentrated under reduced pressure to give 25.1 g (94 % yield) of the title compound. LC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m/z = 237 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.106 (0.86), 1.224 (0.57), 2.518 (0.92), 2.522 (0.59), 3.333 (16.00), 7.363 (5.43), 7.370 (6.53), 7.427 (5.18), 7.434 (3.91), 7.450 (5.24), 7.458 (4.44), 7.917 (5.29), 7.940 (4.89), 8.581 (5.00), 8.587 (5.31), 8.764 (8.08), 8.770 (7.41). Intermediate 22 quinolin-6-yl acetate Quinolin-6-ol (10.0 g, 68.9 mmol) was solubilised in dichloromethane (100 ml) and pyridine (6.7 ml, 83 mmol) was added. Under argon, the mixture was cooled to 0°C and acetyl chloride (5.9 ml, 83 mmol; CAS-RN:[75-36-5]) was added. The mixture was stirred overnight at rt. Sat. NaHCO3 solution was added and the mixture was extracted with DCM. The organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 12.1 g (93 % yield) of the title compound. LC-MS (Method 3): R t = 0.64 min; MS (ESIpos): m/z = 188 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.345 (16.00), 2.518 (0.42), 3.360 (0.49), 7.550 (1.11), 7.557 (1.24), 7.560 (1.27), 7.563 (1.35), 7.570 (1.13), 7.580 (1.75), 7.586 (1.34), 7.755 (1.79), 7.762 (1.61), 8.048 (1.43), 8.071 (1.32), 8.359 (0.77), 8.362 (0.77), 8.380 (0.73), 8.383 (0.74), 8.900 (1.16), 8.904 (1.15), 8.910 (1.16), 8.914 (1.09).
Intermediate 23 3-bromoquinolin-6-yl acetate N O Br O C H 3 Quinolin-6-yl acetate (1.00 g, 5.34 mmol) was solubilised in 1,1,2,2-tetrachloroethane (20 ml) and pyridine (1.3 ml, 16 mmol) was added. Under argon, the mixture was cooled to 0°C and bromine (823 µL, 16.03 mmol) was added. The mixture was stirred for 3 h at 90°C. The mixture was diluted with DCM and washed with water, Na2S2O3 solution, water and brine. It was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 1.18 g (83 % yield) of the title compound. LC-MS (Method 3): R t = 1.06 min; MS (ESIpos): m/z = 266 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.349 (16.00), 2.518 (0.90), 2.522 (0.56), 7.611 (1.32), 7.618 (1.54), 7.634 (1.34), 7.641 (1.66), 7.742 (2.03), 7.749 (1.77), 8.067 (1.60), 8.090 (1.42), 8.737 (1.49), 8.743 (1.56), 8.952 (2.53), 8.957 (2.36). Intermediate 24 3-bromoquinolin-6-ol 3-Bromoquinolin-6-yl acetate (1.18 g, 4.43 mmol) was solubilised in methanol (50 ml), under argon, lithium hydroxide (636 mg, 26.6 mmol) was added and the mixture was stirred overnight at rt. The mixture was evaporated to give 1.90 g of the title compound, which was used without further purification. LC-MS (Method 3): R t = 0.85 min; MS (ESIpos): m/z = 224 [M+H] + Intermediate 25 5-bromo-2-[(2E)-2-butylidenehydrazinyl]pyridine
5-Bromo-2-hydrazinylpyridine (25.0 g, 133 mmol) was solubilised in methanol (250 ml), butanal (24 ml, 270 mmol; CAS-RN:[123-72-8]) was added and the mixture was stirred for 4 h at 70°C. The mixture was evaporated to give 34.3 g of the title compound, which was used without further purification. LC-MS (Method 1): R t = 1.27 min; MS (ESIpos): m/z = 242 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.899 (6.43), 0.917 (16.00), 0.935 (7.64), 1.450 (0.55), 1.468 (2.25), 1.486 (4.08), 1.505 (4.17), 1.523 (2.27), 1.541 (0.48), 2.166 (2.10), 2.180 (2.56), 2.185 (3.41), 2.199 (3.43), 2.203 (2.22), 2.216 (1.94), 2.521 (1.52), 2.526 (1.02), 6.951 (3.32), 6.974 (3.52), 7.328 (1.55), 7.341 (3.18), 7.355 (1.50), 7.694 (2.01), 7.700 (2.04), 7.716 (1.87), 7.722 (1.94), 8.106 (3.57), 8.112 (3.64), 10.491 (3.12). Intermediate 26 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 5-Bromo-2-[(2E)-2-butylidenehydrazinyl]pyridine (34.3 g, 94 % purity, 133 mmol) and polyphosphoric acid (130.0 g, 3.2 mol) were stirred under nitrogen for 15 min at 160°C. The mixture was allowed to cool down to rt and diluted with water. The mixture was cooled to 0°, conc. NH3 solution was added (pH 9-10) and extracted 3x with DCM. The combined organic layers were dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 5.24 g (17 % yield) of the title compound. LC-MS (Method 1): R t = 1.13 min; MS (ESIpos): m/z = 225 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.215 (6.38), 1.234 (16.00), 1.253 (7.19), 2.521 (1.13), 2.526 (0.82), 2.646 (1.17), 2.649 (1.21), 2.665 (3.69), 2.668 (3.79), 2.676 (0.44), 2.685 (3.31), 2.686 (3.43), 2.703 (1.06), 2.705 (1.08), 7.309 (2.38), 8.164 (3.89), 8.170 (4.68), 8.221 (4.22), 8.227 (3.37), 11.556 (0.81). Intermediate 27 (rac)-5-bromo-3-ethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2 -one N H N O Br C H 3
5-Bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (4.00 g, 17.8 mmol) was solubilised in acetonitrile (800 ml), under argon, N-Chlorosuccinimide (2.61 g, 19.55 mmol) was added and the mixture was stirred overnight at rt. Half sat. Na2S2O3 solution was added and the organic solvent was evaporated. The mixture was extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.68 g (62 % yield) of the title compound. LC-MS (Method 3): R t = 0.89 min; MS (ESIpos): m/z = 241 [M+H] + Intermediate 28 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (rac)-5-Bromo-3-ethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2 -one (2.67 g, 11.1 mmol) was solubilised in POCl3 (30 ml), and the mixture was stirred overnight at 100°C. The mixture was added dropwise into Na2CO3 solution (2 L, pH 8) and extracted with DCM. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.73 g (95 % yield) of the title compound. LC-MS (Method 3): R t = 1.30 min; MS (ESIpos): m/z = 259 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.139 (6.81), 1.158 (16.00), 1.176 (7.03), 2.331 (0.54), 2.335 (0.40), 2.526 (2.43), 2.640 (2.00), 2.658 (6.19), 2.668 (1.06), 2.677 (6.54), 2.696 (1.90), 8.210 (5.10), 8.216 (6.75), 8.249 (7.15), 8.255 (5.47), 12.503 (1.16). Intermediate 29 5-bromo-2-[(2E)-2-propylidenehydrazinyl]pyridine 5-Bromo-2-hydrazinylpyridine (10.0 g, 53.2 mmol) was solubilised in methanol (100 ml), propanal (7.7 ml, 110 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was evaporated to give 13.1 g of the title compound, which was used without further purification. LC-MS (Method 1): R t = 1.16 min; MS (ESIpos): m/z = 228 [M+H] +
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.771 (0.44), 0.828 (0.56), 0.843 (0.73), 0.862 (0.62), 0.879 (0.70), 0.893 (0.47), 1.023 (7.67), 1.038 (16.00), 1.053 (7.66), 2.202 (1.21), 2.213 (1.34), 2.218 (3.73), 2.228 (3.75), 2.233 (3.50), 2.242 (3.41), 2.247 (1.20), 2.257 (1.11), 2.514 (1.13), 2.518 (1.01), 2.522 (0.81), 6.958 (3.66), 6.976 (3.86), 7.352 (1.79), 7.363 (3.64), 7.373 (1.74), 7.695 (2.12), 7.701 (2.15), 7.713 (2.02), 7.718 (2.07), 8.103 (3.53), 8.104 (3.62), 8.108 (3.60), 10.494 (3.30). Intermediate 30 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine 5-Bromo-2-[(2E)-2-propylidenehydrazinyl]pyridine (13.1 g, 57.3 mmol) and polyphosphoric acid (55.5 g, 1.4 mol) were stirred under nitrogen for 10 min at 160°C. The mixture was allowed to cool down to rt and diluted with water. The mixture was cooled to 0°, conc. NH3 solution was added (pH 9-10) and extracted 3x with DCM. The combined organic layers were dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 956 mg (8 % yield) of the title compound. LC-MS (Method 1): R t = 1.08 min; MS (ESIpos): m/z = 211 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.129 (0.47), 2.228 (16.00), 2.230 (15.77), 2.327 (0.54), 2.518 (2.17), 2.523 (1.46), 7.300 (2.35), 7.302 (2.38), 8.141 (3.07), 8.145 (3.49), 8.218 (4.31), 8.224 (3.72), 11.530 (0.88). Intermediate 31 5-bromo-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyr rolo[2,3-b]pyridine 5-Bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.37 mmol) was solubilised in acetonitrile (20 ml), N,N-diisopropylethylamine (1.0 ml, 5.9 mmol) and [2-
(chloromethoxy)ethyl](trimethyl)silane (460 µl, 2.6 mmol) were added. The mixture was stirred overnight at rt. The mixture was diluted with water and extracted 2x with EtOAc. The combined organic layers were dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 601 mg (74 % yield) of the title compound. LC-MS (Method 1): R t = 1.66 min; MS (ESIpos): m/z = 341 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.120 (0.42), -0.116 (0.49), -0.108 (16.00), -0.100 (0.47), -0.002 (1.37), 0.000 (1.78), 0.777 (0.49), 0.797 (0.55), 0.817 (0.50), 2.240 (2.05), 2.243 (2.10), 3.440 (0.54), 3.460 (0.58), 3.480 (0.54), 5.534 (1.82), 7.463 (0.47), 7.465 (0.47), 8.213 (0.79), 8.218 (0.80), 8.306 (0.61), 8.312 (0.56). Intermediate 32 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine 5-Bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (7.95 g, 34.3 mmol) was solubilised in 1,4-dioxane (160 ml), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxa borolane (9.59 g, 37.8 mmol), potassium acetate (10.1 g, 103 mmol), dppf (952 mg, 1.72 mmol) and Pd(dppf)2Cl2*DCM were added. The mixture was stirred overnight at 100°C. The mixture was diluted with DCM, filtered and evaporated. The residue was purified by flash chromatography to give 9.50 g (99 % yield) of the title compound. LC-MS (Method 1): R t = 0.90 min; MS (ESIpos): m/z = 279 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (7.26), 1.155 (8.93), 1.323 (16.00), 2.518 (0.45), 3.939 (0.82), 7.720 (1.98), 8.129 (1.21), 8.133 (1.29), 8.516 (1.11), 8.520 (1.11). The following compounds (intermediate 33 to 41) were prepared in analogy to intermediate 32: Intermediate 33 3-cyclobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo[2,3-b]pyridine
LC-MS (Method 3): Rt = 0.69 min; MS (ESIpos) Intermediate 34 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine LC-MS (Method 1): R t = 1.09 min; MS (ESIpos): m/z = 259 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (2.88), 1.156 (3.04), 1.314 (16.00), 2.261 (3.42), 2.264 (3.44), 2.518 (0.67), 2.522 (0.42), 3.940 (0.49), 7.228 (0.64), 7.231 (0.64), 8.150 (0.86), 8.152 (0.87), 8.419 (1.11), 8.423 (1.06). Intermediate 35 {6-[(propan-2-yl)oxy]quinolin-3-yl}boronic acid LC-MS (Method 3): R t = 0.51 min; MS (ESIpos): m/z = 232 [M+H] + Intermediate 36 [6-(trifluoromethyl)quinolin-3-yl]boronic acid LC-MS (Method 1): R t = 0.52 min; MS (ESIpos): m/z = 242 [M+H] + Intermediate 37
[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid LC-MS (Method 1): R t = 0.65 min; MS (ESIpos): m/z = 205 [M+H] + Intermediate 38 3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-p yrrolo[2,3-b]pyridine LC-MS (Method 1): R t = 1.18 min; MS (ESIpos): m/z = 273 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (16.00), 1.155 (13.89), 1.227 (1.02), 1.246 (2.38), 1.265 (1.04), 1.314 (9.94), 2.518 (0.48), 2.703 (0.55), 2.706 (0.55), 2.722 (0.53), 2.725 (0.53), 3.318 (0.41), 3.943 (2.68), 7.946 (0.78), 8.161 (0.53), 8.163 (0.53), 8.418 (0.72), 8.422 (0.70). Intermediate 39 [6-(acetyloxy)quinolin-3-yl]boronic acid LC-MS (Method 3): R t = 0.55 min; MS (ESIpos): m/z = 232 [M+H] + Intermediate 40 (6-methoxyquinolin-3-yl)boronic acid LC-MS (Method 1): R t = 0.38 min; MS (ESIpos): m/z = 203 [M+H] + Intermediate 41 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{ [2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridine LC-MS (Method 3): R t = 1.71 min; MS (ESIpos): m/z = 389 [M+H] + Intermediate 42 (3-bromo-1H-pyrazol-1-yl)methanol 3-Bromo-1H-pyrazole (30.0 g, 204 mmol) was solubilised in methanol (300 ml), formaldehyde (61 ml, 37 % purity, 820 mmol; CAS-RN:[50-00-0]) was added and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure to give 36.1 g (100 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.334 (0.53), 2.520 (2.82), 2.525 (1.79), 5.311 (9.24), 5.329 (9.42), 5.463 (0.73), 6.369 (0.46), 6.375 (0.47), 6.404 (14.66), 6.410 (15.83), 6.883 (1.80), 6.902 (4.87), 6.920 (1.68), 7.821 (16.00), 7.827 (15.86), 9.567 (0.45). Intermediate 43 tert-butyl 3-(3-bromo-1H-pyrazol-5-yl)-3-hydroxyazetidine-1-carboxylate
(3-Bromo-1H-pyrazol-1-yl)methanol (3.10 g, 17.5 mmol) was solubilised in THF (90 ml), cooled to -78°C and LDA (18 ml, 2.0 M in THF/heptane/ethylbenzene, 35 mmol) was added dropwise. The mixture was allowed to warm up to -20°C and was stirred for 45 min at -20°C. The mixture was cooled to -78°C and tert-butyl 3-oxoazetidine-1-carboxylate (2.50 g, 14.6 mmol), solubilised in THF (25 ml), was added dropwise. It was stirred for 2 h at -78°C and was allowed to warm up to rt overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 3.69 g (79 % yield) of the title compound. LC-MS (Method 1): R t = 0.94 min; MS (ESIpos): m/z = 318 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (16.00), 2.519 (0.90), 2.524 (0.58), 3.960 (0.47), 4.063 (0.48), 6.419 (0.94). Intermediate 44 tert-butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-3-hydroxyazetidine-1- carboxylate Tert-butyl 3-(3-bromo-1H-pyrazol-5-yl)-3-hydroxyazetidine-1-carboxylate (3.68 g, 11.57 mmmol) was dissolved in THF (65 mL) under nitrogen. Sodium hydride (509 mg, 801 mmol) was added and the mixture was stirred for 10 min at rt. [2-(chloromethoxy)ethyl](trimethyl)silane (2.3 mLl, 13 mmol) was added and the mixture was stirred overnight at rt. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.31 g (45 % yield) of the title compound.
LC-MS (Method 1): R t = 1.49 min; MS (ESIpos): m/z = 448 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.061 (2.74), 0.860 (0.76), 0.880 (0.97), 0.900 (0.80), 1.235 (0.51), 1.440 (16.00), 2.050 (0.93), 2.581 (0.52), 3.617 (0.90), 3.638 (1.08), 3.657 (0.87), 5.479 (2.73), 6.453 (2.57), 6.571 (2.91). Intermediate 45 tert-butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-3-(2-ethoxy-2- oxoethoxy)azetidine-1-carboxylate tert-Butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-3-hydroxyazetidine-1- carboxylate (4.20 g, 9.37 mmol) was solubilised in THF (60 ml) under nitrogen, NaH (562 mg, 60 % purity, 14.0 mmol) was added and the mixture was stirred for 10 min at rt. ethyl bromoacetate (1.6 ml, 14 mmol) was added and the mixture was stirred overnight at 60°C. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 4.41 g (88 % yield) of the title compound. LC-MS (Method 1): R t = 1.61 min; MS (ESIpos): m/z = 534 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.046 (10.31), 0.077 (1.27), 0.862 (0.81), 0.870 (0.44), 0.882 (1.14), 0.890 (0.44), 0.902 (0.90), 1.183 (0.78), 1.201 (1.75), 1.213 (2.08), 1.219 (0.89), 1.231 (4.70), 1.249 (2.23), 1.451 (16.00), 1.457 (6.77), 2.597 (0.96), 2.601 (0.60), 3.627 (0.94), 3.647 (1.41), 3.667 (0.88), 3.995 (3.45), 4.006 (0.75), 4.086 (0.66), 4.104 (0.68), 4.116 (0.65), 4.134 (2.02), 4.151 (2.12), 4.169 (0.96), 4.201 (0.46), 5.434 (0.61), 5.520 (2.73), 6.736 (3.20), 6.930 (1.02). Intermediate 46 ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate
tert-Butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-3-(2-ethoxy-2- oxoethoxy)azetidine-1-carboxylate (1.00 g, 1.87 mmol) was solubilised in dichloromethane (20 ml) and TFA (2.2 ml, 28 mmol) was added. The mixture was stirred overnight at rt. The mixture was diluted with toluene and concentrated under reduced pressure to give 1.30 g (43 % purity, 98 % yield) of the title compound, which was used without further purification. Intermediate 47 ethyl {[3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)azetidin-3-y l]oxy}acetate Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (1.30 g, 43 % purity, 1.84 mmol), isocyanatoethane (157 mg, 2.21 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.2 mmol) were solubilised in dichloromethane (1.1 ml) and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 680 mg (99 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.50), 0.951 (0.41), 0.957 (0.92), 0.969 (1.43), 0.975 (4.61), 0.985 (2.46), 0.993 (6.84), 1.003 (1.54), 1.011 (2.90), 1.021 (0.51), 1.031 (0.46), 1.082 (2.21), 1.093 (2.16), 1.100 (9.99), 1.111 (4.02), 1.118 (2.92), 1.125 (2.48), 1.138 (3.48), 1.143 (6.45), 1.162 (7.12), 1.180 (2.80), 1.240 (0.57), 1.363 (0.54), 1.586 (0.95), 1.624 (0.46), 1.642 (0.75), 1.666 (7.61), 2.090 (2.53), 2.524 (0.72), 2.529 (0.49), 2.965 (1.02), 2.980 (1.18), 2.983 (1.62), 2.997 (1.44), 3.000 (1.34), 3.009 (0.74), 3.013 (0.89), 3.027 (0.57), 3.031 (0.41), 3.215 (0.67), 3.231 (1.01), 3.242 (0.98), 3.248 (1.29), 3.260 (0.88), 3.264 (1.03), 3.275 (0.62), 3.281 (0.69), 3.336 (16.00), 3.507 (1.26), 3.622 (0.72), 3.626 (0.85), 3.908 (1.51), 3.934 (1.65), 3.948 (1.75), 3.951 (1.82), 3.966 (1.66), 3.969 (1.20), 3.978 (3.24), 3.986 (0.68), 3.992 (1.39), 4.000 (1.64), 4.018 (1.06), 4.031 (1.74), 4.035 (1.43), 4.043 (0.64), 4.047 (0.87), 4.052 (1.99), 4.057 (1.07), 4.064 (2.59), 4.070 (3.14), 4.082 (1.90), 4.087 (1.92), 4.101 (0.69), 4.105 (0.73),
4.135 (0.63), 4.165 (0.98), 4.189 (0.71), 4.304 (1.44), 4.336 (0.79), 4.363 (0.49), 4.501 (0.41), 4.583 (0.47), 4.610 (0.45), 4.699 (0.45), 4.851 (0.59), 5.764 (9.95), 6.436 (0.51), 6.451 (0.52), 6.576 (0.95), 6.778 (0.42), 6.782 (1.97), 6.847 (0.51), 6.849 (2.48), 6.975 (1.08), 7.075 (2.30), 8.538 (0.44). Intermediate 48 3-(5-bromo-1H-pyrazol-3-yl)-N-ethyl-3-(2-hydroxyethoxy)azeti dine-1-carboxamide Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)azetidin-3-y l]oxy}acetate (680 mg, 1.81 mmol) was solubilised in THF (14 ml) under nitrogen, lithium borohydride (2.2 ml, 4.0 M in THF, 11 mmol) was added dropwise and the mixture was stirred overnight at rt. It was cooled to 0°C, diluted with sat. NH4Cl solution and extracted with EtOAc. The organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated to give 330 mg (55 % yield) of the title compound, which was used without further purification. Intermediate 491 2'-bromo-N-ethyl-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[ 5,1-c][1,4]oxazine]-1-carboxamide 3-(5-Bromo-1H-pyrazol-3-yl)-N-ethyl-3-(2-hydroxyethoxy)azeti dine-1-carboxamide (330 mg, 990 µmol) was solubilised in THF (5.0 ml), PPh3 (364 mg, 1.39 mmol) was added and DIAD (250 µl, 1.29 mmol) was added dropwise. The mixture was stirred overnight at rt. DIAD (250 µl, 1.29 mmol) were added dropwise and the mixture was stirred for 3 h at rt. It was evaporated and purified by flash chromatography to give 90.0 mg (29 % yield) of the title compound.
Intermediate 50 tert-butyl 3-(5-bromo-1H-pyrazol-3-yl)-3-(2-ethoxy-2-oxoethoxy)azetidin e-1-carboxylate Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (569 mg, 1.87 mmol) was solubilised in dichloromethane (30 ml), di-tert-butyl dicarbonate (210 µl, 940 µmol) and triethylamine (1.6 ml, 11 mmol) were added and the mixture was stirred overnight at rt. It was diluted with water and extracted 3x with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to give 530 mg (70 % yield) of the title compound, which was used without further purification. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.53), 1.077 (0.59), 1.092 (0.59), 1.095 (1.17), 1.109 (0.47), 1.112 (0.73), 1.116 (0.45), 1.134 (0.62), 1.137 (0.45), 1.144 (2.09), 1.148 (1.17), 1.153 (1.34), 1.162 (4.29), 1.166 (2.41), 1.171 (2.33), 1.180 (2.06), 1.183 (1.05), 1.189 (1.11), 1.244 (0.68), 1.393 (16.00), 1.572 (1.38), 1.580 (3.39), 1.606 (7.17), 1.671 (0.58), 2.530 (0.55), 3.937 (0.75), 3.951 (1.39), 3.962 (0.61), 3.968 (0.58), 3.992 (0.92), 4.019 (0.45), 4.024 (0.52), 4.035 (0.84), 4.042 (0.47), 4.046 (0.57), 4.052 (1.89), 4.064 (1.06), 4.070 (1.92), 4.075 (1.70), 4.081 (1.51), 4.088 (1.00), 4.093 (1.07), 4.099 (1.26), 4.111 (0.99), 4.116 (1.14), 4.140 (0.47), 5.770 (4.51), 6.852 (0.71), 6.923 (0.94), 7.149 (0.58). Intermediate 51 2-{[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}ethan-1-ol Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (containing tert-butyl 3-(5-bromo- 1H-pyrazol-3-yl)-3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxy late) (530 mg, 1.74 mmol) was solubilised in THF (200 ml), and lithium borohydride (2.6 ml, 4.0 M in THF, 10 mmol) were added and the mixture was stirred overnight at rt. It was poured into water and NH4Cl was added. The aq. layer was extracted 3x with DCM and the combined organic layers were dried with Na2SO4
and evaporated. The residue was purified by flash chromatography to give 156 mg (34 % yield) of the title compound. Intermediate 52 tert-butyl 2'-bromo-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1 ,4]oxazine]-1-carboxylate tert-Butyl 3-(5-bromo-1H-pyrazol-3-yl)-3-(2-hydroxyethoxy)azetidine-1-c arboxylate (153 mg, 422 µmol) was solubilised in THF (2.0 ml), PPh3 (155 mg, 591 µmol) was added and DIAD (110 µl, 0.55 mmol) was added dropwise. The mixture was stirred overnight at rt. It was evaporated to give 200 mg of the title compound, which was used without further purification. Intermediate 53 1-tert-butyl 4-methyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)piperidine-1,4-d icarboxylate 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate (10.4 g, 42.7 mmol) was solubilised in THF (100 ml), cooled to -78°C and LiHMDS (73 ml, 1.0 M, 73 mmol) was added dropwise. The mixture was stirred at -78°C for 1 h and (3-bromopropoxy)(tert-butyl)dimethylsilane (17 ml, 73 mmol), solubilised in THF (50 ml), was added dropwise. It was allowed to warm up to rt overnight. The mixture was diluted with sat. NH4Cl solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 11.5 g (65 % yield) of the title compound. LC-MS (Method 1): R t = 1.74 min; MS (ESIpos): m/z = 316 [M+H]-BOC + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (2.38), 0.005 (12.87), 0.012 (0.50), 0.838 (0.94), 0.845 (16.00), 0.852 (0.90), 1.275 (0.47), 1.280 (0.43), 1.285 (0.46), 1.304 (0.46), 1.314 (0.45), 1.376 (12.17), 1.480 (0.42), 2.518 (0.45), 3.495 (0.45), 3.511 (0.96), 3.526 (0.43), 3.628 (5.17).
Intermediate 54 tert-butyl 4-(3-tert-butoxy-3-oxopropanoyl)-4-(3-{[tert-butyl(dimethyl) silyl]oxy}propyl)piperidine- 1-carboxylate LDA (69 ml, 2.0 M in THF/heptane/ethylbenzene, 140 mmol) was solubilised in THF (150 ml), at -78°C under argon and tert-butyl acetate (19 ml, 140 mmol), solubilized in THF (30 ml) was added dropwise. The mixture was stirred at -78°C for 1 h and 1-tert-butyl 4-methyl 4-(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)piperidine-1,4-dicarboxylate (11.5 g, 27.7 mmol), solubilised in THF (40 ml), was added dropwise. It was allowed to warm up to rt overnight. The mixture was diluted with sat. NH4Cl solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 6.10 g (44 % yield) of the title compound. LC-MS (Method 1): R t = 1.75 min; MS (ESIpos): m/z = 500 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.015 (0.91), -0.013 (1.38), 0.828 (1.42), 0.830 (1.44), 0.838 (16.00), 1.321 (0.47), 1.363 (13.37), 1.373 (15.28), 1.447 (0.60), 1.530 (0.44), 3.477 (0.70), 3.493 (1.26), 3.509 (0.72), 3.528 (2.60). Intermediate 55 tert-butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-(3-hydroxy-1H -pyrazol-5-yl)piperidine-1- carboxylate
tert-Butyl 4-(3-tert-butoxy-3-oxopropanoyl)-4-(3-{[tert-butyl(dimethyl) silyl]oxy}propyl)piperidine- 1-carboxylate (6.10 g, 12.2 mmol) was solubilised in ethanol (25 ml), hydrazine—water (1/1) (1.8 ml, 37 mmol; CAS-RN:[7803-57-8]) was added and the mixture was stirred overnight at 80°C. It was evaporated and the residue was purified by flash chromatography to give 4.36 g (81 % yield) of the title compound. LC-MS (Method 1): R t = 1.08 min; MS (ESIpos): m/z = 440 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.026 (2.10), 0.846 (0.78), 0.853 (16.00), 0.859 (0.81), 0.878 (0.41), 1.401 (10.39), 2.547 (0.40), 3.453 (0.75). Intermediate 56 tert-butyl 4-(3-hydroxypropyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine- 1-carboxylate tert-Butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-(3-hydroxy-1H -pyrazol-5-yl)piperidine-1- carboxylate (4.36 g, 9.92 mmol) was solubilised in THF (80 ml) under nitrogen, TBAF (14 ml, 1.0 M in THF, 13.9 mmol) was added and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 2.74 g (85 % yield) of the title compound. LC-MS (Method 1): R t = 0.56 min; MS (ESIpos): m/z = 326 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (0.91), 0.865 (0.45), 1.140 (0.44), 1.154 (0.62), 1.160 (0.42), 1.172 (0.72), 1.375 (16.00), 1.399 (1.07), 1.421 (0.81), 1.441 (0.48), 1.933 (0.53), 1.968 (0.48), 1.987 (1.12), 3.231 (0.88), 3.244 (0.88), 3.584 (0.51), 3.618 (0.47), 4.310 (0.42), 4.323 (0.88), 4.336 (0.41), 5.276 (1.10), 5.757 (0.63). Intermediate 57 tert-butyl 2'-hydroxy-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[ 1,5-a]pyridine]-1- carboxylate
tert-Butyl 4-(3-hydroxypropyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine- 1-carboxylate (2.73 g, 8.39 mmol) was solubilised in THF (45 ml), PPh3 (3.08 g, 11.7 mmol) was added and DIAD (2.1 ml, 10.9 mmol) was added dropwise. It was evaporated and purified by flash chromatography to give 1.97 g (76 % yield) of the title compound. LC-MS (Method 1): R t = 0.75 min; MS (ESIpos): m/z = 308 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.404 (16.00), 1.591 (0.67), 1.604 (0.50), 1.616 (0.43), 1.643 (0.41), 1.760 (0.40), 1.765 (0.42), 1.781 (0.56), 1.895 (0.42), 2.518 (0.57), 3.735 (0.56), 3.751 (1.05), 3.766 (0.51), 5.338 (2.55), 9.407 (0.75). Intermediate 58 tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-6',7'-dihydro-5'H-spiro[p iperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxylate tert-Butyl 2’-hydroxy-6’,7’-dihydro-5’H-spiro[piperidine-4,4’ -pyrazolo[1,5-a]pyridine]-1- carboxylate (1.97 g, 6.41 mmol), 1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methanesulfonamide (2.52 g, 7.05 mmol) and N,N- diisopropylethylamine (3.3 ml, 19 mmol) were solubilised in THF (50 ml) and the mixture was stirred overnight at 60°C. It was evaporated and the residue was purified by flash chromatography to give 2.78 g (99 % yield) of the title compound. LC-MS (Method 1): R t = 1.45 min; MS (ESIpos): m/z = 440 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.408 (16.00), 1.660 (0.67), 1.690 (0.44), 1.708 (0.41), 1.718 (0.44), 1.866 (0.44), 1.884 (0.56), 1.966 (0.42), 1.977 (0.44), 2.518 (0.87), 2.523 (0.53), 3.977 (0.54), 3.992 (1.04), 4.007 (0.48), 6.442 (2.20). Intermediate 59
tert-butyl 4-(3-bromo-1H-pyrazol-5-yl)-4-hydroxypiperidine-1-carboxylat e (3-Bromo-1H-pyrazol-1-yl)methanol (2.66 g, 15.1 mmol) was solubilised in THF (75 ml), cooled to -78°C and LDA (15 ml, 2.0 M in THF/heptane/ethylbenzene, 30 mmol) was added dropwise. The mixture was allowed to warm up to -20°C and was stirred for 45 min at -20°C. The mixture was cooled to -78°C and tert-butyl 4-oxopiperidine-1-carboxylate (2.50 g, 12.5 mmol), solubilised in THF (25 ml), was added dropwise. It was stirred for 2 h at -78°C and was allowed to warm up to rt overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was stirred in DCM, filtered and dried under reduced pressure. The filtrate was purified by flash chromatography. The combined fractions and the solid were combined to give 3.16 g (72 % yield) of the title compound. LC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m/z = 346 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (1.99), 1.035 (0.46), 1.053 (0.86), 1.070 (0.46), 1.382 (0.58), 1.398 (16.00), 1.712 (0.81), 2.518 (0.72), 2.523 (0.47), 5.460 (0.76), 6.244 (0.63), 6.249 (0.67). Intermediate 60 tert-butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-4-hydroxypiperidine- 1-carboxylate
tert-Butyl 4-(3-bromo-1H-pyrazol-5-yl)-4-hydroxypiperidine-1-carboxylat e (3.15 g, 9.10 mmol) was solubilised in THF (50 ml) under nitrogen, NaH (400 mg, 60 % purity, 10.0 mmol) was added and the mixture was stirred for 10 min at rt. [2-(chloromethoxy)ethyl](trimethyl)silane (1.8 ml, 10 mmol) was added and the mixture was stirred overnight at rt. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.57 g (59 % yield) of the title compound. LC-MS (Method 1): R t = 1.55 min; MS (ESIpos): m/z = 476 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.007 (1.24), 0.071 (2.95), 0.853 (0.85), 0.873 (1.24), 0.893 (0.89), 1.246 (0.44), 1.460 (16.00), 1.709 (0.46), 1.742 (0.66), 1.887 (0.53), 2.061 (0.82), 3.598 (0.92), 3.619 (1.47), 3.638 (1.25), 3.666 (0.42), 5.269 (1.53), 5.445 (2.99), 6.565 (2.48). Intermediate 61 tert-butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-4-(2-ethoxy-2- oxoethoxy)piperidine-1-carboxylate tert-Butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-4-hydroxypiperidine- 1-carboxylate (3.48 g, 7.30 mmol) was solubilised in THF (50 ml) under nitrogen, NaH (438 mg, 60 % purity, 11.0 mmol) was added and the mixture was stirred for 10 min at rt. ethyl bromoacetate (1.2 ml, 11 mmol) was added and the mixture was stirred overnight at 60°C. It was stirred for 3 d at 80°C and overnight at 90°C. The mixture was diluted with dioxane (50 ml), THF was evaporated. The mixture was stirred for 6 d at 120°C. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 1.80 g (44 % yield) of the title compound. LC-MS (Method 1): R t = 1.67 min; MS (ESIpos): m/z = 562 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.039 (0.42), 0.047 (12.00), 0.056 (0.46), 0.862 (0.86), 0.868 (0.52), 0.881 (1.26), 0.901 (0.94), 0.908 (0.47), 1.208 (2.04), 1.226 (4.79), 1.242 (3.16), 1.260 (1.45), 1.471 (16.00), 1.482 (7.27), 1.989 (0.76), 2.002 (1.31), 2.016 (0.88), 2.075 (0.97),
2.605 (1.62), 2.610 (1.00), 3.454 (1.07), 3.462 (0.75), 3.466 (0.76), 3.606 (0.86), 3.626 (1.21), 3.645 (0.82), 3.653 (0.63), 3.721 (0.46), 3.872 (1.28), 3.880 (3.49), 4.096 (0.58), 4.113 (1.83), 4.127 (0.41), 4.131 (1.85), 4.144 (0.82), 4.149 (0.64), 4.162 (0.75), 5.503 (2.75), 5.634 (0.89), 5.845 (0.64), 6.622 (1.06), 6.699 (2.66). Intermediate 62 ethyl {[4-(5-bromo-1H-pyrazol-3-yl)piperidin-4-yl]oxy}acetate tert-Butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3 -yl)-4-(2-ethoxy-2- oxoethoxy)piperidine-1-carboxylate (1.00 g, 1.78 mmol) was solubilised in dichloromethane (20 ml) and TFA (4.5 ml, 58 mmol) was added. The mixture was stirred overnight at rt. The mixture was diluted with toluene and concentrated under reduced pressure to give 1.20 g (49 % purity, 100 % yield) of the title compound, which was used without further purification. Intermediate 63 ethyl {[4-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)piperidin-4- yl]oxy}acetate Ethyl {[4-(5-bromo-1H-pyrazol-3-yl)piperidin-4-yl]oxy}acetate (1.20 g, 49 % purity, 1.77 mmol), isocyanatoethane (170 µl, 2.1 mmol) and N,N-diisopropylethylamine (1.5 ml, 8.9 mmol) were solubilised in dichloromethane (1.2 ml) and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 780 mg of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.58), 0.975 (4.92), 0.984 (1.69), 0.992 (12.18), 1.001 (1.38), 1.010 (8.13), 1.016 (2.74), 1.027 (2.05), 1.034 (1.37), 1.052 (0.49), 1.069 (0.40),
1.073 (0.69), 1.085 (0.55), 1.092 (1.44), 1.110 (4.67), 1.123 (6.83), 1.128 (14.87), 1.136 (3.01), 1.146 (16.00), 1.153 (3.08), 1.159 (1.11), 1.164 (5.73), 1.170 (2.19), 1.176 (0.46), 1.180 (0.45), 1.187 (3.82), 1.197 (0.50), 1.205 (1.92), 1.215 (0.44), 1.230 (0.72), 1.250 (0.47), 1.392 (0.45), 1.549 (0.41), 1.641 (0.80), 1.651 (8.05), 1.693 (0.83), 1.755 (0.66), 1.795 (0.70), 1.813 (0.42), 1.906 (2.09), 1.917 (3.42), 1.934 (1.84), 2.064 (0.51), 2.083 (0.68), 2.517 (1.33), 2.521 (0.88), 2.970 (0.40), 2.975 (0.41), 2.988 (0.82), 2.996 (0.94), 3.002 (1.23), 3.006 (1.25), 3.014 (1.97), 3.020 (1.25), 3.027 (2.24), 3.032 (2.19), 3.041 (1.21), 3.045 (2.14), 3.058 (0.97), 3.063 (1.05), 3.072 (0.61), 3.077 (0.47), 3.210 (0.75), 3.229 (2.36), 3.244 (2.95), 3.246 (2.95), 3.262 (2.90), 3.279 (1.52), 3.293 (0.73), 3.425 (1.78), 3.438 (1.77), 3.452 (1.05), 3.458 (1.26), 3.472 (0.70), 3.592 (2.29), 3.651 (0.52), 3.876 (7.91), 3.894 (1.57), 3.904 (0.87), 3.933 (0.44), 4.016 (1.48), 4.034 (4.33), 4.052 (4.31), 4.069 (1.54), 4.087 (0.75), 4.105 (1.71), 4.123 (1.63), 4.140 (0.54), 4.475 (1.04), 4.480 (0.72), 4.498 (0.42), 4.507 (2.42), 6.462 (0.49), 6.475 (0.94), 6.488 (1.41), 6.502 (0.75), 6.517 (1.14), 6.639 (0.51), 6.672 (1.16), 6.736 (7.22), 6.968 (0.58), 8.432 (0.61), 8.447 (1.22), 8.462 (0.61). Intermediate 64 4-(5-bromo-1H-pyrazol-3-yl)-N-ethyl-4-(2-hydroxyethoxy)piper idine-1-carboxamide Ethyl {[4-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)piperidin-4- yl]oxy}acetate (730 mg, 1.81 mmol) was solubilised in THF (17 ml) under nitrogen, lithium borohydride (2.2 ml, 4.0 M in THF, 11 mmol) was added dropwise and the mixture was stirred overnight at rt. It was cooled to 0°C, diluted with sat. NH4Cl solution and extracted with EtOAc. The organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated to give 350 mg (54 % yield) of the title compound, which was used without further purification. Intermediate 65 2'-bromo-N-ethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo [5,1-c][1,4]oxazine]-1-carboxamide
4-(5-Bromo-1H-pyrazol-3-yl)-N-ethyl-4-(2-hydroxyethoxy)pi peridine-1-carboxamide (350 mg, 969 µmol) was solubilised in THF (5.0 ml), PPh3 (356 mg, 1.36 mmol) was added and DIAD (250 µl, 1.29 mmol) was added dropwise. The mixture was stirred overnight at rt. It was evaporated and purified by flash chromatography to give 170 mg (55 % purity, 28 % yield) of the title compound. Intermediate 66 1-(ethylcarbamoyl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-p yrazolo[1,5-a]pyridin]-2'-yl trifluoromethanesulfonate Trifluoroacetic acid—6’,7’-dihydro-5’H-spiro[piperidine-4,4’-pyraz olo[1,5-a]pyridin]-2’-yl trifluoromethanesulfonate (1/1) (1.11 g, 74 % purity, 1.82 mmol), isocyanatoethane (220 µl, 2.7 mmol; CAS-RN:[109-90-0]) and N,N-diisopropylethylamine (1.6 ml, 9.1 mmol) were solubilised in dichloromethane (25 ml) and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 729 mg (98 % yield) of the title compound. LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m/z = 411 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (4.81), 0.989 (7.05), 1.007 (16.00), 1.025 (6.99), 1.137 (0.68), 1.154 (0.66), 1.603 (1.11), 1.636 (2.58), 1.660 (1.24), 1.670 (1.46), 1.688 (1.40), 1.698 (1.53), 1.722 (0.69), 1.732 (0.57), 1.854 (1.33), 1.862 (1.61), 1.867 (1.69), 1.883 (2.27), 1.974 (1.57), 1.985 (1.69), 1.998 (1.07), 2.332 (0.78), 2.518 (3.66), 2.522 (2.39), 2.673 (0.80), 2.911 (0.92), 2.918 (1.04), 2.945 (1.91), 2.973 (1.16), 2.981 (0.89), 3.014 (0.85), 3.032 (2.68), 3.045 (2.81), 3.050 (2.78), 3.063 (2.55), 3.081 (0.78), 3.350 (1.12), 3.728 (1.84), 3.753 (0.97),
3.762 (1.71), 3.975 (2.05), 3.990 (4.08), 4.005 (1.92), 6.403 (9.85), 6.440 (0.96), 6.454 (1.90), 6.467 (0.93). The following compounds (intermediate 67 to intermediate 80) were prepared in analogy to example 1: Intermediate 67 tert-butyl 2'-(isoquinolin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrr olo[1,2-b]pyrazole]-1- carboxylate LC-MS (Method 1): R t = 1.20 min; MS (ESIpos): m/z = 377 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.420 (16.00), 2.518 (0.61), 2.523 (0.40), 2.919 (0.60), 2.936 (0.92), 2.954 (0.65), 4.130 (0.90), 4.245 (0.67), 4.263 (0.98), 4.280 (0.63), 6.843 (3.12), 7.723 (0.41), 7.726 (0.60), 7.743 (0.41), 7.815 (0.43), 7.832 (0.60), 7.836 (0.45), 8.167 (0.55), 8.187 (0.51), 8.727 (2.58), 8.777 (0.57), 8.779 (0.56), 8.798 (0.54), 8.800 (0.52), 9.274 (1.49). Intermediate 68 tert-butyl 2'-(8-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4' -pyrrolo[1,2-b]pyrazole]-1- carboxylate LC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m/z = 395 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.426 (16.00), 2.518 (1.22), 2.522 (0.76), 2.889 (0.57), 2.907 (0.87), 2.924 (0.61), 4.098 (0.73), 4.115 (0.74), 4.202 (0.62), 4.220 (0.94), 4.237 (0.59), 7.055 (2.80), 7.545 (0.41), 7.572 (0.46), 7.576 (0.65), 7.596 (0.42), 7.609 (0.43), 7.830 (0.52), 7.833 (0.56), 7.854 (0.43), 8.756 (0.55), 8.760 (0.90), 8.765 (0.55), 9.402 (1.16), 9.407 (1.12).
Intermediate 69/Example 11 tert-butyl 2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospi ro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate LC-MS (Method 1): R t = 1.12 min; MS (ESIpos): m/z = 380 [M+H] + Intermediate 70/Example 17 tert-butyl 2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospir o[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate LC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m/z = 394 [M+H] + Intermediate 71 tert-butyl 2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydr ospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate LC-MS (Method 1): R t = 1.31 min; MS (ESIpos): m/z = 420 [M+H] + Intermediate 72/Example 170 tert-butyl 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospi ro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate
LC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m/z = 400 [M+H] + Intermediate 73 tert-butyl 2'-(3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo [2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole]-1-carbo xylate LC-MS (Method 1): R t = 1.66 min; MS (ESIpos): m/z = 539 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.111 (0.41), -0.075 (0.61), -0.067 (16.00), -0.059 (0.54), 0.836 (0.49), 0.855 (0.59), 0.876 (0.50), 1.071 (1.53), 1.088 (3.40), 1.106 (1.46), 1.446 (0.45), 1.466 (8.49), 2.319 (1.88), 2.322 (1.90), 2.474 (0.50), 2.554 (0.41), 3.458 (0.83), 3.471 (0.82), 3.476 (0.73), 3.488 (0.73), 3.509 (0.52), 3.529 (0.59), 3.549 (0.49), 4.221 (0.49), 4.381 (0.42), 4.394 (0.83), 4.406 (0.41), 5.584 (1.26), 6.872 (1.12), 7.410 (0.56), 7.412 (0.56), 8.319 (0.73), 8.324 (0.72), 8.742 (0.66), 8.747 (0.64). Intermediate 74 tert-butyl 2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidi ne-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxylate
LC-MS (Method 2): R t = 1.31 min; MS (ESIpos): m/z = 449 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.439 (16.00), 1.700 (0.51), 1.801 (0.41), 1.887 (0.43), 1.907 (0.49), 2.030 (0.41), 2.518 (0.68), 2.523 (0.46), 3.899 (6.90), 4.127 (0.47), 4.142 (0.92), 4.157 (0.45), 6.970 (2.34), 7.336 (0.59), 7.343 (0.93), 7.366 (2.23), 7.373 (0.53), 7.886 (0.83), 7.907 (0.77), 8.575 (0.87), 8.580 (0.89), 9.173 (1.53), 9.178 (1.41). Intermediate 75 tert-butyl 2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro-5'H-spi ro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxylate LC-MS (Method 2): R t = 1.61 min; MS (ESIpos): m/z = 477 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.351 (7.09), 1.367 (7.28), 1.381 (0.63), 1.396 (0.55), 1.441 (16.00), 1.700 (0.51), 1.802 (0.42), 1.888 (0.44), 1.907 (0.50), 2.031 (0.42), 2.521 (0.46), 4.127 (0.47), 4.142 (0.92), 4.156 (0.46), 4.757 (0.40), 4.772 (0.55), 4.787 (0.41), 6.961 (2.21), 7.297 (0.59), 7.304 (0.69), 7.320 (0.57), 7.327 (0.80), 7.363 (1.01), 7.370 (0.81), 7.871 (0.94), 7.893 (0.85), 8.552 (0.88), 8.557 (0.91), 9.159 (1.47), 9.164 (1.38). Intermediate 76 tert-butyl 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5' H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxylate
LC-MS (Method 1): R t = 1.26 min; MS (ESIpos): m/z = 442 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (0.57), 1.066 (12.77), 1.404 (2.96), 1.432 (16.00), 1.642 (0.46), 1.676 (0.60), 1.772 (0.45), 1.797 (0.49), 1.865 (0.56), 1.884 (0.66), 2.009 (0.50), 2.523 (0.72), 3.750 (0.55), 3.941 (2.11), 4.083 (0.52), 4.098 (1.01), 4.112 (0.51), 5.757 (1.99), 6.893 (2.13), 7.670 (1.07), 7.677 (1.08), 8.234 (1.11), 8.238 (1.13), 8.761 (1.27), 8.765 (1.27), 11.972 (0.56). Intermediate 77 tert-butyl 2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[piperidine-4, 4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate LC-MS (Method 1): R t = 1.26 min; MS (ESIpos): m/z = 435 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.434 (16.00), 1.645 (0.49), 1.709 (0.47), 2.450 (0.60), 2.468 (0.96), 2.518 (0.67), 2.522 (0.44), 3.585 (0.41), 3.902 (6.49), 4.219 (0.60), 4.236 (0.95), 4.254 (0.57), 6.972 (2.26), 7.345 (0.93), 7.355 (0.87), 7.363 (1.60), 7.885 (0.71), 7.910 (0.65), 8.562 (0.84), 8.567 (0.85), 9.182 (1.28), 9.187 (1.31). Intermediate 78 tert-butyl 2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-p yrazolo[1,5-a]pyridine]-1- carboxylate
LC-MS (Method 1): R t = 1.29 min; MS (ESIpos): m/z = 419 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (7.11), 1.438 (16.00), 1.703 (0.48), 1.910 (0.47), 2.518 (1.20), 2.523 (0.79), 4.134 (0.45), 4.149 (0.90), 4.164 (0.44), 7.014 (2.31), 7.605 (0.41), 7.608 (0.61), 7.625 (0.40), 7.629 (0.40), 7.701 (0.40), 7.705 (0.41), 7.721 (0.62), 7.725 (0.46), 7.981 (0.54), 7.984 (0.55), 7.993 (0.63), 7.995 (0.63), 8.001 (0.53), 8.005 (0.47), 8.015 (0.54), 8.670 (0.80), 8.675 (0.82), 9.354 (1.36), 9.359 (1.29). Intermediate 79 tert-butyl 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospi ro[azetidine-3,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate LC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m/z = 416 [M+H] + Intermediate 80/Example 169 tert-butyl 2'-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-di hydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate LC-MS (Method 1): R t = 1.27 min; MS (ESIpos): m/z = 428 [M+H] +
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.011 (0.58), -0.002 (14.76), 0.005 (0.52), 1.066 (1.56), 1.118 (0.44), 1.180 (1.32), 1.199 (3.00), 1.209 (0.44), 1.218 (1.41), 1.228 (0.75), 1.246 (0.41), 1.371 (0.86), 1.384 (12.94), 1.408 (4.20), 1.419 (16.00), 2.518 (4.19), 2.523 (2.60), 2.678 (0.63), 2.697 (0.93), 2.716 (0.90), 2.855 (0.71), 2.872 (1.09), 2.881 (0.74), 2.890 (0.79), 2.899 (0.86), 2.917 (0.50), 4.026 (0.80), 4.049 (1.22), 4.073 (1.06), 4.092 (0.99), 4.133 (0.72), 4.150 (1.07), 4.167 (0.66), 4.178 (0.55), 4.196 (0.79), 4.213 (0.47), 5.758 (0.86), 6.432 (0.61), 6.667 (1.08), 6.670 (1.11), 6.844 (2.47), 7.496 (0.43), 7.500 (0.41), 7.503 (0.44), 7.513 (1.10), 7.517 (0.97), 7.521 (1.13), 7.532 (0.96), 7.539 (0.98), 7.562 (0.85), 7.566 (0.85), 7.580 (0.82), 7.584 (0.71), 7.693 (1.00), 7.696 (1.20), 7.713 (0.95), 7.722 (0.96), 7.727 (1.08), 7.743 (0.89), 8.254 (1.28), 8.259 (1.33), 8.640 (1.38), 8.645 (1.36), 12.226 (0.82). Intermediate 81 trifluoroacetic acid—2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1) tert-Butyl 2’-(quinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’ -pyrrolo[1,2-b]pyrazole]-1- carboxylate (750 mg, 1.99 mmol) was solubilised in dichloromethane (15 ml) and TFA (5.0 ml, 65 mmol) was added. The mixture was stirred for 2 h at rt. The mixture was diluted with toluene and concentrated under reduced pressure to give 1.80 g of the title compound, which was used without further purification. LC-MS (Method 1): R t = 0.87 min; MS (ESIpos): m/z = 277 [M+H] + ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.532 (2.40), 1.907 (0.51), 2.298 (5.83), 2.515 (4.04), 2.518 (3.99), 2.522 (3.06), 2.987 (2.50), 3.001 (3.50), 3.015 (2.67), 4.215 (3.11), 4.230 (4.63), 4.244 (4.24), 4.255 (2.28), 4.269 (2.38), 4.281 (1.57), 4.290 (0.96), 4.304 (0.51), 5.758 (16.00), 7.044 (10.81), 7.143 (0.64), 7.165 (0.96), 7.179 (1.35), 7.233 (1.20), 7.248 (1.42), 7.263 (0.56), 7.658 (1.08), 7.660 (1.20), 7.674 (2.33), 7.688 (1.42), 7.690 (1.42), 7.777 (1.37), 7.780 (1.40), 7.791 (1.18), 7.794 (2.30), 7.797 (1.59), 7.808 (1.27), 7.811 (1.25), 8.043 (2.25), 8.060 (1.98), 8.091 (1.96), 8.106 (1.81), 8.752 (2.70), 8.757 (2.70), 8.949 (0.69), 9.386 (4.68), 9.391 (4.58). The following compounds (intermediate 82 to intermediate 98) were prepared in analogy to intermediate 81:
Intermediate 82 trifluoroacetic acid—2'-(isoquinolin-4-yl)-5',6'-dihydrospiro[azetidine-3, 4'-pyrrolo[1,2-b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.86 min; MS (ESIpos): m/z = 277 [M+H] + Intermediate 83 trifluoroacetic acid—2'-(8-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidi ne-3,4'-pyrrolo[1,2- b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.86 min; MS (ESIpos): m/z = 295 [M+H] + Intermediate 84 trifluoroacetic acid—2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro [azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.73 min; MS (ESIpos): m/z = 266 [M+H] + Intermediate 85 trifluoroacetic acid—2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dih ydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)
LC-MS (Method 1): R t = 0.79 min; MS (ESIpos): m/z = 280 [M+H] + Intermediate 86 trifluoroacetic acid—2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihy drospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.86 min; MS (ESIpos): m/z = 294 [M+H] + Intermediate 87 trifluoroacetic acid—2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6' -dihydrospiro[azetidine- 3,4'-pyrrolo[1,2-b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.97 min; MS (ESIpos): m/z = 320 [M+H] + Intermediate 88/Intermediate 91 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dih ydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)
LC-MS (Method 1): R t = 0.82 min; MS (ESIpos): m/z = 300 [M+H] + Intermediate 89 trifluoroacetic acid—2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole] (1/1) LC-MS (Method 1): R t = 1.05 min; MS (ESIpos): m/z = 342 [M+H] + Intermediate 90 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dih ydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.90 min; MS (ESIpos): m/z = 328 [M+H] + Intermediate 91/Intermediate 88 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dih ydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)
LC-MS (Method 1): R t = 0.83 min; MS (ESIpos): m/z = 300 [M+H] + Intermediate 92 trifluoroacetic acid—2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[p iperidine-4,4'- pyrazolo[1,5-a]pyridine] (1/1) LC-MS (Method 1): R t = 0.99 min; MS (ESIpos): m/z = 349 [M+H] + Intermediate 93 trifluoroacetic acid—2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro- 5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine] (1/1) LC-MS (Method 1): R t =1.15 min; MS (ESIpos): m/z = 377 [M+H] + Intermediate 94 trifluoroacetic acid—6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-2'-yl trifluoromethanesulfonate (1/1)
LC-MS (Method 1): R t = 1.06 min; MS (ESIpos): m/z = 340 [M+H] + Intermediate 95 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dih ydro-5'H- spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine] (1/1) LC-MS (Method 1): R t = 1.05 min; MS (ESIpos): m/z = 342 [M+H] + Intermediate 96 trifluoroacetic acid—2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[piperi dine-4,4'-pyrrolo[1,2- b]pyrazole] (1/1) LC-MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 336 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (0.96), 1.876 (0.61), 1.896 (0.88), 1.911 (1.44), 1.926 (0.76), 1.943 (0.75), 1.956 (1.48), 1.969 (0.85), 1.991 (0.59), 2.327 (1.02), 2.332 (0.72), 2.518 (3.40), 2.523 (2.38), 2.537 (1.62), 2.555 (2.25), 2.573 (1.49), 2.673 (0.70), 3.252 (2.41), 3.915 (16.00), 4.254 (1.50), 4.272 (2.26), 4.289 (1.43), 6.984 (3.21), 7.393 (1.02), 7.400 (1.96), 7.414 (1.88), 7.419 (5.84), 7.924 (1.50), 7.944 (0.65), 7.950 (1.35), 8.573 (0.62), 8.641 (1.87), 8.645 (1.87), 9.222 (3.09), 9.228 (3.00). Intermediate 97
trifluoroacetic acid—2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine -4,4'-pyrazolo[1,5- a]pyridine] (1/1) LC-MS (Method 1): R t = 1.03 min; MS (ESIpos): m/z = 319 [M+H] + Intermediate 98 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dih ydrospiro[azetidine-3,4'- pyrazolo[5,1-c][1,4]oxazine] (1/1) LC-MS (Method 1): R t = 0.78 min; MS (ESIpos): m/z = 316 [M+H] + The following compound (intermediate 99) was prepared in analogy to example 1: Intermediate 99 N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro [azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxamide LC-MS (Method 1): R t = 0.57 min; MS (ESIpos): m/z = 364 [M+H] + Intermediate 100 6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyrid in]-2'-yl trifluoromethanesulfonate trifluoroacetate (1:1) tert-Butyl (800 mg, 1.82 mmol) was solubilised in dichloromethane (20 mL) and TFA (4.6 mL, 59 mmol) was added. The mixture was stirred overnight at rt. The mixture was concentrated, the residue was treated twice with toluene and concentrated under reduced pressure to give 1.11 g of the title compound, which was used without further purification. LC-MS (Method 1): R t = 1.06 min; MS (ESIpos): m/z = 340 [M+H] + EXPERIMENTAL SECTION – EXAMPLES Example 1 tert‐butyl 2'‐(2‐fluoroquinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxylate To a solution of tert‐butyl 2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[az etidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (intermediate 6) (100 mg, 252 µmol) in 1,4‐dioxane (4.0 ml) we re added (2‐fluoroquinolin‐3‐yl)boronic acid (96.1 mg, 503 µmol, CAS‐RN [745784‐10‐5]), K 3 PO 4 (1.5 ml, 0.50 M, 750 µmol) and XPhos Pd G2 (29.7 mg, 37.7 µmol; CAS‐RN:[14221‐01‐3]). The mixture was sti rred overnight at 100°C. The mixture was diluted with Et OAc, washed with sat. NaCl solution and the organic phase was dried and concentrated under reduced pressu re. The mixture was purified by preparative HPLC to yield the title compound (5.00 mg, 95 % pu rity, 5 % yield). LC‐MS (Method 1): Rt = 1.20 mi n; MS (ESIpos): m/z = 395 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.42 1 (16.00), 2.518 (0.75), 2.523 (0.48), 2.896 (0.60), 2.913 (0.89), 2.931 (0.64), 4.0 99 (0.86), 4.112 (0.72), 4.211 (0.64), 4.229 (0.99), 4.246 (0.65), 6.823 (0.97), 6.833 (0.95), 7.630 (0.57), 7.7 90 (0.55), 7.793 (0.43), 7.872 (0.68), 7.893 (0.43), 8.123 (0.52), 8.142 (0.48), 8.967 (0.63), 8.992 (0.64). The following compounds (example 2 to example 16) we re synthesized in analogy to example 1:
Example 2 tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxy late (prepared from intermediate 6 and quinolin‐3‐ylboro nic acid, CAS‐RN: [191162‐39‐7]) 1 H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.426 (16.00), 2.884 (0.72), 2.901 (1.22), 2.919 (0.76), 4 .100 (1.32), 4.111 (1.35), 4.191 (0.78), 4.208 (1.32), 4.2 26 (0.73), 7.016 (2.33), 7.617 (0.68), 7.634 (0.47), 7.731 (0.66), 7.999 (0.97), 8.016 (0.77), 8.021 (0.82), 8.6 75 (1.07), 8.679 (1.07), 9.358 (1.25), 9.363 (1.23). Example 3 tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐ 1‐carboxylate (prepared from intermediate 6 and 1H‐pyrrolo[2,3‐b] pyridin‐5‐ylboronic acid, CAS‐RN: [944059‐24‐9] ) LC‐MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 366 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.420 (16.00), 2.518 (1.57), 2.523 (0.96), 2.539 (1.41), 2.853 (0.58), 2.871 (0.93), 2.888 (0.62), 3.566 (0.53), 4.0 85 (1.15), 4.131 (0.66), 4.149 (0.99), 4.166 (0.60), 6.450 (0.68), 6.454 (0.73), 6.459 (0.71), 6.463 (0.67), 6.7 70 (2.92), 7.458 (0.59), 7.465 (0.71), 7.472 (0.57), 8.269 (0.93), 8.273 (0.95), 8.652 (1.25), 8.657 (1.21), 11. 643 (0.45). Example 4 tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxylate (prepared from intermediate 6 and (2‐aminopyrimidin 5‐yl)boronic acid, CAS‐RN: [936250‐22‐5])
LC‐MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 343 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.407 (16.00), 2.827 (0.83), 2.844 (1.44), 2.861 (0.87), 4.032 (1.12), 4.066 (1.22), 4.088 (1.52), 4.105 (1.61), 4.1 23 (0.88), 6.654 (2.21), 6.720 (2.35), 8.591 (4.30). Example 5 tert‐butyl 2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐ 1‐carboxylate (prepared from intermediate 6 and 6‐(4,4,5,5‐tetram ethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[3,2‐ b]pyridine, CAS‐RN: [1045855‐91‐1]) LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 366 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.399 (0.62), 1.422 (16.00), 2.518 (1.19), 2.522 (0.74), 2.858 (0.61), 2.876 (0.97), 2.893 (0.65), 4.089 (1.56), 4.1 41 (0.68), 4.159 (1.04), 4.176 (0.62), 6.530 (0.55), 6.533 (0.55), 6.537 (0.56), 6.822 (2.64), 7.624 (0.52), 7.6 31 (0.73), 7.638 (0.51), 8.047 (0.87), 8.050 (0.98), 8.052 (0.95), 8.054 (0.87), 8.770 (1.51), 8.774 (1.42), 11. 349 (0.52). Example 7 tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐y l]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b ]pyrazole]‐ 1‐carboxylate (prepared from intermediate 6 and [5‐(pyrrolidin‐1 yl)pyridin‐3‐yl]boronic acid, CAS‐RN: [1218790‐ 56‐ 7]) LC‐MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 396 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.413 (16.00), 1.955 (0.76), 1.964 (0.95), 1.971 (2.19), 1.979 (1.02), 1.988 (0.83), 2.518 (1.14), 2.523 (0.73), 2.8 45 (0.62), 2.862 (1.00), 2.879 (0.66), 3.275 (0.79), 3.290 (2.02), 3.307 (0.83), 4.062 (0.78), 4.077 (0.86), 4.1 33 (0.69), 4.150 (1.05), 4.168 (0.63), 6.828 (2.72), 7.185 (0.55), 7.190 (0.73), 7.197 (0.56), 7.845 (1.01), 7.8 52 (0.98), 8.241 (1.15), 8.246 (1.14). Example 8
tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2 ,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and (2‐oxo‐2,3‐dihy dro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)boronic acid, CAS‐ RN: [1111637‐70‐7]) LC‐MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 382 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.401 (0.68), 1.413 (16.00), 2.518 (1.32), 2.523 (0.91), 2.840 (0.58), 2.858 (0.94), 2.875 (0.63), 3.584 (1.94), 4.0 51 (0.66), 4.074 (0.74), 4.111 (0.71), 4.128 (0.99), 4.145 (0.61), 6.736 (2.76), 7.893 (0.80), 7.898 (0.79), 8.4 63 (0.93), 8.468 (0.91), 11.033 (0.76). Example 9 tert‐butyl 2'‐[5‐(trifluoromethyl)pyridin‐3‐yl] 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and [5‐(trifluoromethyl )pyridin‐3‐yl]boronic acid, CAS‐RN: [947533‐51‐ 9]) LC‐MS (Method 1): Rt = 1.28 min; MS (ESIpos): m/z = 395 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.415 (16.00), 2.870 (0.58), 2.888 (0.88), 2.905 (0.62), 4.058 (0.59), 4.101 (0.59), 4.176 (0.64), 4.194 (0.94), 4.2 11 (0.60), 7.089 (2.74), 8.448 (0.44), 8.451 (0.72), 8.456 (0.46), 8.458 (0.40), 8.879 (0.68), 8.882 (0.69), 8.8 85 (0.60), 9.284 (0.77), 9.288 (0.76). Example 10
tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and 1H‐pyrazolo[3,4‐b ]pyridin‐5‐ylboronic acid, CAS‐RN: [1417985‐25‐ 1]) LC‐MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 367 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.399 (0.50), 1.420 (16.00), 2.522 (1.10), 2.539 (0.78), 2.863 (0.64), 2.880 (1.02), 2.898 (0.67), 4.080 (0.85), 4.0 95 (0.90), 4.151 (0.69), 4.168 (1.08), 4.186 (0.64), 6.865 (2.50), 8.160 (1.66), 8.519 (1.36), 8.524 (1.39), 8.9 72 (1.28), 8.977 (1.25). Example 11/Intermediate 69 tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and 3‐methyl‐5‐(4,4 ,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111637‐95‐6]) LC‐MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 380 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.421 (16.00), 2.272 (3.92), 2.273 (3.80), 2.518 (2.17), 2.523 (1.36), 2.856 (0.61), 2.874 (0.99), 2.891 (0.65), 4.0 89 (1.02), 4.130 (0.71), 4.148 (1.06), 4.165 (0.63), 6.801 (2.81), 7.221 (0.77), 7.223 (0.77), 8.236 (1.00), 8.2 40 (1.02), 8.629 (1.27), 8.634 (1.24), 11.285 (0.54). Example 12 tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (prepared from intermediate 6 and 7‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)p yrido[2,3‐ b]pyrazine, CAS‐RN: [1210047‐44‐1]) LC‐MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 379 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.427 (16.00), 2.327 (0.42), 2.518 (2.00), 2.522 (1.21), 2.669 (0.43), 2.899 (0.62), 2.917 (0.97), 2.934 (0.66), 4.1 01 (0.74), 4.122 (0.79), 4.227 (0.67), 4.245 (1.04), 4.262
(0.63), 7.211 (2.65), 8.772 (1.30), 8.777 (1.30), 9.066 (1.08), 9.070 (1.54), 9.088 (1.82), 9.093 (1.31 ), 9.648 (1.34), 9.654 (1.27). Example 13 tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxylate (prepared from intermediate 6 and 6‐(4,4,5,5‐tetram ethyl‐1,3,2‐dioxaborolan‐2‐yl)furo[3,2‐b]pyridine, CAS‐RN: [1188539‐34‐5]) LC‐MS (Method 1): Rt = 1.13 min; MS (ESIpos): m/z = 367 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.420 (16.00), 2.518 (0.94), 2.523 (0.61), 2.864 (0.61), 2.882 (0.95), 2.899 (0.66), 4.073 (0.66), 4.098 (0.71), 4.1 61 (0.69), 4.178 (1.03), 4.195 (0.64), 6.940 (2.76), 7.135 (0.90), 7.138 (0.94), 7.141 (0.93), 7.143 (0.90), 8.3 10 (1.91), 8.312 (1.15), 8.316 (2.63), 8.319 (0.97), 8.992 (1.53), 8.997 (1.52). Example 14 tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and 2‐methyl‐5‐(4,4 ,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111638‐03‐9]) LC‐MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 380 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.418 (16.00), 2.387 (3.61), 2.518 (2.14), 2.522 (1.31), 2.539 (0.91), 2.847 (0.62), 2.864 (1.01), 2.882 (0.66), 4.0 80 (1.16), 4.119 (0.73), 4.137 (1.09), 4.154 (0.64), 6.141 (0.92), 6.143 (0.92), 6.732 (2.76), 8.101 (0.99), 8.1 05 (1.01), 8.520 (1.22), 8.526 (1.22), 11.454 (0.60). Example 15 tert‐butyl 2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyrid in‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and 3‐methyl‐5‐(4,4 ,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrazolo[3,4‐b]pyridine, CAS‐RN: [1111637‐76‐3]) LC‐MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 381 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.399 (0.43), 1.421 (16.00), 2.331 (0.42), 2.517 (8.12), 2.522 (1.89), 2.539 (0.60), 2.673 (0.43), 2.864 (0.57), 2.8 81 (0.89), 2.898 (0.60), 4.074 (0.66), 4.101 (0.66), 4.146 (0.63), 4.164 (0.95), 4.181 (0.58), 6.879 (2.87), 8.5 10 (1.46), 8.515 (1.50), 8.932 (1.43), 8.937 (1.40). Example 16 N N N N F O O H 3 C H 3 C C H 3 tert‐butyl 2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[az etidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (prepared from intermediate 6 and (6‐fluoroquinolin 3‐yl)boronic acid, CAS‐RN: [1264511‐20‐7]) LC‐MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 395 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.425 (16.00), 2.518 (0.73), 2.523 (0.45), 2.886 (0.62), 2.904 (0.97), 2.921 (0.66), 4.099 (0.95), 4.109 (0.98), 4.1 95 (0.66), 4.213 (1.03), 4.230 (0.62), 7.019 (2.56), 7.634 (0.43), 7.641 (0.49), 7.786 (0.48), 7.793 (0.47), 7.8 10 (0.49), 7.816 (0.44), 8.055 (0.42), 8.069 (0.43), 8.679 (0.88), 8.683 (0.89), 9.333 (1.07), 9.338 (1.05). Example 17/Intermediate 70 tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxylate
To a solution of [1‐(tert‐butoxycarbonyl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐ yl]boronic acid (50.0 mg, 171 µmol, see intermediate 7) and 5‐bromo‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyri dine (57.6 mg, 256 µmol, preparation described in WO2018/ 167147) in DMSO (1.5 ml) were added Pd(PPh 3 ) 4 (19.7 mg, 17.1 µmol; CAS‐RN:[865‐47‐4]) and Na 2 CO 3 (2.0 M, 340 µl). The mixture was stirred ov ernight at 110°C. The mixture was diluted with EtOAc, washe d with sat. NaCl solution and the organic layer was dried and concentrated under reduced pressure. The re sidue was purified by preparative HPLC to yield the title compound (24.9 mg, 95 % purity, 35 % yie ld). LC‐MS (Method 1): Rt = 1.21 min; MS (ESIpos) : m/z = 394 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.24 7 (1.83), 1.266 (4.03), 1.284 (1.83), 1.402 (2.27), 1.415 (16.00), 1.428 (0.61), 2.513 (1.23), 2.518 (0.84), 2.705 (0.92), 2.707 (0.92), 2.724 (0.91), 2.726 (0.91), 2.849 (0.61), 2.866 (0.92), 2.884 (0.62 ), 4.078 (1.05), 4.125 (0.66), 4.142 (0.98), 4.159 ( 0.59), 6.805 (2.86), 7.215 (0.72), 7.218 (0.68), 7.221 (0.71 ), 8.250 (0.92), 8.255 (0.95), 8.623 (0.79), 8.627 ( 0.78), 11.298 (0.48). Example 18 tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6' ‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] ‐1‐ carboxylate To a stirred solution of tert‐butyl 6'‐methyl‐2'‐(trifluoromethanesulfonyloxy)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate (intermediate 11) (15 g , 36.4 mmol, 1.00 equiv) in dioxane (300 mL) was added quinolin‐3‐ylboronic acid (19.0 g, 109.2 mmol, 3.00 equiv, CAS‐RN: [191162‐39‐7]), this was followed by addition of Cs 2 CO 3 (35.6 g, 109.2 mmol, 3.00 equiv), Pd(dppf)Cl 2 (3.64 g, 3.65 mmol, 0.10 equiv). The mixture was stirred at 110 °C in an oil bath under nitrogen atmosphere for 4 h. The resulting mixture w as filtrated. The filtrate was then purified by flas h chromatography directly.The collected fractions were evaporated to give 9.5 g (65 %) of the title compound. LC‐MS: (ES, m/z): 391 [M+H]+. 1 H‐NMR: (300 MHz, CDCl 3 , ppm):δ 9.52‐9.50 (m, 1H), 8.73‐ 8.70 (m, 1H), 8.33‐8.27 (m, 1H), 7.99‐7.93 (m, 1 H), 7.85‐7.77 (m, 1H), 7.71‐7.63 (m, 1H), 6.70 ( s, 1H), 4.62‐4.50 (m, 1H), 4.35‐4.31 (m, 1H), 4.27 ‐4.1 0 (m, 3H), 3.18‐3.06 (m, 1H), 2.58‐2.48 (m, 1H), 1.63 (d, J = 6.4 Hz, 3H), 1.52 (s, 9H). Example 19 (pyrimidin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihy drospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Into a 40‐mL vial was placed a solution of py rimidine‐ 4‐carboxylic acid (29 mg, 1.50 equiv, 0.234 mmol) in DMF (3 mL). To this was added DIPEA (201,61 mg, 10.00 equiv, 1.56 mmol). This was followed by the a ddition of HATU (119 mg, 2.00 equiv, 0.312 mmol). The resulting mixture was stirred for 5 h at ambien t temperature. To this was added 2'‐(quinolin‐3‐ yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zole] trifluoroacetate (1:1) (61 mg, 1.00 equiv, 0.15 6 mmol). The resulting mixture stirred for 2 h at rt. The crude mixture was purified by HPLC to provide the title compound. 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.236 (0 .82), 2.271 (1.10), 2.727 (1.53), 2.969 (3.83), 2.991 (6.34), 3.015 (4.77), 4.230 (4.26), 4.2 53 (6.89), 4.276 (4.30), 4.356 (2.03), 4.392 (6.22), 4.413 (6.26), 4.449 (2.07), 4.925 (7.90), 7.053 (16.00), 7.587 (1.76), 7.614 (3.87), 7.641 (3.01), 7.709 (2.66), 7.731 (3.72), 7.759 (2.43), 7.992 (5.83), 8.015 (8.88 ), 8.027 (9.11), 8.032 (7.12), 8.660 (5.36), 8.667 ( 5.99), 9.066 (8.33), 9.084 (8.37), 9.310 (8.45), 9.315 (9.19 ), 9.350 (7.63), 9.357 (8.18). The following compounds (example 20 to example 33) w ere synthesized in analogy to example 19: Example 20
(1‐methyl‐1H‐pyrazol‐5‐yl)[2'‐(quinolin‐3‐yl )‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b] pyrazol]‐ 1‐yl]methanone (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐methyl‐1H‐pyraz ole‐5‐carboxylic acid, CAS‐RN: [16034‐46‐1]) LC‐MS: (ES, m/z): 385, [M+H] + , H‐NMR: (300 MHz,DMSO‐d6, ppm): δ 9.36 (d , J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.05‐7.96 (m, 2H), 7.83‐7.56 (m, 2H ), 7.52 (d, J = 2.1 Hz, 1H), 7.05 (s, 1H), 6.70 (d, J = 2.1 Hz, 1H), 4.64 (s, 2H), 4.53‐4.15 (m, 4H), 4.07 (s, 3H ), 3.03‐2.91 (m, 2H). Example 21 4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]buta nenitrile (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐cyanopropanoic aci d, CAS‐RN: 16051‐87‐9) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.234 (0 .54), 2.272 (0.52), 2.638 (6.38), 2.659 (8.38), 2.681 (3.09), 2.913 (4.33), 2.935 (7.16), 2.959 (4.83), 3.616 (0.72 ), 4.123 (1.26), 4.162 (9.03), 4.195 (1.47), 4.218 ( 4.87), 4.241 (7.85), 4.264 (4.56), 4.415 (14.27), 6.992 (16. 00), 7.594 (1.80), 7.620 (3.83), 7.647 (3.24), 7.709 (2.61), 7.714 (2.66), 7.738 (3.88), 7.742 (3.89), 7.7 60 (2.43), 7.765 (2.61), 8.000 (9.48), 8.031 (8.42), 8.667 (6.25), 8.673 (7.07), 9.353 (8.16), 9.360 (8.70). Example 22
3‐methoxy‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] propan‐ 1‐one (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐methoxypropanoic a cid, CAS‐RN: [2544‐06‐1]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.341 (3 .30), 2.362 (7.04), 2.383 (3.55), 2.900 (2.54), 2.923 (4.13), 2.946 (2.88), 3.317 (16.00), 3.549 (3.93), 3.570 (8.35), 3.592 (3.69), 4.083 (0.54), 4.120 (5.63), 4.153 (0.71), 4.212 (2.85), 4.235 (4.54), 4.258 (2.73), 4.406 (8.45), 6.983 (10.63), 7. 591 (1.06), 7.614 (1.83), 7.618 (2.40), 7.641 (1.72), 7.645 (1.84), 7.707 (1.52 ), 7.712 (1.48), 7.735 (2.37), 7.740 (2.16), 7.758 ( 1.35), 7.763 (1.40), 7.999 (5.06), 8.028 (4.58), 8.672 (3.67 ), 8.678 (3.81), 9.358 (5.07), 9.365 (5.17). Example 23 3‐(1H‐pyrazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razol]‐1‐ yl]propan‐1‐one (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐(1H‐pyrazol‐1 yl)propanoic acid, CAS‐RN: [89532‐73‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.076 (0.56), 2.273 (0.54), 2.641 (5.32), 2.663 (10.85), 2.685 (5.49), 2.855 (4.86), 2.878 (8.32), 2.902 (5.25), 4.058 (1.41), 4.092 (10.99), 4. 131 (1.55), 4.194 (5.47), 4.217 (9.19), 4.240 (5.97), 4.264 (16.00), 4.337 (5.9 6), 4.359 (11.88), 4.382 (5.64), 6.257 (5.61), 6.263 (8.89), 6.269 (5.58), 6.926 (15.13), 7.479 (8.37), 7.594 (2.24), 7.620 (4.78), 7.645 (3.66), 7.720 (8.78), 7.727 (9.16), 7.737 (5.71), 7.760 (2.78), 8.003 (9.27 ), 8.031 (8.30), 8.664 (7.50), 8.670 (7.70), 9.350 ( 8.52), 9.357 (8.66). Example 24
2‐(morpholin‐4‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ol]‐1‐ yl]ethan‐1‐one (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxylate (see example 2) and morpholin‐4‐ylaceti c acid, CAS‐RN: [3235‐69‐6]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.438 (8 .23), 2.468 (9.36), 2.902 (3.91), 2.925 (6.61), 2.949 (4.68), 3.011 (0.69), 3.063 (16.00), 3.114 (0.94), 3.281 (0.9 5), 3.585 (9.83), 3.600 (12.72), 3.615 (9.89), 4.109 (0.85), 4.144 (9.62), 4.179 (1.14), 4.210 (4.52), 4.2 34 (7.62), 4.256 (4.34), 4.489 (12.88), 6.992 (14.64) , 7.593 (1.73), 7.620 (3.88), 7.643 (2.81), 7.646 (2.88 ), 7.708 (2.39), 7.713 (2.36), 7.736 (3.79), 7.741 ( 3.35), 7.760 (2.10), 7.764 (2.08), 8.002 (8.37), 8.030 (7.25 ), 8.673 (6.14), 8.679 (6.27), 9.363 (7.76), 9.370 ( 7.65). Example 25 2‐(pyrimidin‐5‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ol]‐1‐ yl]ethan‐1‐one (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyrimidin‐5‐ylaceti c acid, CAS‐RN: [5267‐07‐2]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.837 (1 .16), 2.890 (0.54), 2.952 (5.04), 2.963 (3.30), 2.971 (3.00), 2.990 (2.05), 3.625 (10.09), 4.102 (0.44), 4.105 (0.44), 4.142 (0.79), 4.175 (5.03), 4.214 (0.98), 4.234 (2.93), 4.257 (5.24), 4.280 (2.30), 4.387 (0.49), 4.553 (8.14), 6.999 (0.75), 7.0 20 (10.23), 7.094 (0.58), 7.597 (1.22), 7.623 (2.46), 7.647 (1.75), 7.651 (1.76 ), 7.712 (1.65), 7.717 (1.47), 7.741 (2.30), 7.745 ( 2.09), 7.763 (1.30), 7.768 (1.30), 8.005 (5.85), 8.034 (4.22), 8.675 (3.96), 8.682 (3.88), 8.717 (16.00), 9.085 (7.84), 9.364 (5.48), 9.372 (4.90). Example 26
(3‐chlorophenyl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐chlorobenzoic acid , CAS‐RN: [535‐80‐8]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.233 (0 .48), 2.728 (0.48), 2.948 (3.54), 2.973 (6.08), 2.994 (4.35), 4.216 (2.95), 4.236 (5.37), 4.256 (3.14), 4.343 (5.71), 4.617 (4.25), 7.052 (16.00), 7.499 (2.27), 7.525 (6.19), 7.551 (5.49), 7.595 (1.97), 7.614 (7.11), 7.6 29 (2.99), 7.641 (5.10), 7.660 (5.87), 7.686 (4.22), 7.707 (2.86), 7.712 (2.83), 7.730 (7.27), 7.735 (11.19), 7.758 (2.88), 7.763 (2.94), 8.000 (8.90), 8.028 (8.48), 8.664 (6.08), 8.670 (6.90), 9.353 (7.76), 9.361 (8.48 ). Example 27 (pyridin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyridine‐4‐carboxyl ic acid, CAS‐RN [55‐22‐1]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.234 (0 .63), 2.274 (0.84), 2.723 (0.67), 2.951 (5.38), 2.973 (8.79), 2.997 (5.74), 4.238 (6.63), 4.323 (1.85), 4.355 (7.87), 4.368 (8.04), 4.403 (1.95), 4.620 (12.11), 7.060 (16.00), 7.594 (2.59), 7.620 (5.23), 7.641 (15.24), 7 .660 (13.05), 7.709 (3.40), 7.736 (4.89), 7.761 (2.97 ), 7.999 (11.92), 8.028 (10.10), 8.671 (8.42), 8.730 (12 .75), 8.749 (12.06), 9.353 (9.17), 9.359 (9.01). Example 28
2‐ethyl‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]bu tan‐1‐one (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐ethylbutanoic acid , CAS‐RN: [88‐09‐5]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.807 (0.79), 0.835 (5.62), 0.860 (13.68), 0.878 (7.89), 0.884 (8.76), 0.902 (13.77), 0.927 (6.82), 1.401 (2.27), 1.425 (2.70), 1.451 (2.76), 1.478 (2.69), 1.496 (2.88), 1.522 (2.36), 1.543 (1.30), 2.109 (0.68), 2.127 (1.33 ), 2.138 (1.51), 2.156 (2.30), 2.173 (1.38), 2.184 ( 1.27), 2.202 (0.66), 2.908 (3.98), 2.931 (6.55), 2.954 (4.33 ), 4.105 (0.84), 4.139 (8.41), 4.177 (1.02), 4.218 ( 4.37), 4.242 (6.66), 4.264 (4.18), 4.376 (1.30), 4.406 (6.40), 4.415 (6.38), 4.444 (1.37), 6.956 (16.00), 7.590 (1.75), 7.617 (3.36), 7.640 (2.69), 7.644 (2.75), 7.7 05 (2.46), 7.710 (2.27), 7.733 (3.35), 7.738 (3.21), 7.756 (2.08), 7.761 (2.07), 7.997 (8.42), 8.029 (7.45), 8.6 90 (5.85), 8.697 (5.94), 9.368 (7.86), 9.375 (7.73). Example 29 1‐{2‐oxo‐2‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihyd rospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethyl}pyrrolidin‐2‐one (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and (2‐oxopyrrolidin‐1 yl)acetic acid, CAS‐RN [53934‐76‐2]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.946 (3 .30), 1.971 (5.11), 1.996 (4.08), 2.237 (5.17), 2.264 (7.53), 2.291 (3.64), 2.728 (0.68), 2.920 (3.72), 2.943 (6.26 ), 2.966 (4.18), 3.381 (4.78), 3.405 (7.71), 3.428 ( 4.48), 3.928 (16.00), 4.167 (8.70), 4.212 (4.69), 4.235 (7.9 6), 4.258 (4.33), 4.441 (11.59), 7.027 (11.92), 7.594 (1.77), 7.620 (3.86), 7.645 (2.94), 7.710 (2.44), 7.7 38 (3.69), 7.762 (2.29), 8.000 (8.87), 8.029 (7.79), 8.679 (6.52), 9.357 (6.87), 9.363 (7.21). Example 30
(pyridin‐3‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyridine‐3‐carboxyl ic acid, CAS‐RN: [59‐67‐6]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.235 (0 .46), 2.074 (0.55), 2.271 (0.45), 2.727 (0.45), 2.957 (3.67), 2.980 (5.54), 3.003 (4.06), 4.223 (2.34), 4.241 (3.74), 4.261 (2.23), 4.363 (4.21), 4.640 (3.43), 7.057 (16.00), 7.508 (2.63), 7.511 (2.64), 7.527 (2.80), 7.534 (2.93), 7.537 (2.85), 7.550 (3.01), 7.553 (2.92), 7.591 (1.73), 7.619 (3.22), 7.645 (2.62), 7.707 (2.36 ), 7.712 (2.10), 7.735 (3.27), 7.740 (3.14), 7.758 ( 1.94), 7.763 (1.95), 7.997 (7.89), 8.028 (7.13), 8.087 (2.54 ), 8.093 (3.60), 8.100 (2.62), 8.113 (2.38), 8.120 ( 3.31), 8.127 (2.34), 8.663 (5.62), 8.670 (5.69), 8.713 (4.42 ), 8.718 (4.47), 8.729 (4.54), 8.734 (4.09), 8.899 ( 5.59), 8.904 (5.55), 9.352 (7.76), 9.359 (7.59). Example 31 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐cyanocyclopropaneca rboxylic acid, CAS‐RN: [6914‐79‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.587 (7.78), 1.622 (13.90), 2.078 (2.18), 2.274 (0.52), 2.957 (3.05), 2.980 (3.12), 3.004 (3.01), 4.227 (8.57), 4.244 (9.86), 4.764 (3.00), 4.8 18 (2.98), 7.078 (16.00), 7.598 (2.42), 7.625 (4.99), 7.650 (3.86), 7.713 (3.08), 7.740 (4.84), 7.765 (2.75), 8.005 (11.53), 8.033 (9.95), 8.694 (8.47), 9.369 (9.07), 9.376 (9.26). Example 32
1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐on e (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and acetic acid, CAS‐RN : [64‐19‐7] 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.837 (16.00), 2.901 (1.70), 2.922 (2.81), 2.947 (1.97), 4.068 (0.40), 4.102 (4.51), 4.137 (0.43), 4.212 (2.19), 4.2 35 (3.67), 4.258 (2.02), 4.388 (6.48), 6.999 (6.76), 7.592 (0.76), 7.619 (1.71), 7.642 (1.23), 7.646 (1.26), 7.7 08 (1.05), 7.713 (1.03), 7.735 (1.65), 7.741 (1.49), 7.759 (0.91), 7.763 (0.93), 8.000 (3.70), 8.028 (3.30), 8.6 69 (2.64), 8.675 (2.77), 9.357 (3.37), 9.364 (3.45). Example 33 (1‐methyl‐1H‐imidazol‐5‐yl)[2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐methyl‐1H‐imida zole‐5‐carboxylic acid, CAS‐RN: [41806‐40‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.952 (1.75), 2.975 (3.08), 2.998 (1.93), 3.855 (16.00), 4.230 (1.93), 4.253 (3.18), 4.276 (2.27), 4.642 (0.81), 7.0 45 (6.90), 7.425 (4.36), 7.428 (4.27), 7.591 (0.78), 7.618 (1.83), 7.641 (1.36), 7.707 (1.14), 7.712 (1.20), 7.7 35 (1.83), 7.740 (1.66), 7.758 (1.08), 7.763 (1.08), 7.831 (4.17), 7.998 (3.63), 8.025 (3.22), 8.671 (2.65), 8.6 77 (2.94), 9.358 (3.52), 9.365 (3.72). Example 34 2‐methoxyethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydro spiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate
Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: A solution of 2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] t rifluoroacetate (1:1) (61 mg, 0.156 mmol, 1 eq.), 2 methoxyethyl carbonochloridoate (32.5 mg, 0.234 mmol, 1.5 eq., CAS‐RN: [628‐12‐6]) and N‐ethyl‐N,N diisopropylamine (201.6 mg, 1.56 mmol, 10 eq.) in te trahydrofuran (3 mL) was stirred under nitrogen at ambient temperature for two hours. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sod ium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC to yield the title compound. 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.903 (2.72), 2.926 (4.66), 2.949 (3.02), 3.329 (16.00), 3.515 (4.11), 3.530 (5.02), 3.546 (4.52), 4.132 (4.49), 4.148 (5.97), 4.152 (5.47), 4.163 (5.64), 4.195 (8.80), 4.221 (6.39), 4.243 (3.37), 7.025 (10.19), 7. 593 (1.19), 7.596 (1.17), 7.616 (2.16), 7.620 (2.74), 7.642 (1.96), 7.646 (2.00 ), 7.708 (1.70), 7.713 (1.73), 7.736 (2.77), 7.741 ( 2.42), 7.759 (1.54), 7.764 (1.52), 8.000 (5.39), 8.028 (4.63 ), 8.671 (4.05), 8.676 (4.40), 9.357 (5.29), 9.365 ( 5.43). The following example was prepared in analogy to exa mple34: Example 35 2‐methoxyethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ole]‐ 1‐carboxylate
(prepared from tert‐butyl 6'‐methyl‐2'‐(quinol in‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐ methoxyethyl carbonochloridoate (CAS‐RN: [628‐12‐ 6]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.470 (4 .28), 1.491 (4.25), 3.090 (0.68), 3.114 (0.81), 3.135 (0.67), 3.159 (0.60), 3.281 (16.00), 3.511 (1.60), 3.526 (1.81), 3.542 (1.81), 4.086 (0.48), 4.113 (0.79), 4.126 (1.86), 4.142 (1.85), 4.158 (1.77), 4.193 (1.27), 4.2 41 (0.89), 4.269 (0.50), 4.492 (0.42), 4.514 (0.72), 4.537 (0.71), 4.558 (0.42), 7.012 (4.56), 7.589 (0.43), 7.6 16 (1.06), 7.643 (0.80), 7.705 (0.63), 7.710 (0.66), 7.734 (1.04), 7.739 (0.88), 7.756 (0.56), 7.762 (0.58), 8.0 02 (1.21), 8.036 (1.10), 8.673 (1.40), 8.680 (1.63), 9.353 (2.12), 9.360 (2.26). The following examples (36 to 50) were prepared in analogy to the procedure described for example 19: Example 36 [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyr imidin‐ 4‐yl)methanone (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyri midine‐4‐carboxylic acid, CAS‐RN: [31462‐59‐6]) LC‐MS: (ES, m/z): 397 [M+H] + , H‐NMR: (300 MHz, DMSO‐d6, ppm): δ 9.43 9.23 (m, 2H), 9.09‐9.06 (m, 1H), 8.67 (d, J = 2.6 Hz, 1H), 8.04‐8.00 (m, 3H) , 7.76‐7.58 (m, 2H), 7.04 (s, 1H), 5.08‐4.75 (m, 2H), 4.63‐ 4.22 (m, 3H), 3.26‐3.06 (m, 1H), 2.62‐2.50 (m, 1 H), 1.51‐1.48 (m, 3H). Example 37
(1‐methyl‐1H‐pyrazol‐5‐yl)[6'‐methyl‐2'‐( quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 1‐ methyl‐1H‐pyrazole‐5‐carboxylic acid, CAS‐RN: [16034‐46‐1]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.500 (2 .14), 2.558 (0.75), 2.583 (0.76), 2.603 (0.82), 3.142 (0.42), 3.166 (0.47), 4.078 (16.00), 4.264 (0.46), 4.336 (0.66), 4.380 (0.52), 4.554 (0.72), 4.580 (0.79), 4.639 (0.56), 4.659 (0.59), 4.697 (0.48), 6.690 (0.68), 6.7 17 (0.69), 7.042 (5.17), 7.524 (1.46), 7.590 (0.54), 7.594 (0.56), 7.616 (1.26), 7.640 (0.89), 7.643 (0.92), 7.7 07 (0.76), 7.711 (0.82), 7.730 (0.63), 7.735 (1.25), 7.739 (1.04), 7.757 (0.71), 7.762 (0.70), 8.005 (1.56), 8.0 12 (1.37), 8.017 (1.33), 8.033 (1.34), 8.039 (1.35), 8.673 (1.76), 8.680 (1.88), 9.357 (2.37), 9.364 (2.45). Example 38 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐3‐(1H‐ pyrazol‐1‐yl)propan‐1‐one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐ (1H‐pyrazol‐1‐yl)propanoic acid, CAS‐RN: [89532 73‐ 0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.149 (0 .90), 1.463 (16.00), 1.484 (15.40), 2.074 (1.95), 2.2 73 (1.85), 2.628 (4.10), 2.650 (8.98), 2.669 (8.76), 2.6 90 (3.49), 3.037 (3.33), 3.062 (3.74), 3.083 (3.28), 3.107 (3.02), 3.999 (2.45), 4.030 (4.12), 4.069 (2.76), 4.0 99 (6.96), 4.127 (2.99), 4.155 (4.75), 4.172 (3.41), 4.200 (4.55), 4.238 (3.08), 4.264 (6.17), 4.287 (3.19), 4.333 (8.97), 4.358 (13.64), 4. 379 (6.18), 4.492 (2.50), 4.513 (4.36), 4.534 (4.25), 4.556 (2.36), 6.266 (7.21), 6.917 (11.21), 7.475 (5.57), 7.488 (5.99), 7.593 (2.94), 7.619 (6.02), 7.645 (4.89), 7.723 (10.87), 7. 761 (4.09), 8.004 (7.37), 8.028 (10.19), 8.051 (6.99) , 8.675 (9.77), 9.355 (10.32). Example 39
1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐2‐ (morpholin‐4‐yl)ethan‐1‐one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and morp holin‐4‐ylacetic acid, CAS‐RN: [3235‐69‐6]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.145 (0 .91), 1.476 (15.78), 1.497 (16.00), 2.073 (3.74), 2.2 71 (1.20), 2.456 (11.74), 2.726 (1.40), 3.050 (9.45), 3. 060 (8.59), 3.090 (2.28), 3.114 (2.44), 3.587 (11.97) , 3.603 (12.03), 4.039 (1.83), 4.072 (3.01), 4.112 (1.73), 4.142 (4.79), 4.174 (1.96), 4.197 (3.23), 4.228 (1.79), 4.397 (1.83), 4.428 (3.04), 4.456 (1.86), 4.4 85 (4.35), 4.508 (3.30), 4.529 (3.55), 4.550 (5.84), 4.572 (2.28), 6.981 (11.48), 7.591 (1.96), 7.616 (4.30), 7.642 (3.43), 7.710 (2.76), 7.734 (4.23), 7.761 (2.59), 8.001 (5.40), 8.017 (5.07), 8.030 (5.21), 8.041 (4.99 ), 8.685 (7.17), 9.357 (7.68), 9.364 (8.34). Example 40 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐2‐ (pyrimidin‐5‐yl)ethan‐1‐one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyri midin‐5‐ylacetic acid, CAS‐RN: [5267‐07‐2]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: ‐0.011 (1.28), 0.011 (0.80), 0.748 (1.11), 0.835 (0.86), 0.883 (0.76), 0.943 (0.77), 1.014 (0.81), 1.034 (2.59), 1.1 32 (2.74), 1.492 (11.97), 1.498 (12.10), 1.514 (12.07 ), 1.519 (11.38), 2.076 (0.65), 2.272 (0.58), 2.563 (3.06), 2.585 (2.43), 2.607 (1.51), 2.729 (0.46), 3.117 (1.94), 3.141 (3.73), 3.162 (3.28), 3.184 (3.27), 3.2 08 (1.92), 3.269 (1.11), 3.372 (1.76), 3.536 (1.09), 3.615
(11.21), 3.628 (10.93), 3.997 (0.59), 4.083 (1.92), 4.115 (3.25), 4.155 (1.82), 4.185 (4.35), 4.213 (1. 96), 4.238 (3.34), 4.270 (1.73), 4.466 (1.95), 4.495 (3.38 ), 4.547 (4.76), 4.564 (5.05), 4.605 (1.22), 4.621 ( 3.32), 4.650 (1.83), 7.012 (13.31), 7.597 (2.17), 7.600 (2.33), 7.623 (5.00), 7.650 (3.71), 7.712 (3.16), 7.717 (3.25), 7.736 (2.76), 7.741 (5.02), 7.745 (4.19), 7.7 63 (2.91), 7.768 (2.72), 8.009 (6.03), 8.029 (5.57), 8.036 (5.53), 8.052 (4.74), 8.191 (2.04), 8.249 (0.72), 8.6 84 (7.17), 8.691 (7.56), 8.713 (15.88), 8.721 (16.00) , 9.088 (10.69), 9.365 (8.72), 9.372 (8.81). Example 41 (3‐chlorophenyl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zol]‐ 1‐yl]methanone (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐ chlorobenzoic acid, CAS‐RN: [535‐80‐8]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.489 (8 .05), 2.270 (2.80), 2.727 (2.31), 4.346 (2.59), 4.540 (2.94), 4.635 (2.55), 7.041 (16.00), 7.522 (3.62), 7.549 (3.05), 7.612 (5.96), 7.640 (4.61), 7.734 (8.90), 7.762 (2.77), 8.002 (4.97), 8.014 (4.54), 8.029 (4.36), 8.6 77 (6.17), 9.350 (7.73), 9.357 (7.95). Example 42 [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyr idin‐4‐ yl)methanone (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyri dine‐4‐carboxylic acid, CAS‐RN: [55‐22‐1])
1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.827 (0 .77), 0.835 (0.77), 1.235 (1.70), 1.314 (1.30), 1.338 (2.23), 1.361 (1.29), 1.464 (8.06), 1.487 (11.39), 1.512 (7.51), 2.273 (1.09), 2.581 (3.74), 2.600 (3.42), 2.727 (1.08), 3.140 (2.90), 3.163 (3.19), 3.184 (2.86), 3.2 08 (2.61), 4.268 (1.79), 4.301 (3.01), 4.376 (4.79), 4.400 (2.47), 4.416 (3.40), 4.452 (1.68), 4.530 (3.18), 4.5 57 (4.94), 4.623 (3.61), 4.645 (3.87), 4.675 (3.43), 4.703 (1.66), 7.049 (16.00), 7.595 (2.36), 7.618 (5.32), 7. 646 (11.96), 7.712 (3.64), 7.736 (5.19), 7.758 (3.13) , 7.823 (1.19), 7.844 (1.22), 8.004 (6.56), 8.018 (6.34 ), 8.030 (6.21), 8.044 (5.83), 8.679 (7.74), 8.738 ( 8.57), 8.794 (1.66), 9.351 (8.38), 9.357 (8.96). Example 43 2‐ethyl‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo l]‐1‐ yl]butan‐1‐one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐ ethylbutanoic acid, CAS‐RN: [88‐09‐5]) 1 H‐NMR (300MHz, DMSO‐d 6 ): δ [ppm]= 0.74 ‐ 0.96 (m, 7H), 1.30 ‐ 1.59 (m, 7H), 2.03 ‐ 2.22 (m, 1H), 3.11 (dd, 1H), 4.00 ‐ 4.25 (m, 2H), 4.28 ‐ 4.61 (m, 3H), 6.94 (d, 1H), 7.56 ‐ 7.66 (m, 1H), 7.73 ( t, 1H), 8.02 (dd, 2H), 8.69 (s, 1H), 9.37 (d, 1H). Example 44 1‐{2‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]‐2‐ oxoethyl}pyrrolidin‐2‐one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐(2‐oxopyrrolidin‐1‐yl)ace tamide, CAS‐RN: [7491‐74‐ 9])
1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.479 (1 5.76), 1.500 (16.00), 1.919 (1.10), 1.945 (3.51), 1.9 70 (5.51), 1.995 (4.38), 2.019 (1.67), 2.238 (4.89), 2.2 64 (7.62), 2.291 (3.60), 2.558 (2.87), 2.576 (1.86), 2.729 (0.48), 3.101 (1.48), 3.124 (1.95), 3.140 (2.22), 3.1 60 (1.77), 3.182 (1.44), 3.380 (4.97), 3.404 (8.16), 3.426 (4.54), 3.919 (9.60), 3.934 (9.51), 4.067 (1.63), 4.0 99 (2.77), 4.142 (1.64), 4.172 (4.88), 4.201 (1.89), 4.224 (3.07), 4.257 (1.63), 4.350 (1.72), 4.379 (2.87), 4.4 38 (3.32), 4.452 (3.30), 4.509 (4.22), 4.534 (4.31), 4.554 (3.37), 4.576 (1.72), 7.017 (13.27), 7.594 (2.02), 7.619 (4.62), 7.643 (3.51), 7.710 (2.84), 7.738 (4.62), 7.761 (2.62), 8.005 (5.94), 8.018 (5.75), 8.032 (5.67 ), 8.044 (5.25), 8.686 (7.54), 9.358 (8.02), 9.364 ( 7.95). Example 45 [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyr idin‐3‐ yl)methanone (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyri dine‐3‐carboxylic acid, CAS‐RN: [59‐67‐6]) 1 H‐NMR (300 MHz, DMSO‐d 6 ): δ [ppm]= 1.48 (br t, 3H), 2.59 (br d, 1H ), 3.11 ‐ 3.23 (m, 1H), 4.23 ‐ 4.47 (m, 2H), 4.50 ‐ 4.74 (m, 3H), 7.04 (s, 1H), 7.48 ‐ 7.56 (m, 1H), 7.57 ‐ 7.65 (m, 1H), 7.73 (t , 1H), 8.02 (dd, 2H), 8.10 (br d, 1H), 8.64 ‐ 8.75 (m, 2H), 8.90 (br s, 1H), 9.35 (d, 1H). Example 46 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 1‐ cyanocyclopropanecarboxylic acid, CAS‐RN: [6914‐79‐ 0])
1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.487 (1 5.64), 1.509 (16.00), 1.584 (5.97), 1.619 (10.99), 2. 075 (1.38), 2.272 (0.52), 2.730 (0.60), 3.182 (1.32), 4.1 51 (1.14), 4.245 (2.20), 4.276 (2.04), 4.558 (1.92), 4.693 (1.26), 4.824 (2.82), 7.064 (14.76), 7.598 (2.16), 7.621 (4.83), 7.648 (3.62), 7.711 (2.94), 7.715 (3.10), 7.738 (4.81), 7.761 (2.66), 7.766 (2.70), 8.008 (6.01 ), 8.021 (5.37), 8.036 (5.33), 8.045 (5.27), 8.690 ( 7.11), 8.697 (7.61), 9.366 (9.17), 9.373 (9.65). Example 47 1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ethan‐1‐ one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and acet ic acid, CAS‐RN: [64‐19‐7]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.478 (1 2.08), 1.499 (12.52), 1.828 (15.71), 1.842 (16.00), 2 .077 (3.35), 2.557 (1.85), 3.077 (1.22), 3.100 (1.75), 3.1 19 (2.19), 3.139 (1.51), 3.144 (1.52), 3.162 (1.19), 4.010 (1.30), 4.042 (2.43), 4.076 (1.34), 4.106 (3.81), 4.1 35 (1.49), 4.164 (2.57), 4.196 (1.39), 4.299 (1.43), 4.327 (2.61), 4.367 (1.58), 4.382 (2.82), 4.395 (2.86), 4.4 10 (1.75), 4.453 (2.60), 4.481 (1.58), 4.509 (1.50), 4.530 (2.69), 4.553 (2.69), 4.574 (1.47), 6.990 (13.40), 7.595 (1.65), 7.618 (3.75), 7.645 (2.77), 7.708 (2.16), 7.713 (2.35), 7.736 (3.67), 7.741 (3.22), 7.759 (2.05 ), 7.764 (2.02), 8.006 (4.77), 8.018 (4.34), 8.033 ( 4.28), 8.042 (4.12), 8.678 (5.45), 8.684 (5.85), 9.357 (6.37 ), 9.365 (6.62). Example 48 (1‐methyl‐1H‐imidazol‐5‐yl)[6'‐methyl‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone
(prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 1‐methyl‐1H‐imidazole‐5‐carboxylic acid, CAS‐RN: [41806‐40‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.494 (5 .11), 1.516 (5.17), 2.561 (1.02), 2.585 (1.06), 2.606 (1.01), 3.142 (1.14), 3.167 (1.32), 3.187 (1.17), 3.211 (1.11), 3.884 (1.94), 3.911 (16.00), 4.376 (0.51), 4.555 (1.04), 4.578 (1.06), 6.636 (0.45), 6.643 (0.47), 7.0 27 (6.67), 7.145 (0.48), 7.309 (0.50), 7.602 (0.76), 7.625 (1.78), 7.651 (1.38), 7.682 (1.74), 7.716 (1.12), 7.7 20 (1.17), 7.744 (1.67), 7.749 (1.41), 7.767 (1.00), 7.771 (1.26), 8.009 (1.93), 8.025 (1.73), 8.036 (1.75), 8.0 48 (1.58), 8.261 (0.42), 8.270 (0.48), 8.305 (2.17), 8.389 (0.50), 8.398 (0.44), 8.690 (2.35), 8.697 (2.51), 9.3 61 (3.36), 9.368 (3.41). Example 49 3‐methoxy‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zol]‐1‐ yl]propan‐1‐one (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐ methoxypropanoic acid, CAS‐RN: [2544‐06‐1]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.475 (9 .10), 1.496 (9.32), 2.326 (1.75), 2.347 (4.30), 2.364 (4.40), 2.384 (1.92), 3.084 (1.11), 3.101 (1.23), 3.107 (1.26 ), 3.121 (1.10), 3.127 (1.11), 3.145 (1.04), 3.151 ( 1.01), 3.248 (16.00), 3.255 (15.94), 3.541 (2.43), 3.546 (2. 59), 3.562 (4.90), 3.568 (4.90), 3.583 (2.52), 3.589 (2.36), 4.020 (0.99), 4.052 (1.79), 4.090 (0.99), 4.1 18 (2.64), 4.148 (1.10), 4.174 (1.89), 4.207 (0.99), 4.315 (1.03), 4.344 (1.85), 4.379 (1.18), 4.395 (2.06), 4.4 08 (2.02), 4.423 (1.20), 4.469 (1.80), 4.498 (1.31), 4.505 (1.30), 4.528 (1.97), 4.549 (1.93), 4.570 (1.02), 6.9 71 (7.00), 7.591 (1.21), 7.614 (2.77), 7.641 (2.04), 7.704 (1.61), 7.708 (1.73), 7.732 (2.73), 7.736 (2.33), 7.7 55 (1.51), 7.759 (1.45), 8.001 (3.59), 8.010 (3.24), 8.029 (3.22), 8.037 (3.09), 8.677 (4.15), 8.683 (4.38), 9.3 55 (4.99), 9.362 (5.09). Example 50
4‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl] ‐4‐ oxobutanenitrile (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐ cyanopropanoic acid, CAS‐RN: [16051‐87‐9]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.148 (0 .41), 1.481 (15.52), 1.503 (16.00), 2.076 (5.37), 2.2 72 (0.71), 2.561 (6.31), 2.637 (5.03), 2.659 (6.98), 2.6 80 (2.99), 2.728 (0.90), 3.099 (1.92), 3.117 (2.11), 3.123 (2.17), 3.137 (1.91), 3.144 (1.88), 3.161 (1.76), 3.1 67 (1.74), 4.061 (1.59), 4.093 (2.68), 4.135 (1.58), 4.165 (4.42), 4.193 (1.80), 4.218 (2.98), 4.250 (1.60), 4.3 29 (1.61), 4.358 (2.96), 4.391 (2.03), 4.404 (3.28), 4.419 (3.15), 4.432 (2.03), 4.483 (2.83), 4.514 (2.73), 4.538 (3.03), 4.560 (2.97), 4.5 81 (1.58), 6.979 (10.30), 6.982 (10.48), 7.592 (2.01), 7.596 (2.09), 7.618 (4.51), 7.642 (3.30), 7.645 (3.27), 7.708 (2.85), 7.713 (3.00), 7.732 (2.82), 7.737 (4.66), 7.741 (3.98), 7.7 59 (2.69), 7.764 (2.57), 8.003 (5.28), 8.022 (5.28), 8.030 (5.21), 8.044 (4.49), 8.674 (6.36), 8.680 (6.69), 9.3 51 (7.17), 9.357 (7.41). Example 51 1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole] Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Into a 40 mL vial, 2‐methylpyrimidine‐5‐ carbaldehyde (29.2 mg, 0.239 mmol, 1.00 equiv) and crude product 2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (84 mg, 1.00 equiv, 0.217 mmol,
1.00 equiv) were dissolved in MeOH (3 mL) followe d by 2 drops of DIEA. The mixture was stirred for 1 h at room temperature. NaBH 3 CN (1.50 equiv) was added. The mixture was stirred for one h at room temperature. The residue was purified by HPLC to aff ord the title compound. 1 H‐NMR (300 MHz, DMSO‐ d6) δ [ppm]: 2.611 (16.00), 2.827 (1.89), 2.850 (3.02), 2.874 (2.03), 3.342 (0.55), 3.441 (1.71), 3.464 (5.63), 3.475 (5.69), 3.498 (1.69), 4.165 (2.01), 4.1 89 (3.09), 4.211 (1.96), 6.951 (7.62), 7.593 (0.80), 7.619 (1.64), 7.643 (1.31), 7.646 (1.37), 7.706 (1.19), 7.7 11 (1.09), 7.734 (1.64), 7.739 (1.65), 7.757 (1.03), 7.762 (1.04), 7.998 (4.19), 8.029 (3.64), 8.140 (4.04), 8.665 (11.83), 8.689 (3.15), 8.697 (3.28), 9.366 (3.91), 9.374 (4.01). The following compounds (example 52 to example 61) w ere synthesized in analogy to example 51: Example 52 N,N‐dimethyl‐5‐{[2'‐(quinolin‐3‐yl)‐5',6'‐di hydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]methyl}‐1,3‐thiazol‐2‐amine (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(dimethylamino)‐1 ,3‐thiazole‐5‐carbaldehyde (CAS‐RN: [1005‐28‐3 ]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.813 (0.99), 2.836 (1.73), 2.859 (1.13), 3.000 (16.00), 3.352 (1.59), 3.376 (2.54), 3.413 (2.49), 3.436 (1.32), 3.6 53 (3.34), 4.161 (1.09), 4.184 (1.72), 4.208 (1.01), 6.906 (2.87), 6.996 (2.36), 7.591 (0.46), 7.617 (0.94), 7.6 40 (0.79), 7.704 (0.60), 7.731 (0.96), 7.755 (0.55), 7.995 (2.19), 8.023 (1.98), 8.693 (1.58), 9.359 (1.66), 9.3 66 (1.79). Example 53 1‐[(1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1H‐imidazole‐2‐ca rbaldehyde, CAS‐RN: [10111‐08‐7])
1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.075 (1 .90), 2.272 (1.84), 2.727 (1.73), 2.816 (4.32), 2.839 (6.93), 2.862 (4.69), 3.432 (4.49), 3.456 (12.06), 3.473 (11. 80), 3.495 (4.36), 3.654 (16.00), 4.161 (4.71), 4.185 (7.19), 4.209 (4.45), 6.901 (14.58), 7.591 (2.15), 7.616 (3.83), 7.643 (3.19), 7.702 (2.59), 7.731 (3.72), 7.753 (2.17), 7.995 (9.12), 8.025 (7.97), 8.674 (6.77 ), 9.351 (7.66), 9.358 (7.77), 11.877 (1.97). Example 54 1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyrazolo[1,5‐a]pyrimi dine‐3‐carbaldehyde, CAS‐RN: [879072‐59‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.274 (0.43), 2.796 (2.97), 2.818 (5.11), 2.842 (3.40), 3.449 (16.00), 3.840 (11.18), 4.148 (3.20), 4.171 (5.26), 4 .194 (3.27), 6.898 (9.69), 7.015 (2.54), 7.028 (2.78) , 7.038 (2.91), 7.052 (2.88), 7.590 (1.29), 7.614 (2.92 ), 7.640 (2.21), 7.705 (1.87), 7.728 (2.89), 7.751 ( 1.74), 7.990 (5.28), 8.018 (4.68), 8.232 (8.66), 8.550 (3.13 ), 8.556 (3.69), 8.564 (3.73), 8.569 (3.62), 8.691 ( 4.85), 9.078 (3.09), 9.083 (3.44), 9.101 (3.45), 9.107 (3.50 ), 9.359 (5.18), 9.366 (5.80). Example 55 1‐[(1H‐indazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1H‐indazole‐3‐car baldehyde, CAS‐RN: [5235‐10‐9]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.144 (0 .79), 2.271 (1.18), 2.726 (0.96), 2.813 (3.00), 2.835 (5.16), 2.859 (3.15), 3.479 (16.00), 3.994 (10.64), 4.148 (3. 17), 4.172 (5.31), 4.195 (3.09), 6.897 (8.03), 7.109 (1.72), 7.132 (3.16), 7.156 (2.27), 7.318 (1.72), 7.3 46 (3.11), 7.369 (2.15), 7.482 (4.04), 7.510 (3.15), 7.590
(1.32), 7.612 (3.06), 7.638 (2.39), 7.702 (1.95), 7.729 (2.99), 7.755 (1.90), 7.901 (3.33), 7.928 (3.28 ), 7.992 (6.57), 8.021 (5.92), 8.679 (4.97), 9.356 (5.17), 12. 839 (4.52). Example 56 1‐(cyclohexylmethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and cyclohexanecarbaldehyde , CAS‐RN: [2043‐61‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.868 (3 .42), 0.907 (4.15), 0.945 (2.06), 1.110 (1.29), 1.183 (5.29), 1.227 (3.13), 1.270 (2.29), 1.649 (6.34), 1.682 (3.47 ), 1.731 (4.75), 1.775 (4.40), 2.284 (5.56), 2.305 ( 5.39), 2.806 (5.24), 2.829 (8.67), 2.853 (5.77), 3.380 (6.53), 4.155 (6.65), 4.179 (9.84), 4.202 (6.30), 6.894 (16.00), 7.586 (2.39), 7.613 (5.54), 7.639 (4.33), 7.699 (3.48), 7.704 (3.40), 7.726 (5.35), 7.732 (5.05), 7.750 (3.08), 7.755 (3.26), 7.994 (11.73), 8.022 (10. 97), 8.687 (8.31), 8.694 (8.92), 9.363 (11.38), 9.371 (11.85). Example 57 6'‐methyl‐1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2 '‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐ methylpyrimidine‐5‐carbaldehyde, CAS‐RN: [90905‐ 33‐2]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.236 (0 .47), 1.448 (7.45), 1.469 (7.62), 2.272 (0.49), 2.396 (1.37), 2.416 (1.37), 2.441 (1.58), 2.460 (1.77), 2.607 (16.00), 2.694 (0.43), 2.728 (0.41), 3.016 (1.21), 3.042 (1.39), 3.061 (1.25), 3.086 (1.08), 3.372 (1.47), 3.3 95 (2.30), 3.435 (1.29), 3.455 (3.82), 3.475 (1.39), 3.495 (2.41), 3.519 (1.24), 3.664 (6.26), 4.453 (0.72), 4.4 73 (1.26), 4.495 (1.20), 4.518 (0.75), 6.928 (7.69), 7.592
(0.92), 7.615 (1.92), 7.642 (1.51), 7.707 (1.26), 7.730 (1.94), 7.735 (1.69), 7.758 (1.12), 8.000 (2.30 ), 8.015 (2.06), 8.028 (2.15), 8.039 (1.93), 8.656 (12.10), 8. 689 (2.77), 8.696 (3.09), 9.364 (3.86), 9.371 (3.84). Example 58 N,N‐dimethyl‐5‐{[6'‐methyl‐2'‐(quinolin‐3‐yl )‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b] pyrazol]‐ 1‐yl]methyl}‐1,3‐thiazol‐2‐amine (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐(dimethylamino)‐1,3‐thiazol e‐5‐carbaldehyde, CAS‐ RN: [1005‐28‐3]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.448 (3 .06), 1.470 (3.05), 2.386 (0.53), 2.405 (0.56), 2.430 (0.63), 2.449 (0.67), 2.999 (16.00), 3.027 (0.72), 3.047 (0.55), 3.072 (0.47), 3.302 (0.95), 3.387 (0.50), 3.410 (2.06), 3.431 (1.84), 3.454 (0.52), 3.652 (2.74), 4.4 73 (0.52), 4.495 (0.53), 6.888 (2.87), 6.995 (2.10), 7.613 (0.78), 7.640 (0.60), 7.705 (0.51), 7.729 (0.77), 7.7 52 (0.44), 7.757 (0.45), 8.000 (0.99), 8.013 (0.94), 8.027 (0.93), 8.037 (0.92), 8.690 (1.17), 8.696 (1.31), 9.3 60 (1.45), 9.367 (1.60). Example 59 6'‐methyl‐1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)meth yl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetid ine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyrazolo¬[1,5‐a]pyrimidine‐3‐carbaldehyde, CAS RN: [879072‐59‐0])
1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.931 (1.57), 0.952 (1.46), 1.231 (0.52), 1.436 (15.93), 1.457 (15.66), 2.273 (0.67), 2.368 (2.72), 2.388 (2.84), 2.412 (3.12), 2.432 (3.22), 2.729 (0.51), 2.987 (2.68), 3.012 (3.03), 3.031 (2.72), 3.056 (2.46), 3.375 (3.59 ), 3.398 (5.44), 3.427 (3.27), 3.446 (8.24), 3.465 ( 3.03), 3.502 (5.18), 3.525 (3.17), 3.594 (0.94), 3.837 (14.95), 4.436 (1.50), 4.457 (2.83), 4.481 (2.53), 4.501 (1.50), 6.880 (16.00), 7.014 (4.30), 7.028 (4.31), 7.038 (4.44), 7.051 (4.54), 7.588 (1.78), 7.611 (4.03), 7.638 (3.04), 7.699 (2.48), 7.703 (2.66), 7.727 (3.94 ), 7.731 (3.52), 7.749 (2.18), 7.754 (2.29), 7.999 ( 7.03), 8.027 (6.41), 8.138 (0.59), 8.231 (14.03), 8.550 (4.84), 8.555 (5.35), 8.563 (5.18), 8.569 (4.95), 8.688 (5.76), 8.695 (6.32), 9.077 (4.93), 9.083 (5.16), 9.1 01 (5.34), 9.107 (5.06), 9.359 (8.07), 9.366 (8.33). Example 60 1‐[(1H‐indazol‐3‐yl)methyl]‐6'‐methyl‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and 1H‐indazole‐3‐carbaldehyde, CAS‐RN: [5235‐10‐ 9]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: ‐0.007 (0.95), 0.946 (0.71), 1.230 (1.04), 1.429 (15.69), 1.451 (15.78), 2.270 (0.91), 2.377 (2.67), 2.397 (2.82), 2.421 (3.10), 2.441 (3.19), 2.720 (0.90), 3.001 (2.70), 3.025 (3.01), 3.044 (2.65), 3.069 (2.54), 3.397 (3.74), 3.419 (5.63), 3.450 (3.66), 3.471 (10.25), 3.492 (3.64), 3.526 (5.53), 3.549 (3.60), 3.985 (16.00), 4.430 (1.77), 4.451 (2.98), 4.475 (3.07), 4.496 (1.74), 6.871 (15.27), 7.101 (2.57), 7.124 (4.95), 7.150 (3.40), 7.313 (2.90), 7.337 (4.70), 7.364 (3.26), 7.475 (6.57), 7.503 (4.81), 7.581 (2.12), 7.604 (4.59), 7.6 27 (3.35), 7.696 (3.13), 7.720 (4.56), 7.724 (4.23), 7.748 (2.70), 7.895 (5.46), 7.921 (5.26), 7.991 (5.95), 8.019 (5.71), 8.677 (7.29), 9.348 (8.02), 9.355 (8.64), 12.833 (2.47). Example 61
1‐(cyclohexylmethyl)‐6'‐methyl‐2'‐(quinolin‐3 ‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 ‐ b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and cyclohexanecarbaldehyde, CAS‐RN: [2043‐61‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: ‐0.022 (0.70), 0.833 (1.32), 0.863 (2.97), 0.903 (3.66), 0.941 (1.73), 1.151 (4.29), 1.181 (4.60), 1.232 (5.96), 1.2 54 (2.74), 1.447 (15.70), 1.469 (16.00), 1.647 (5.27) , 1.730 (3.89), 1.774 (3.51), 2.075 (4.63), 2.277 (8.94 ), 2.300 (8.32), 2.377 (2.72), 2.396 (2.92), 2.421 ( 3.15), 2.440 (3.32), 2.728 (0.60), 2.996 (2.72), 3.020 (3.07 ), 3.040 (2.71), 3.064 (2.59), 3.247 (4.10), 3.269 ( 5.39), 3.374 (14.84), 3.389 (5.46), 4.444 (1.48), 4.465 (2.6 1), 4.488 (2.66), 4.508 (1.59), 6.876 (14.45), 7.588 (1.78), 7.610 (4.07), 7.637 (3.12), 7.702 (2.62), 7.7 26 (3.98), 7.749 (2.29), 7.753 (2.30), 7.998 (5.31), 8.030 (5.15), 8.693 (5.95), 8.699 (6.45), 9.363 (7.38), 9.3 70 (7.83). Example 62 1‐(cyclopropanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6 '‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole ] Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Into a 40 mL via, crude 2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq.) was dissolved in DMF (3 mL) and was cooled in an ice bath. DIPEA (201 mg, 1.56 mmol, 10 equiv) was adde d. Then cyclopropanesulfonyl chloride, (33 mg, 1.50 eq., 0.234 mmol, CAS‐RN: [139631‐62‐2]) was added slowly to the above solution. The reaction mixture w as allowed to ambient temperature and stirred for 3 h. The mixture was diluted with 1 mL of water. The mixture was purified by HPLC to afford the titl e compound. 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.982 (1 .30), 0.998 (4.59), 1.006 (4.87), 1.014 (4.58), 1.021 (5.40), 1.034 (1.96), 1.072 (0.69), 1.086 (0.54 ), 1.098 (0.54), 1.122 (2.51), 1.135 (4.43), 1.144 ( 4.90), 1.162 (5.15), 1.169 (3.60), 1.185 (1.10), 2.073 (0.54 ), 2.866 (0.89), 2.883 (1.75), 2.893 (1.96), 2.909 ( 3.36), 2.925 (1.98), 2.935 (2.37), 2.945 (4.41), 2.968 (6.68), 2.991 (4.48), 4.155 (5.36), 4.182 (13.18), 4.212 (16.00), 4.239 (12.41), 4.263 (4.52), 7.024 (15.56), 7.595 (1.63), 7.622 (3.54), 7.645 (2.65), 7.649 (2.80 ), 7.710 (2.35), 7.715 (2.18), 7.737 (3.48), 7.742 (3.29 ), 7.761 (1.99), 7.765 (2.07), 8.004 (7.77), 8.032 ( 7.46), 8.702 (5.75), 8.709 (5.88), 9.381 (7.64), 9.388 (7.72 ).
The following compound (example 63) was synthesized in analogy to example 62: Example 63 1‐(cyclopropanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐ 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1, 2‐ b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and cyclopropanesulfonyl chloride, CAS‐RN: [139631‐ 62‐2]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.980 (1 .49), 0.996 (5.08), 1.003 (5.65), 1.018 (5.85), 1.032 (2.34), 1.070 (0.70), 1.137 (4.82), 1.147 (4.37), 1.163 (5.24 ), 1.483 (15.76), 1.504 (16.00), 2.272 (0.55), 2.573 (3.08), 2.594 (3.06), 2.728 (0.60), 2.872 (0.84), 2.8 89 (1.72), 2.899 (2.00), 2.915 (3.32), 2.931 (1.94), 2.941 (1.77), 2.957 (0.88), 3.137 (2.69), 3.161 (3.04), 3.181 (2.62), 3.205 (2.48), 4.1 48 (4.70), 4.170 (13.04), 4.198 (1.70), 4.295 (6.14), 4.322 (4.57), 4.512 (1.55), 4.535 (2.90), 4.557 (2.94), 4.579 (1.57), 7.016 (14.69), 7.598 (1.77), 7.621 (4.08), 7.648 (3.13), 7.714 (2.63), 7.738 (3.91), 7.742 (3.63), 7.761 (2.27), 7.765 (2.32), 8.008 (5.04), 8.023 (4.71), 8.036 (4.72 ), 8.047 (4.50), 8.709 (5.99), 8.715 (6.68), 9.383 ( 7.38), 9.390 (8.11). Example 64 N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐ carboxamide Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next
step without further purification. Step 2: Into a 40 mL via, 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate ((61 mg , 0.156 mmol, 1 eq., 1.00 eq) was dissolved in 3 mL DMF and was cooled in an ice‐bath. DIPEA (201 mg, 1.56 mmol, 10 eq, 1.56 mmol) was added. Then 3‐ isocyanatopyridine, (28 mg, 0.234 mmol, 1.5 eq., CAS RN: [15268‐31‐2]) was added slowly to the above solution. The reaction mixture was stirred at ambient temperature for 3 h. The mixture was diluted with 1 mL of water. The mixture was purified by HPLC to afford the title compound. 1 H‐NMR (300 MHz, DMSO‐ d6) δ [ppm]: 2.940 (1.78), 2.963 (3.11), 2.986 (2.06), 4.234 (2.41), 4.259 (16.00), 7.047 (6.32), 7.276 (1.20), 7.292 (1.38), 7.304 (1.50), 7.320 (1.56), 7.5 94 (0.73), 7.619 (1.78), 7.646 (1.45), 7.712 (1.12), 7.735 (1.76), 7.763 (0.99), 7.955 (1.34), 7.999 (3.79), 8.0 27 (3.27), 8.169 (2.11), 8.181 (2.13), 8.691 (3.01), 8.704 (2.98), 8.712 (3.07), 8.846 (3.60), 9.370 (3.25), 9.3 77 (3.66). The following compounds (example 65 to example 67) w ere synthesized in analogy to example 64: Example 65 N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[ azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxami de (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxylate (see example 2) and isocyanatoethane, CAS RN: [109‐90‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.009 (5.01), 1.025 (3.86), 1.033 (11.37), 1.047 (5.48), 1.056 (5.25), 1.071 (2.15), 2.870 (1.90), 2.894 (3.14), 2.9 17 (2.10), 3.011 (0.71), 3.035 (2.19), 3.054 (2.49), 3.059 (2.46), 3.078 (2.18), 3.103 (0.93), 3.109 (1.07), 3.1 27 (1.06), 3.133 (1.03), 3.151 (0.94), 3.649 (0.71), 3.672 (0.70), 4.030 (16.00), 4.200 (2.05), 4.224 (3.16), 4.246 (1.96), 6.462 (0.92), 6.481 (1.85), 6.499 (0.94), 6.984 (7.93), 7.590 (0.82), 7.594 (0.86), 7.617 (1.92 ), 7.640 (1.35), 7.644 (1.40), 7.705 (1.13), 7.710 ( 1.26), 7.733 (1.91), 7.738 (1.59), 7.756 (1.04), 7.761 (1.04 ), 7.991 (2.17), 7.998 (2.42), 8.018 (1.81), 8.026 ( 2.10), 8.680 (2.78), 8.686 (2.87), 9.364 (3.88), 9.372 (3.86 ). Example 66
6'‐methyl‐N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐ 1‐carboxamide (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐ isocyanatopyridine, CAS‐RN: [15268‐31‐2]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.166 (5.94), 1.188 (5.94), 1.242 (1.69), 1.264 (1.74), 1.496 (15.02), 1.517 (15.19), 2.272 (0.51), 2.569 (2.70), 2 .589 (2.56), 2.729 (0.51), 3.123 (2.35), 3.146 (2.81) , 3.167 (2.40), 3.191 (2.20), 3.681 (0.40), 4.171 (3.24 ), 4.199 (5.41), 4.236 (3.13), 4.256 (6.01), 4.264 ( 6.16), 4.284 (3.33), 4.318 (5.44), 4.346 (3.21), 4.533 (1.47 ), 4.555 (2.61), 4.578 (2.80), 4.599 (1.42), 4.898 ( 0.65), 4.941 (0.66), 7.035 (16.00), 7.275 (2.85), 7.291 (2.99), 7.303 (3.11), 7.318 (3.23), 7.404 (0.73), 7.447 (0.66), 7.594 (1.72), 7.617 (3.87), 7.644 (2.93), 7.7 07 (2.32), 7.711 (2.51), 7.735 (3.77), 7.739 (3.26), 7.758 (2.18), 7.762 (2.15), 7.947 (2.12), 7.952 (2.76), 7.9 60 (2.60), 7.974 (2.15), 7.983 (2.71), 7.988 (2.37), 8.005 (5.10), 8.037 (4.80), 8.098 (0.65), 8.164 (4.15), 8.1 69 (4.35), 8.180 (4.32), 8.184 (4.22), 8.689 (5.54), 8.696 (6.40), 8.702 (7.08), 8.711 (6.63), 8.842 (7.81), 9.3 69 (7.86), 9.377 (8.11). Example 67 N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxamide (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and isocyanatoethane, CAS‐RN: [109‐90‐0]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.922 (0.48), 0.943 (0.55), 1.006 (7.54), 1.030 (16.00), 1.054 (7.68), 1.471 (12.15), 1.492 (12.33), 2.455 (2.84), 2 .475 (4.20), 2.728 (0.46), 3.008 (1.33), 3.032 (3.85) , 3.055 (6.48), 3.075 (5.11), 3.098 (3.18), 3.122 (2.01 ), 3.947 (2.82), 3.974 (5.23), 3.997 (3.40), 4.022 ( 7.28),
4.046 (3.04), 4.097 (4.88), 4.123 (3.19), 4.496 (1 .32), 4.517 (2.34), 4.539 (2.36), 4.560 (1.33), 6.455 (1.68), 6.473 (3.36), 6.492 (1.83), 6.970 (11.03), 7.591 (1.39), 7.614 (3.14), 7.641 (2.46), 7.708 (2.01), 7.732 (3.05), 7.759 (1.84), 8.002 (6.55), 8.031 (5.93), 8.6 84 (4.78), 8.690 (5.35), 9.363 (5.66), 9.370 (6.18). Example 68 1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Into a 40 mL vial, was placed a solution of crude 2'‐(quin olin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq .) in dioxane (3 mL). Then 3‐bromopyridine, (37 mg, 0 .234 mmol, 1.5 eq., CAS‐RN: [626‐55‐1]) and Cs 2 CO 3 (153 mg, 0.468 mmol, 3 equiv) were added, Xantphos (18.1 mg, 0.0312 mmol, 0.20 equiv), Pd 2 (dba) 3 (14.3 mg, 0.0156 mmol, 0.10 equiv) was added, protec ted by nitrogen. The mixture was stirred overnight at 100 °C. The residue was purified by HPLC to af ford the title compound. 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.266 (0.99), 2.734 (1.48), 2.984 (5.25), 3.007 (8.80), 3.030 (5.71), 4.120 (6.11), 4.145 (16.0 0), 4.170 (15.81), 4.195 (7.09), 4.252 (5.72), 4.275 (9.11), 4.298 (6.01), 6.940 (2.85), 6.966 (3.76), 6.998 (15.36), 7.208 (3.71), 7.224 (4.23), 7.235 (3.72), 7.251 (3.71), 7.585 (2.04), 7.610 (4.60), 7.636 (3.80), 7.705 (3.03), 7.729 (4.47), 7.756 (3.04), 7.936 (5.77), 7.944 (6.56), 7.979 (5.12), 7.994 (11.27), 8.006 (10.68), 8.021 (7.27), 8.678 (8.07), 9.357 (7.71), 9. 364 (9.11). The following compound (example 69) was synthesized i n analogy to example 68: Example 69
6'‐methyl‐1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3 ‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 ‐b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and 3‐bromopyridine, CAS‐RN: [626‐55‐1]) 1 H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.234 (0 .61), 1.509 (15.79), 1.530 (16.00), 2.075 (2.53), 2.5 61 (2.72), 2.581 (2.69), 2.605 (2.83), 2.625 (2.85), 3.1 69 (2.62), 3.194 (2.99), 3.214 (2.60), 3.238 (2.46), 4.064 (3.91), 4.088 (5.89), 4.151 (3.00), 4.165 (6.39), 4.1 75 (7.32), 4.190 (4.66), 4.203 (7.23), 4.228 (3.15), 4.547 (1.51), 4.568 (2.67), 4.591 (2.70), 4.612 (1.52), 6.9 27 (2.28), 6.932 (2.29), 6.954 (2.78), 6.959 (3.03), 6.981 (15.22), 7.206 (3.17), 7.221 (3.47), 7.233 (2.87), 7.249 (2.94), 7.581 (1.65), 7.608 (3.61), 7.635 (2.91), 7.699 (2.36), 7.704 (2.25), 7.727 (3.53), 7.732 (3.44), 7.754 (2.20), 7.930 (5.38), 7.939 (5.64), 7.994 (12.83), 8.006 (5.83), 8.024 (8.47), 8.677 (5.99), 8. 684 (6.49), 9.357 (7.47), 9.364 (7.89). Example 70 N‐(2‐chloroethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxamide Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (50.0 mg, 181 µmol) was dissolved in DCM (2.1 ml), DIPEA (95 µl, 540 µmol; CAS‐RN:[7087‐68‐5]) was added, c ooled to 0°C and 1‐chloro‐2‐isocyanatoethane (19 .1 mg, 181 µmol) was added and the mixture was stirred ov ernight at ambient temperature. The mixture was evaporated and purified by preparative HPLC to yield the title compound (4.80 mg, 7 % yield). LC‐MS (Method 1): Rt = 0.93 min; MS (ESIpos): m/z = 382 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.073 (1.94), 2.517 (3.68), 2.522 (2.31), 2.884 (1.84), 2.9 01 (2.95), 2.919 (2.01), 3.299 (0.47), 3.310 (1.37), 3.585 (2.78), 3.601 (5.42), 3.618 (2.14), 4.061 (16.00), 4.103 (0.40), 4.206 (2.04), 4.223 (3.15), 4.240 (1.94), 6.834 (0.94), 6.848 (1.91), 6.862 (0.87), 6.992 (8.10 ), 7.596 (0.87), 7.599 (0.87), 7.617 (1.91), 7.634 ( 1.27), 7.636 (1.27), 7.710 (1.14), 7.714 (1.21), 7.727 (1.00 ), 7.731 (1.94), 7.735 (1.41), 7.749 (1.00), 7.752 ( 1.00), 7.991 (2.01), 7.998 (2.31), 8.009 (1.71), 8.019 (2.01 ), 8.682 (2.74), 8.687 (2.74), 9.362 (3.88), 9.367 ( 3.85).
The following compounds (example 71 to example 79) were synthesized in analogy to example 70: Example 71 N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxamide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐isocyanatopropane, CAS‐RN: [1795‐48‐8]) LC‐MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 362 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.995 (1 .07), 1.012 (1.08), 1.064 (15.84), 1.081 (16.00), 1.2 43 (0.45), 1.260 (0.47), 2.518 (2.04), 2.523 (1.29), 2.5 40 (0.54), 2.869 (1.56), 2.886 (2.36), 2.904 (1.68), 3.715 (0.54), 3.731 (0.79), 3.751 (0.80), 3.767 (0.55), 4.017 (13.64), 4.202 (1.73), 4.221 (2.54), 4.237 (1.60), 5.759 (0.63), 6.254 (1.53), 6.273 (1.49), 6.990 (7.79 ), 7.596 (0.72), 7.599 (0.76), 7.613 (1.09), 7.617 ( 1.57), 7.634 (1.06), 7.636 (1.07), 7.710 (1.00), 7.713 (1.05 ), 7.727 (0.85), 7.731 (1.62), 7.734 (1.20), 7.748 ( 0.91), 7.752 (0.87), 7.991 (1.54), 8.000 (1.75), 8.007 (1.40 ), 8.011 (1.31), 8.019 (1.54), 8.683 (2.15), 8.688 ( 2.24), 9.364 (3.41), 9.370 (3.45). Example 72 2'‐(quinolin‐3‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxamide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1,1,1‐trifluoro‐2 isocyanatoethane, CAS‐RN: [371‐92‐6]) LC‐MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 402 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (0.82), 2.522 (0.56), 2.539 (16.00), 2.897 (0.54), 2.914 (0.83), 2.932 (0.57), 3.821 (0.43), 3.829 (0.40), 3.8 45 (0.40), 4.111 (3.46), 4.209 (0.58), 4.227 (0.89), 4.244
(0.57), 5.758 (0.57), 7.006 (2.78), 7.233 (0.56), 7.617 (0.56), 7.732 (0.61), 7.736 (0.45), 7.992 (0.54 ), 7.998 (0.61), 8.008 (0.49), 8.012 (0.46), 8.020 (0.55), 8.6 83 (0.77), 8.689 (0.80), 9.363 (1.22), 9.368 (1.21). Example 73 N‐cyclopentyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydro spiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and isocyanatocyclopentane, CAS‐RN: [4747‐71‐1]) LC‐MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 388 [M+H] + 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 1.34 ‐ 1.43 (m, 2H), 1.44 ‐ 1.52 (m, 2H), 1.59 ‐ 1.67 (m, 2H), 1.74 ‐ 1.85 (m, 2H), 2.89 (t, 2H), 3.84 ‐ 3.96 (m, 1H), 4.02 (s, 4H), 4.22 (t, 2H), 6.34 (d, 1H), 6. 99 (s, 1H), 7.62 (ddd, 1H), 7.73 (ddd, 1H), 8.00 (td, 2H), 8.68 (d, 1H), 9.36 (d, 1H). Example 74 N‐tert‐butyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydr ospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐isocyanato‐2‐me thylpropane, CAS‐RN: [1609‐86‐5]) LC‐MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 376 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.200 (1.06), 1.272 (16.00), 2.518 (1.48), 2.522 (0.98), 2.857 (0.58), 2.874 (0.86), 2.892 (0.61), 4.010 (5.01), 4.2 00 (0.62), 4.218 (0.92), 4.235 (0.59), 5.853 (1.17), 6.977 (2.94), 7.617 (0.60), 7.637 (0.40), 7.731 (0.62), 7.7 35 (0.45), 7.991 (0.56), 7.997 (0.63), 8.008 (0.50), 8.012 (0.48), 8.019 (0.56), 8.685 (0.79), 8.690 (0.82), 9.3 64 (1.29), 9.370 (1.22). Example 75
methyl [2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[aze tidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]carbamate (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and methyl carbonisocyanat idoate, CAS‐RN: [5843‐42‐5]) LC‐MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 378 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (0.60), 2.886 (1.41), 2.904 (2.22), 2.921 (1.54), 3.636 (16.00), 3.688 (0.80), 4.038 (0.62), 4.201 (2.31), 4.219 (4.30), 4.236 (2.64), 6.984 (0.48), 6.997 (6.53), 7.595 (0.74), 7.598 (0.71), 7.612 (1.09), 7.615 (1.56 ), 7.633 (1.02), 7.636 (1.02), 7.710 (0.93), 7.714 ( 0.92), 7.728 (0.86), 7.731 (1.53), 7.735 (1.13), 7.749 (0.84 ), 7.752 (0.80), 7.997 (2.33), 8.014 (1.39), 8.018 ( 1.89), 8.678 (2.05), 8.682 (2.16), 9.358 (3.16), 9.364 (3.07 ), 9.772 (0.95). Example 76 N‐[(furan‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo le]‐1‐ carboxamide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(isocyanatomethyl)f uran, CAS‐RN: [71189‐15‐6]) LC‐MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 400 [M+H] + 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 2.89 (t, 2H), 4.07 (s, 4H), 4.18 ‐ 4.25 (m, 4H), 6.22 ‐ 6.24 (m, 1H), 6.40 (dd, 1H), 6.99 (s, 1H), 7.05 (t, 1H), 7.58 (d d, 1H), 7.61 (td, 1H), 7.73 (ddd, 1H), 8.00 (dd, 2 H), 8.68 (d, 1H), 9.36 (d, 1H). Example 77
N‐(2‐methoxyethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐ carboxamide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐isocyanato‐2‐me thoxyethane, CAS‐RN: [42170‐95‐6]) LC‐MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 378 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.133 (0 .64), 1.150 (0.67), 2.872 (1.43), 2.889 (2.25), 2.907 (1.53), 3.159 (0.67), 3.174 (2.23), 3.189 (2.55), 3.204 (1.01 ), 3.231 (0.58), 3.237 (0.49), 3.327 (2.63), 3.340 ( 4.91), 3.358 (16.00), 4.040 (12.29), 4.200 (1.54), 4.218 (2. 41), 4.235 (1.50), 5.758 (0.42), 6.565 (0.70), 6.579 (1.47), 6.593 (0.69), 6.984 (6.42), 7.594 (0.68), 7.5 97 (0.68), 7.612 (1.03), 7.615 (1.47), 7.632 (0.97), 7.635 (0.99), 7.709 (0.89), 7.713 (0.95), 7.727 (0.79), 7.7 30 (1.48), 7.734 (1.11), 7.747 (0.80), 7.751 (0.79), 7.990 (1.46), 8.000 (1.70), 8.007 (1.35), 8.011 (1.27), 8.0 20 (1.49), 8.680 (2.08), 8.685 (2.16), 9.363 (2.93), 9.368 (3.00). Example 78 N‐phenyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro [azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxam ide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and isocyanatobenzene, CAS ‐RN: [103‐71‐9]) LC‐MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 396 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.326 (0 .54), 2.522 (1.53), 2.539 (0.40), 2.668 (0.53), 2.933 (2.07), 2.950 (3.33), 2.967 (2.20), 4.207 (0.55), 4.226 (16.00), 4.251 (3.77), 4.269 (2.18), 6.933 (1.21), 6.951 (2.63), 6.970 (1.51), 7.039 (8.81), 7.236 (2.75), 7.2 57 (4.14), 7.275 (2.87), 7.524 (3.86), 7.526 (4.32), 7.545 (3.83), 7.548 (3.11), 7.596 (1.03), 7.599 (0.99), 7.6 16 (2.12), 7.634 (1.37), 7.636 (1.41), 7.711 (1.30), 7.715 (1.32), 7.728 (1.15), 7.732 (2.12), 7.736 (1.57), 7.7 50 (1.13), 7.753 (1.13), 7.997 (2.99), 8.018 (2.37), 8.021 (2.36), 8.629 (4.18), 8.685 (3.08), 8.690 (3.13), 9.3 69 (4.29), 9.375 (4.11).
Example 79 H 3 C N N N N H N S H 3 C N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carbothioamide (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and isot hiocyanatoethane, CAR‐RN: [542‐85‐8]) LC‐MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 378 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.085 (6 .97), 1.103 (16.00), 1.121 (7.14), 1.481 (10.98), 1.4 98 (11.08), 2.074 (1.50), 2.518 (1.76), 2.523 (2.46), 2.539 (2.90), 2.556 (1.86), 3.090 (1.68), 3.108 (1.93), 3.124 (1.71), 3.141 (1.58), 3.427 (0.94), 3.445 (2.93 ), 3.459 (3.23), 3.462 (3.22), 3.476 (2.83), 3.494 ( 0.84), 4.123 (2.32), 4.146 (3.29), 4.210 (2.00), 4.231 (5.24 ), 4.253 (2.30), 4.277 (3.59), 4.301 (2.03), 4.528 ( 1.00), 4.544 (1.87), 4.561 (1.87), 4.577 (0.96), 6.993 (12.65), 7.593 (1.33), 7.595 (1.26), 7.610 (2.12), 7.612 (2.72), 7.630 (1.81), 7.633 (1.95), 7.696 (1.38), 7.7 09 (4.24), 7.726 (2.53), 7.730 (2.90), 7.733 (2.30), 7.747 (1.50), 7.750 (1.58), 8.001 (6.28), 8.023 (4.89), 8.6 83 (4.11), 8.688 (4.29), 9.361 (5.80), 9.366 (5.70). The following compounds (example 80 and example 81) were synthesized in analogy to example 62: Example 80 1‐(methanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and methanesulfonyl chlori de, CAS‐RN: [124‐63‐0]) 1 H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.239 (0.43), 1.907 (0.68), 2.518 (4.42), 2.522 (2.82), 2. 937 (1.55), 2.954 (2.16), 2.972 (1.67), 3.145 (16.00), 4. 149 (12.94), 4.218 (1.62), 4.236 (2.32), 4.253 (1.53) , 7.043 (6.87), 7.606 (0.67), 7.609 (0.67), 7.626 (1.46 ), 7.644 (0.93), 7.646 (0.95), 7.720 (0.92), 7.724 ( 0.93), 7.738 (0.76), 7.742 (1.51), 7.745 (1.04), 7.759 (0.84 ), 7.763 (0.77), 8.011 (1.80), 8.032 (1.74), 8.705 ( 1.83), 8.710 (1.85), 9.374 (3.06), 9.379 (2.91). Example 81
1‐(methanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and meth anesulfonyl chloride, CAS‐RN: [124‐63‐0]) LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 369 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.479 (6 .19), 1.496 (6.19), 2.518 (4.00), 2.523 (2.81), 2.540 (1.08), 2.558 (1.09), 2.574 (1.03), 3.129 (1.12), 3.145 (16.00), 3.162 (1.06), 3.181 (0.97), 4.074 (1.45), 4.095 (2.36), 4.127 (1.42), 4.142 (2.33), 4.148 (2.20), 4.1 62 (1.28), 4.224 (2.23), 4.245 (1.58), 4.517 (0.55), 4.533 (0.97), 4.550 (0.95), 4.566 (0.50), 7.029 (7.52), 7.6 01 (0.72), 7.604 (0.72), 7.618 (1.08), 7.621 (1.48), 7.641 (1.02), 7.716 (1.03), 7.720 (0.84), 7.733 (0.86), 7.7 37 (1.50), 7.741 (1.22), 7.754 (0.86), 7.758 (0.88), 8.009 (1.56), 8.029 (3.33), 8.046 (1.25), 8.700 (2.08), 8.7 05 (2.19), 9.370 (3.31), 9.376 (3.19). Example 82 ethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azeti dine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (50.0 mg, 181 µmol) was dissolved in DCM (930 µl), DIPEA (95 µl, 540 µmol; CAS‐RN:[7087‐68‐5]) was added, c ooled to 0°C and ethyl carbonochloridate (19.6 mg, 181 µmol) was added and the mixture was stirred overnig ht at rt. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.7 0 mg, 95 % purity, 3 % yield). LC‐MS (Method 3): Rt
= 1.01 min; MS (ESIpos): m/z = 349 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.183 (7 .43), 1.201 (16.00), 1.218 (7.57), 2.326 (0.58), 2.522 (1.74), 2.664 (0.42), 2.668 (0.58), 2.902 (2.69), 2.919 (4.31), 2.936 (2.84), 4.037 (2.28), 4.055 (7.00), 4.073 (6.89 ), 4.091 (2.21), 4.166 (4.21), 4.198 (3.99), 4.216 ( 4.81), 4.233 (2.84), 7.025 (10.46), 7.598 (1.19), 7.618 (2.47), 7.635 (1.63), 7.638 (1.68), 7.712 (1.56), 7.716 (1.44), 7.733 (2.44), 7.736 (1.93), 7.750 (1.30), 7.7 54 (1.30), 7.999 (5.00), 8.020 (4.52), 8.670 (3.77), 8.675 (3.77), 9.354 (4.97), 9.359 (4.92). The following compound (example 83) was synthesized i n analogy to example 82: Example 83 Ethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihy drospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and ethy l carbonochloridoate, CAS‐RN: [79‐22‐1]) LC‐MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 363 [M+H] + 1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 1.20 (t, 3H), 1.28 (s, 2H), 1.48 (d, 3H), 4.06 (q, 2H), 4.14 4.31 (m, 4H), 4.52 (sxt, 1H), 7.01 (s, 1H), 7.62 (ddd, 1H), 7.73 (ddd, 1H), 7.98 ‐ 8.05 (m, 2H), 8.68 ( d, 1H), 9.36 (d, 1H). Example 84 1‐[(4‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐
yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 ‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (60.0 mg, 217 µmol) and 5‐methyl‐1H‐imidazole‐2‐ carbaldehyde (26.3 mg, 239 µmol) were dissolved in THF (2.9 ml). Acetic acid (12 µl, 220 µmol; C AS‐ RN:[64‐19‐7]) and sodium triacetoxyborohydride (63.3 mg, 299 µmol; CAS‐RN:[56553‐60‐7]) were added and the mixture was stirred overnight at room temper ature under argon. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.10 mg, 95 % purity, 1 % yield). LC‐M S (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 371 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.905 (1.33), 2.099 (4.22), 2.135 (1.22), 2.197 (1.07), 2.518 (10.00), 2.522 (6.67), 2.819 (3.37), 2.836 (5.11), 2.853 (3.56), 3.414 (4.44), 3.432 (8.33), 3.460 (8.63), 3.478 (4.33), 3.575 (13.96), 4.164 (3.93), 4.182 (5.85), 4.199 (3.74), 4.251 (0.48), 6.900 (16.00), 6.951 (0.52), 7.037 (1.15), 7.596 (1.89), 7.615 (3.41), 7.633 (2.52), 7.636 (2.52), 7.708 (2.56), 7.712 (2.19 ), 7.725 (2.30), 7.729 (3.41), 7.733 (3.07), 7.746 ( 2.00), 7.750 (2.19), 7.996 (8.59), 8.020 (7.11), 8.668 (5.52 ), 8.673 (5.85), 9.350 (7.70), 9.356 (7.81). The following compounds (example 85 to example 98) w ere synthesized in analogy to example 84: Example 85 1‐[(imidazo[1,5‐a]pyridin‐3‐yl)methyl]‐2'‐(quino lin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrr olo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and imidazo[1,5‐a]pyridine‐3‐carba ldehyde, CAS‐RN: [56671‐66‐0]) LC‐MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 407 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.907 (1 .28), 2.518 (8.29), 2.522 (5.53), 2.810 (3.39), 2.827 (5.25), 2.845 (3.73), 3.469 (7.60), 4.100 (5.11), 4.149 (4.08 ), 4.166 (5.91), 4.183 (3.90), 6.711 (1.66), 6.713 ( 1.76), 6.729 (3.42), 6.744 (2.63), 6.748 (2.45), 6.780 (2.66 ), 6.782 (2.73), 6.796 (1.83), 6.798 (1.73), 6.803 ( 2.73), 6.805 (2.90), 6.819 (1.94), 6.917 (16.00), 7.304 (8.09), 7.540 (4.39), 7.563 (3.97), 7.594 (1.94), 7.597 (1.66), 7.611 (2.83), 7.614 (3.63), 7.632 (2.38), 7.6 35 (2.70), 7.707 (2.66), 7.711 (2.07), 7.724 (2.21), 7.729 (3.42), 7.732 (3.08), 7.746 (2.00), 7.749 (2.21), 7.9 96 (8.74), 8.016 (6.19), 8.019 (6.36), 8.356 (3.46), 8.359 (3.49), 8.374 (3.32), 8.376 (3.25), 8.676 (5.29), 8.6 82 (5.56), 9.353 (8.33), 9.358 (8.02). Example 86
1‐{[1‐(propan‐2‐yl)‐1H‐imidazol‐2‐yl]methyl} ‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine ‐3,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1‐(propan‐2‐yl)‐1H‐imidazo le‐2‐carbaldehyde, CAS‐RN: [53332‐64‐2]) LC‐MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 399 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.404 (1 6.00), 1.421 (15.86), 2.518 (3.21), 2.522 (2.13), 2.8 04 (1.91), 2.822 (2.81), 2.839 (2.04), 3.378 (1.78), 3.3 95 (6.31), 3.406 (5.95), 3.423 (1.68), 3.725 (7.91), 4.155 (2.07), 4.173 (3.01), 4.190 (1.98), 4.659 (0.94), 4.6 75 (1.26), 4.692 (0.90), 6.791 (4.23), 6.793 (4.22), 6.874 (9.37), 7.254 (4.77), 7.257 (4.76), 7.595 (0.95), 7.5 98 (0.95), 7.613 (1.41), 7.615 (2.05), 7.618 (1.14), 7.633 (1.33), 7.636 (1.33), 7.708 (1.35), 7.712 (1.32), 7.7 25 (1.12), 7.729 (2.14), 7.733 (1.55), 7.746 (1.21), 7.750 (1.15), 7.997 (2.14), 8.005 (1.77), 8.008 (1.80), 8.0 17 (1.82), 8.025 (1.66), 8.663 (2.61), 8.668 (2.70), 9.347 (4.40), 9.352 (4.13). Example 87 2'‐(quinolin‐3‐yl)‐1‐{[4‐(trifluoromethyl)‐1H imidazol‐2‐yl]methyl}‐5',6'‐dihydrospiro[azetidine ‐3,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 4‐(trifluoromethyl)‐1H‐imidazo le‐2‐carbaldehyde, CAS‐RN: [102808‐02‐6]) LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 425 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (3 .97), 2.522 (2.75), 2.834 (3.29), 2.852 (4.90), 2.869 (3.55), 3.469 (4.07), 3.487 (9.43), 3.508 (8.87), 3.527 (3.81), 3.706 (14.92), 4.169 (3.62), 4.187 (5.27), 4.204 (3.43), 6.913 (16.00), 7.597 (1.65), 7.599 (1.46), 7.614 (2.57), 7.617 (3.23), 7.620 (2.09), 7.634 (2.19), 7.637 (2.31), 7.710 (6.50), 7.727 (2.07), 7.730 (3.20 ), 7.734 (2.90), 7.748 (1.74), 7.751 (2.05), 7.996 ( 6.59), 7.998 (6.37), 8.020 (6.89), 8.660 (4.90), 8.665 (4.90 ), 9.345 (7.79), 9.351 (7.69), 12.621 (0.90).
Example 88 1‐(2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 2‐methylpropanal, CAS‐RN: [78 84‐2]) LC‐MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 333 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.882 (1 5.27), 0.899 (16.00), 1.534 (0.64), 1.550 (1.15), 1.5 67 (1.39), 1.584 (1.13), 1.600 (0.60), 2.256 (4.30), 2.2 73 (4.20), 2.326 (0.76), 2.668 (0.73), 2.819 (2.56), 2.835 (4.31), 2.853 (2.70), 3.399 (5.30), 3.415 (4.02), 4.1 63 (2.66), 4.181 (4.36), 4.198 (2.64), 6.901 (5.20), 7.552 (0.44), 7.594 (1.28), 7.612 (2.39), 7.631 (1.72), 7.7 07 (1.40), 7.726 (2.20), 7.743 (1.29), 7.994 (4.98), 8.015 (4.47), 8.693 (3.83), 9.365 (3.74). Example 89 1‐{[1‐(2‐methoxyethyl)‐1H‐imidazol‐2‐yl]methyl }‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1‐(2‐methoxyethyl)‐1H‐imidaz ole‐2‐carbaldehyde, CAS‐RN: [558446‐64‐3]) LC‐MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 415 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.803 (1.03), 2.820 (1.56), 2.838 (1.10), 3.271 (16.00), 3.392 (1.19), 3.410 (3.40), 3.419 (3.26), 3.437 (0.92), 3.6 49 (1.31), 3.663 (2.76), 3.677 (1.46), 3.725 (3.96), 4.154 (1.12), 4.164 (0.44), 4.172 (1.68), 4.189 (1.09), 4.2 10 (1.24), 4.223 (2.26), 4.237 (1.12), 6.765 (2.61), 6.769 (2.69), 6.901 (4.82), 7.119 (2.60), 7.122 (2.53), 7.5 94 (0.53), 7.596 (0.45), 7.611 (0.81), 7.613 (0.92), 7.631 (0.69), 7.634 (0.73), 7.706 (0.72), 7.710 (0.62), 7.7 24 (0.60), 7.727 (0.93), 7.731 (0.85), 7.745 (0.57), 7.748 (0.60), 7.998 (2.45), 8.000 (1.97), 8.019 (1.75), 8.0 21 (2.16), 8.666 (1.64), 8.671 (1.64), 9.354 (2.42), 9.359 (2.34). Example 90
2'‐(quinolin‐3‐yl)‐1‐[(1,4,5‐trimethyl‐1H‐im idazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1,4,5‐trimethyl‐1H‐imidazole 2‐carbaldehyde, CAS‐RN: [185910‐12‐7]) LC‐MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 399 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.977 (8 .88), 2.061 (8.45), 2.518 (0.86), 2.522 (0.58), 2.539 (7.17), 2.795 (1.29), 2.813 (1.89), 2.831 (1.37), 3.397 (4.68), 3.408 (4.36), 3.425 (1.22), 3.502 (16.00), 3.616 (5.39), 4.149 (1.37), 4.159 (0.54), 4.168 (2.05), 4.1 85 (1.33), 6.903 (6.12), 7.594 (0.70), 7.597 (0.57), 7.611 (1.04), 7.615 (1.14), 7.632 (0.88), 7.635 (0.95), 7.7 06 (0.93), 7.710 (0.80), 7.724 (0.79), 7.727 (1.18), 7.731 (1.08), 7.745 (0.76), 7.749 (0.79), 7.995 (3.01), 7.9 98 (2.45), 8.017 (2.13), 8.019 (2.79), 8.678 (2.07), 8.683 (2.00), 9.359 (2.84), 9.364 (2.91). Example 91 1‐[(1H‐benzimidazol‐2‐yl)methyl]‐2'‐(quinolin‐ 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1, 2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1H‐benzimidazole‐2‐carbaldehyd e, CAS‐RN: [3314‐30‐5]) LC‐MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 407 [M+H] + 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 2.89 (t, 2H), 3.51 ‐ 3.57 (m, 2H), 3.57 ‐ 3.63 (m, 2H), 3.90 (s, 2H), 4.20 (t, 2H), 6.93 (s, 1H), 7.10 ‐ 7.20 (m, 2H), 7.43 ‐ 7.49 (m, 1H), 7.57 (d, 1H), 7.59 ‐ 7. 66 (m, 1H), 7.73 (ddd, 1H), 8.01 (d, 2H), 8.66 (d, 1H), 9.35 (d, 1H ), 12.31 (br s, 1H). Example 92
1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1‐methyl‐1H‐imidazole‐2‐ca rbaldehyde, CAS‐RN: [13750‐81‐7]) LC‐MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 371 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.799 (1 .38), 2.817 (2.13), 2.834 (1.48), 3.402 (1.44), 3.419 (5.22), 3.426 (5.01), 3.443 (1.12), 3.693 (16.00), 3.697 (7.77), 4.150 (1.48), 4.168 (2.25), 4.185 (1.44), 6.759 (3.40), 6.763 (3.28), 6.912 (5.60), 7.087 (3.06), 7.0 90 (3.07), 7.592 (0.65), 7.595 (0.58), 7.609 (1.04), 7.612 (1.31), 7.629 (0.88), 7.632 (0.92), 7.704 (0.83), 7.7 08 (0.75), 7.722 (0.76), 7.725 (1.29), 7.729 (1.06), 7.743 (0.69), 7.746 (0.71), 7.997 (2.71), 8.018 (2.59), 8.6 82 (2.02), 8.687 (2.02), 9.364 (2.85), 9.369 (2.76). Example 93 1‐[(1H‐pyrazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1H‐pyrazole‐5‐carbaldehyde, C AS‐RN: [948552‐36‐1]) LC‐MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 357 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.522 (0.50), 2.539 (16.00), 2.822 (0.54), 2.839 (0.89), 2.857 (0.58), 3.698 (0.41), 4.163 (0.64), 4.181 (1.01), 4.1 99 (0.64), 6.911 (2.13), 7.615 (0.60), 7.633 (0.44), 7.636 (0.47), 7.729 (0.56), 7.732 (0.51), 7.996 (1.32), 8.0 19 (1.20), 8.677 (0.90), 8.682 (0.93), 9.354 (1.19), 9.359 (1.17). Example 94
N N N N C H 3 H N N 1‐[(4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 4‐methyl‐1H‐imidazole‐5‐ca rbaldehyde, CAS‐RN: [68282‐53‐1]) LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 371 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.907 (0.51), 2.163 (16.00), 2.518 (1.13), 2.523 (0.78), 2.539 (0.68), 2.792 (2.13), 2.810 (3.21), 2.827 (2.27), 3.3 61 (7.38), 3.378 (8.68), 3.395 (7.42), 3.413 (3.22), 4.152 (2.36), 4.161 (0.90), 4.170 (3.49), 4.187 (2.25), 6.872 (9.54), 7.421 (11.41), 7. 592 (1.11), 7.596 (0.97), 7.610 (1.69), 7.613 (2.10), 7.616 (1.42), 7.630 (1.43 ), 7.633 (1.59), 7.705 (1.61), 7.709 (1.28), 7.722 ( 1.22), 7.726 (2.13), 7.730 (1.87), 7.744 (1.16), 7.747 (1.29 ), 7.993 (4.52), 7.995 (4.29), 8.017 (4.70), 8.676 ( 3.34), 8.682 (3.32), 9.354 (5.21), 9.359 (5.14). Example 95 1‐[(2‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐p yrrolo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 2‐methyl‐1H‐imidazole‐5‐ca rbaldehyde, CAS‐RN: [35034‐22‐1]) LC‐MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 371 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.259 (16.00), 2.518 (0.44), 2.822 (1.28), 2.839 (1.95), 2.857 (1.37), 3.500 (1.57), 3.519 (2.98), 3.544 (2.96), 3.5 63 (1.56), 4.161 (1.47), 4.171 (0.62), 4.180 (2.15), 4.196 (1.40), 6.845 (3.61), 6.887 (5.98), 7.596 (0.68), 7.5 99 (0.58), 7.613 (0.97), 7.615 (1.26), 7.618 (0.85), 7.633 (0.85), 7.636 (0.94), 7.709 (0.95), 7.713 (0.74), 7.7 26 (0.77), 7.731 (1.23), 7.734 (1.08), 7.747 (0.69), 7.751 (0.79), 7.998 (3.11), 8.019 (2.24), 8.022 (2.31), 8.6 64 (1.93), 8.670 (2.04), 9.347 (3.03), 9.353 (3.09). Example 96
1‐[(1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl )‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b] pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1H‐pyrrole‐2‐carbaldehyde, CA S‐RN: [1003‐29‐8]) LC‐MS (Method 3): Rt = 1.00 min; MS (ESIpos): m/z = 356 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.898 (1 .36), 0.913 (1.36), 2.518 (4.68), 2.523 (3.30), 2.539 (0.81), 2.544 (1.16), 2.548 (1.06), 2.807 (3.40), 2.824 (4.96 ), 2.842 (3.48), 3.296 (1.06), 3.339 (6.21), 3.358 ( 8.73), 3.372 (1.36), 3.389 (8.14), 3.408 (4.04), 3.551 (12.50), 4.162 (3.62), 4.171 (1.55), 4.180 (5.20), 4.187 (1.50), 4.197 (3.45), 5.898 (1.18), 5.906 (2.98), 5.9 10 (3.28), 5.916 (2.39), 5.919 (2.93), 5.925 (4.83), 5.932 (3.13), 5.940 (1.28), 6.641 (2.19), 6.645 (2.88), 6.6 47 (4.22), 6.651 (4.27), 6.654 (2.64), 6.658 (2.05), 6.882 (16.00), 6.896 (0.94), 7.595 (1.73), 7.598 (1.45), 7.613 (2.69), 7.615 (2.88), 7.633 (2.19), 7.636 (2.29), 7.708 (2.42), 7.712 (1.95), 7.725 (2.02), 7.729 (2.91 ), 7.732 (2.69), 7.746 (1.75), 7.749 (1.90), 7.995 ( 7.67), 7.998 (5.89), 8.016 (5.33), 8.019 (6.51), 8.673 (5.03 ), 8.679 (4.91), 9.352 (7.42), 9.357 (7.27), 9.367 ( 0.49), 10.699 (1.58). Example 97 1‐[(1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1H‐imidazole‐5‐carbaldehyde, CAS‐RN: [3034‐50‐2]) LC‐MS (Method 3): Rt = 0.79 min; MS (ESIpos): m/z = 357 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (1 .48), 2.523 (1.06), 2.805 (3.03), 2.822 (4.60), 2.840 (3.22), 3.377 (3.41), 3.394 (6.17), 3.420 (7.38), 3.438 (3.62 ), 3.551 (4.16), 4.159 (3.50), 4.169 (1.30), 4.178 ( 5.10), 4.195 (3.33), 6.885 (16.00), 7.560 (7.83), 7.563 (8.10), 7.592 (1.62), 7.596 (1.41), 7.610 (2.43), 7.613 (3.24), 7.616 (2.02), 7.630 (2.07), 7.633 (2.27), 7.7 05 (2.23), 7.710 (1.95), 7.723 (1.79), 7.726 (3.40), 7.730
(2.63), 7.744 (1.80), 7.747 (1.81), 7.995 (6.24), 8.016 (5.77), 8.678 (4.50), 8.683 (4.56), 9.356 (7.29 ), 9.361 (7.17). Example 98 1‐[(5‐methyl‐1H‐pyrrol‐2‐yl)methyl]‐2'‐(quin olin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyr rolo[1,2‐ b]pyrazole] (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 5‐methyl‐1H‐pyrrole‐2‐carb aldehyde, CAS‐RN: [1192‐79‐6]) LC‐MS (Method 3): Rt = 1.06 min; MS (ESIpos): m/z = 370 [M+H] + 1 H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.14 (s, 3H), 2.83 (t, 2H), 3.32 (br s, 2H), 3.37 ‐ 3.42 (m, 2H), 3.48 (s, 2H), 4.18 (t, 2H), 5.58 (t, 1H), 5.74 (t, 1H), 6.87 (s, 1H), 7.58 ‐ 7.65 (m, 1H), 7.73 (ddd, 1H), 7.97 ‐ 8.04 (m, 2H), 8.68 (d, 1H), 9.35 (d, 1H), 10.42 (br s, 1H). Example 99 3‐(ethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1 yl]cyclobut‐3‐ene‐1,2‐dione Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (50.0 mg, 128 µmol) was dissolved in EtOH (1.5 ml), triethylamine (36 µl, 260 µmol; CAS‐RN:[121‐44‐ 8]) and 3,4‐diethoxycyclobut‐3‐ene‐1,2‐dione (4 3.6 mg,
256 µmol) were added. The mixture was stirred fo r 4 h at reflux. Ethanamine (320 µl, 2.0 M in TH F, 640 µmol; CAS‐RN:[75‐04‐7]) was added dropwise and the mixture was stirred for 4 h at reflux. Ethanami ne (320 µl, 2.0 M in THF, 640 µmol; CAS‐RN:[75‐04‐7]) was added dropwise and the mixture was stirred overnight at 70°C. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.40 mg, 95 % purity, 3 % yield). LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 40 0 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.094 (0.86), 1.112 (1.76), 1.121 (0.60), 1.130 (1.03), 1.140 (1.03), 1.150 (7.19), 1.168 (16.00), 1.185 (7.45), 1.206 (0.93), 1.223 (0.93), 1.747 (0.70), 2.518 (4.24), 2.535 (1.09), 2.986 (2.98), 3.004 (5.10), 3.0 20 (3.21), 3.171 (1.95), 4.216 (3.38), 4.233 (5.50), 4.250 (3.21), 4.603 (2.88), 4.625 (9.41), 4.643 (8.68), 4.665 (2.68), 7.099 (11.63), 7. 597 (1.52), 7.599 (1.42), 7.617 (3.15), 7.637 (2.22), 7.712 (1.92), 7.715 (1.79 ), 7.733 (2.98), 7.736 (2.48), 7.750 (1.66), 7.753 ( 1.69), 7.999 (7.69), 8.021 (6.19), 8.666 (4.84), 8.671 (5.07 ), 9.352 (6.29), 9.357 (6.33). The following compound (example 100) was synthesized in analogy to example 99: Example 100 3‐(dimethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol] 1‐ yl]cyclobut‐3‐ene‐1,2‐dione (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and N‐methylmethanamine, CAS‐RN: [ 124‐40‐3]) LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 400 [M+H] + 1 H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 3.01 (t, 2H), 3.14 (br s, 6H), 4.24 (t, 2H), 4.61 ‐ 4.72 (m, 4H), 7.07 (s, 1H), 7.58 ‐ 7.65 (m, 1H), 7.70 ‐ 7.77 (m, 1H), 8.02 (d, 2H), 8.67 (d, 1H), 9.36 (d, 1H). Example 101 2‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol] 1‐ yl]ethan‐1‐one
Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (180 mg, 43 % purity, 198 µmol) was dissolved in DCM (2.0 ml, 31 mmol; CAS‐RN:[75‐09‐2]), N,N‐dimethylglycine (24.5 mg, 238 µmol), DIPEA (170 µl, 990 µmol; CA S‐ RN:[7087‐68‐5]) and PyBroP (111 mg, 238 µmol; CA S‐RN:[132705‐51‐2]) were added and it was stirre d overnight at rt. The mixture was evaporated and puri fied by preparative HPLC (ACN/H2O+0,2% NH3) and preparative TLC (DCM/MeOH) to yield the title compound (6.90 mg, 95 % purity, 9 % yield). LC‐MS (Method 1): R t = 0.88 min; MS (ESIpos): m/z = 362 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.21 3 (16.00), 2.518 (1.86), 2.522 (1.15), 2.902 (0.78), 2.919 (1.16), 2.936 (0.86), 2.982 (3.82), 4.129 (1.15), 4.140 (1.14), 4.210 (0.90), 4.228 (1.36), 4.245 (0.84 ), 4.443 (1.96Luck), 6.998 (3.73), 7.615 (0.59), 7.61 9 (0.73), 7.621 (0.49), 7.636 (0.50), 7.638 (0.52), 7.7 12 (0.55), 7.716 (0.45), 7.730 (0.45), 7.733 (0.73), 7.737 (0.65), 7.754 (0.45), 7.998 (1.47), 8.000 (1.46), 8.0 21 (1.53), 8.679 (1.13), 8.684 (1.11), 9.359 (1.73), 9.364 (1.67). The following compounds (example 102 to example 108) were synthesized in analogy to example 101: Example 102 3‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrroli din‐2‐ one (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 2‐oxopyrrolidine‐3‐carboxylic acid, CAS‐RN: [96905‐67‐8]) LC‐MS (Method 1): R t = 0.81 min; MS (ESIpos): m/z = 388 [M+H]⁺ 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 2.12 (dtt, 1H), 2.34 ‐ 2.41 (m , 1H), 2.94 (dd, 2H), 3.16 ‐ 3.25 (m, 1H), 3.25 ‐ 3.31 (m, 1H), 3.37 ‐ 3.46 (m, 1H), 4.10 ‐ 4.21 (m, 2H), 4.24 (t, 2H), 4.48 (dd, 1 H), 4.68 (dd, 1H), 6.94 ‐ 7.03 (m, 1H), 7.59 ‐ 7.66 (m, 1H), 7.73 (ddt, 1H), 7.88 (d, 1H), 8.01 (d, 2H), 8.69 (dd, 1H), 9.36 (dd, 1H). Example 103
4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrroli din‐2‐ one (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 5‐oxopyrrolidine‐3‐carboxylic acid, CAS‐RN: [7268‐43‐1]) LC‐MS (Method 1): R t = 0.79 min; MS (ESIpos): m/z = 388 [M+H]⁺ 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 2.30 ‐ 2.35 (m, 2H), 2.89 ‐ 2.98 (m, 2H), 3.26 ‐ 3.31 (m, 1H), 3.39 ‐ 3.50 (m, 1H), 4.11 ‐ 4.19 (m, 2H), 4.21 ‐ 4.28 (m, 2H), 4.38 ‐ 4.49 (m, 2H), 7.02 (d, 1H) , 7.59 ‐ 7.68 (m, 2H), 7.74 (ddd, 1H), 7.97 ‐ 8.05 (m, 2H), 8.68 ( s, 1H), 9.36 (dd, 1H). Example 104 2‐(1H‐imidazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl) ‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]p yrazol]‐1‐ yl]ethan‐1‐one (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 1H‐imidazol‐1‐ylacetic acid, CAS‐RN: [22884‐10‐2]) LC‐MS (Method 1): R t = 0.83 min; MS (ESIpos): m/z = 385 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.983 (0.51) , 1.833 (0.93), 2.326 (2.58), 2.669 (2.53), 2.935 (5 .07), 2.952 (8.06), 2.969 (5.36), 4.166 (1.90), 4.190 (8.23 ), 4.200 (7.98), 4.228 (5.74), 4.247 (8.23), 4.264 ( 4.43), 4.387 (0.72), 4.445 (14.86), 4.787 (0.59), 4.830 (13. 00), 4.834 (12.96), 4.876 (0.55), 6.786 (0.68), 6.901 (10.60), 6.967 (0.51), 7.004 (16.00), 7.124 (10.43), 7.485 (0.55), 7.590 (10.64), 7.606 (3.04), 7.625 (5.2 3), 7.643 (3.50), 7.722 (3.12), 7.741 (4.90), 7.758 (2.62 ), 8.007 (7.35), 8.028 (6.33), 8.678 (7.77), 8.682 ( 7.56), 9.361 (9.25), 9.366 (8.53). Example 105
4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospi ro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]buta namide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 4‐amino‐4‐oxobutanoic acid, CAS‐RN: [638‐32‐4]) LC‐MS (Method 1): R t = 0.78 min; MS (ESIpos): m/z = 376 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.188 (0.58) , 1.204 (0.64), 1.231 (1.68), 1.751 (2.25), 1.907 (0 .69), 1.955 (1.44), 2.287 (2.37), 2.303 (7.45), 2.316 (9.59), 2.326 (10.86), 2.337 (9.07), 2.352 (2.48), 2.362 (1.33), 2.387 (0.64), 2.408 (0.64), 2.540 (14.21), 2.563 (4.79), 2.669 (1.96), 2.781 (1.44), 2.905 (3.00), 2.910 (3.12), 2.922 (5.55), 2.928 (5.72), 2.941 (5.03 ), 4.071 (1.44), 4.096 (8.20), 4.103 (8.26), 4.128 ( 1.50), 4.218 (5.08), 4.236 (10.05), 4.253 (4.97), 4.419 (15. 48), 5.758 (1.04), 6.795 (3.29), 6.993 (16.00), 7.010 (0.52), 7.333 (3.23), 7.599 (2.31), 7.619 (4.62), 7.6 39 (3.29), 7.714 (2.89), 7.717 (2.83), 7.735 (4.33), 7.752 (2.43), 7.755 (2.48), 8.000 (10.92), 8.023 (9.47), 8. 672 (7.28), 8.677 (7.51), 9.354 (8.78), 9.360 (8.84). Example 106 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐(4H‐1 ,2,4‐triazol‐ 4‐yl)ethan‐1‐one (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and 4H‐1,2,4‐triazol‐4‐ylacetic acid, CAS‐RN: [110822‐97‐4]) LC‐MS (Method 1): R t = 0.78 min; MS (ESIpos): m/z = 386 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.322 (0.79) , 2.326 (1.10), 2.331 (0.86), 2.664 (0.79), 2.669 (1 .10), 2.673 (0.90), 2.952 (1.76), 2.969 (2.76), 2.986 (2.03 ), 4.184 (0.66), 4.208 (2.97), 4.219 (3.07), 4.243 ( 2.00), 4.257 (2.79), 4.272 (1.38), 4.277 (1.45), 4.502 (6.10 ), 4.945 (4.62), 4.949 (5.03), 7.003 (7.59), 7.607 ( 0.83), 7.610 (0.97), 7.627 (2.00), 7.647 (1.38), 7.721 (1.10 ), 7.724 (1.28), 7.738 (1.00), 7.742 (1.93), 7.745 ( 1.66), 7.759 (1.03), 7.762 (1.07), 8.008 (2.34), 8.019 (2.17), 8.029 (2.14), 8.037 (1.97), 8.439 (16.00), 8.678 (2.83), 8.682 (3.07), 9.362 (3.76), 9.368 (4.03). Example 107
1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]prop‐2‐en 1‐one (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and prop‐2‐enoic acid, CAS‐RN: [79‐10‐7]) LC‐MS (Method 2): R t = 0.69 min; MS (ESIpos): m/z = 331 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.000 (0.60) , 0.838 (0.90), 1.231 (1.33), 1.376 (0.73), 2.333 (0 .97), 2.519 (6.77), 2.523 (4.20), 2.540 (2.07), 2.670 (1.40 ), 2.674 (1.03), 2.931 (3.33), 2.947 (5.27), 2.950 ( 5.27), 2.965 (3.77), 4.175 (1.20), 4.201 (5.13), 4.213 (5.27 ), 4.223 (4.70), 4.240 (7.47), 4.258 (3.97), 4.476 ( 1.10), 4.498 (5.43), 4.506 (5.33), 4.529 (1.07), 5.714 (3.47 ), 5.720 (3.27), 5.739 (3.33), 5.745 (3.80), 6.143 ( 2.80), 6.149 (2.93), 6.186 (4.37), 6.191 (4.27), 6.341 (4.10), 6.367 (4.17), 6.384 (2.97), 6.410 (2.50), 7.028 (16.00), 7.598 (1.70), 7.600 (1.57), 7.615 (2.67), 7.618 (3.53), 7.635 (2.30), 7.638 (2.47), 7.714 (2.23), 7.717 (2.17), 7.731 (2.03), 7.734 (3.60), 7.738 (2.77 ), 7.752 (1.93), 7.755 (1.93), 7.999 (6.70), 8.021 ( 6.10), 8.673 (5.10), 8.677 (5.23), 9.355 (7.23), 9.360 (7.40 ). Example 108 3‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol] 1‐ yl]propan‐1‐one (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and N,N‐dimethyl‐beta‐alanine hyd rochloride, CAS‐RN: [14788‐12‐6]) LC‐MS (Method 1): R t = 0.88 min; MS (ESIpos): m/z = 376 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.145 (16.00), 2.230 (0.65), 2.248 (1.30), 2.267 (0.90), 2.463 (1.15), 2.482 (2.07), 2.518 (1.04), 2.523 (0.73), 2.9 05 (0.49), 2.921 (0.85), 2.926 (0.85), 2.941 (0.59), 4.100 (1.05), 4.109 (1.04), 4.216 (0.76), 4.234 (1.31), 4.2 51 (0.70), 4.409 (1.83), 6.996 (3.10), 7.617 (0.52), 7.619 (0.58), 7.636 (0.42), 7.639 (0.45), 7.713 (0.45), 7.7 34 (0.60), 7.738 (0.54), 7.999 (1.49), 8.021 (1.08), 8.023 (1.32), 8.675 (1.03), 8.680 (0.98), 9.357 (1.45), 9.3 63 (1.34). Example 109
N'‐cyano‐N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6' ‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] ‐1‐ carboximidamide Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (100 mg, 256 µmol) was dissolved in DCM (4.5 ml), diphenyl cyanocarbonimidate (67.1 mg, 282 µmol) and triethylam ine (71 µl, 510 µmol; CAS‐RN:[121‐44‐8]) were added and the mixture was stirred for 2 h at rt. The mixture was diluted with water and extracted 3x with DCM. The combined organic phases were dried and concentrated under reduced pressure to yield phenyl N‐cyano‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[ azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidate (120 mg), which was used without furthe r purification. LC‐MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 421 [M+H] + . Step 3: phenyl N‐cyano‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboximidate (60.0 mg, 50 % purity, 71.3 µmol) was dissolved in 2‐ propanol (740 µl) and ethanamine (360 µl, 2.0 M, 710 µmol; CAS‐RN:[75‐04‐7]) was added. The mixt ure was stirred overnight at 80°C. The mixture was evap orated and purified by preparative HPLC to yield the title compound (1.60 mg, 100 % purity, 6 % yield). LC‐MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/ z = 372 [M+H] + . 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 1.08 (t, 3H), 2.96 (t, 2H), 3.12 ‐ 3.22 (m, 2H), 4.23 (t, 2H), 4.35 ‐ 4.49 (m, 4H), 7.05 ‐ 7.12 (m, 2H), 7.59 ‐ 7.65 (m, 1H), 7.74 (ddd, 1H), 8.01 (d, 2H), 8.68 (d, 1H), 9.36 (d, 1H). The following compound (example 110) was synthesized in analogy to example 109: Example 110
N'‐cyano‐N,N‐dimethyl‐2'‐(quinolin‐3‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zole]‐1‐ carboximidamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carb oxylate (see example 2) and N‐methylmethanamine, CAS‐RN: [ 124‐40‐3]) LC‐MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 372 [M+H] + 1 H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.077 (0 .58), 2.074 (0.60), 2.905 (0.78), 2.923 (0.68), 2.940 (1.10), 2.958 (0.85), 2.988 (16.00), 4.208 (0.76), 4.226 (1.15), 4.243 (0.72), 4.456 (3.37), 4.458 (3.32), 7.038 (3.09), 7.075 (0.48), 7.617 (0.56), 7.619 (0.68), 7.6 22 (0.49), 7.637 (0.48), 7.640 (0.52), 7.714 (0.52), 7.717 (0.45), 7.731 (0.46), 7.735 (0.67), 7.738 (0.62), 7.7 55 (0.44), 8.002 (1.71), 8.004 (1.34), 8.023 (1.20), 8.026 (1.35), 8.676 (1.08), 8.682 (1.14), 9.357 (1.47), 9.3 63 (1.49). Example 111 N‐[3‐(dimethylamino)propyl]‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide Step 1: To a solution of tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐ 3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: To a solution of crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro‐ [azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacet ate (1.40 g, 3.59 mmol) in dichlormethane (59 mL) was added at ambient temperature under argon triethyl amine (5.0 ml, 36 mmol; CAS‐RN:[121‐44‐8]) and 4‐nitrophenyl carbonochloridate (867 mg, 4.30 mmol). The reaction was stirred at ambient temperature overnight. DMA (18 mL) was added and the dichlormethane was removed under reduced pressure. The DMA solution containing crude 4‐nitrophenyl 2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate was directly used in the next step. Step 3: To a solution of 4‐nitrophenyl 2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate (31.3 mg, 70.9 µmol) in N,N‐ dimethylacetamide (1.0 ml) under nitrogen were added N 1 ,N 1 ‐dimethylpropane‐1,3‐diamine (72.5 mg, 709 µmol) and K 2 CO 3 (14.4 mg, 142 µmol; CAS‐RN:[121‐44‐8]). The mixture was stirred overnight at 60°C. The mixture was purified by preparative HPLC to yiel d title compound (15.1 mg, 95 % purity, 50 % yield ).
LC‐MS (Method 1): R t = 0.96 min; MS (ESIpos): m/z = 405 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.551 (0.56), 1.588 (0.45), 1.605 (1.17), 1.623 (1.62 ), 1.641 (1.17), 1.815 (0.43), 1.834 (0.53), 1.856 ( 0.43), 1.906 (0.77), 2.156 (0.91), 2.173 (3.94), 2.322 (2.29 ), 2.326 (2.98), 2.332 (3.06), 2.349 (3.94), 2.518 ( 8.60), 2.522 (5.91), 2.539 (1.65), 2.554 (1.36), 2.664 (1.17 ), 2.668 (1.60), 2.673 (1.17), 2.877 (2.34), 2.895 ( 4.15), 2.912 (3.22), 2.930 (0.83), 3.031 (1.14), 3.060 (15.28), 3.079 (1.68), 3.093 (1.49), 3.109 (1.41), 3.125 (0.75), 3.793 (1.36), 4.036 (16.00), 4.057 (5.75), 4.163 (4.34), 4.206 (2.34), 4.216 (2.61), 4.224 (3.86), 4.233 (2.58), 4.240 (2.48), 4.250 (1.04), 4.287 (0.72 ), 6.603 (0.72), 6.618 (1.41), 6.632 (0.72), 6.698 ( 0.69), 6.953 (3.14), 6.977 (8.97), 6.989 (2.42), 7.597 (1.22 ), 7.600 (1.28), 7.618 (2.80), 7.635 (1.76), 7.637 ( 1.81), 7.712 (1.49), 7.715 (1.70), 7.720 (0.75), 7.732 (2.61 ), 7.736 (2.29), 7.750 (1.38), 7.753 (1.41), 7.998 ( 4.45), 8.015 (3.17), 8.020 (3.81), 8.678 (4.18), 8.682 (3.33 ), 8.694 (0.85), 9.360 (6.12), 9.365 (6.15). The following compounds (example 112 to example 129) were synthesized in analogy to example 111: Example 112 N‐(oxan‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and tetrahydro‐2H‐pyran ‐4‐amine, CAS‐RN: [38041‐19‐9]) LC‐MS (Method 1): R t = 0.88 min; MS (ESIpos): m/z = 404 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.395 (0.47) , 1.415 (1.09), 1.425 (1.14), 1.445 (1.29), 1.456 (1 .14), 1.474 (0.57), 1.485 (0.52), 1.669 (1.50), 1.675 (1.50 ), 1.700 (1.19), 1.705 (1.19), 2.332 (0.67), 2.518 ( 4.14), 2.522 (2.69), 2.669 (0.98), 2.673 (0.72), 2.874 (1.86 ), 2.891 (2.90), 2.909 (2.02), 3.296 (1.55), 3.321 ( 3.83), 3.598 (0.47), 3.608 (0.62), 3.617 (0.52), 3.627 (0.62 ), 3.636 (0.47), 3.823 (1.45), 3.829 (1.45), 3.852 ( 1.29), 3.858 (1.29), 4.036 (16.00), 4.204 (2.02), 4.221 (3.16), 4.239 (1.97), 5.757 (0.67), 6.384 (1.97), 6.404 (1.92), 6.994 (9.53), 7.596 (0.93), 7.599 (0.98), 7.6 13 (1.40), 7.617 (2.02), 7.634 (1.35), 7.636 (1.35), 7.710 (1.29), 7.714 (1.35), 7.727 (1.09), 7.731 (2.07), 7.7 35 (1.50), 7.748 (1.09), 7.752 (1.09), 7.990 (1.97), 7.997 (2.23), 8.007 (1.71), 8.010 (1.66), 8.019 (1.97), 8.6 82 (2.80), 8.687 (2.80), 9.363 (4.40), 9.368 (4.14). Example 113
N‐{[oxolan‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐(tetrahydrofuran‐ 2‐yl)methanamine, CAS‐RN: [4795‐29‐3]) LC‐MS (Method 1): R t = 0.92 min; MS (ESIpos): m/z = 405 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.521 (0.76) , 1.531 (0.52), 1.538 (0.99), 1.546 (0.64), 1.555 (0 .64), 1.562 (0.52), 1.567 (0.76), 1.584 (0.47), 1.764 (0.47 ), 1.779 (0.87), 1.784 (0.81), 1.793 (1.16), 1.800 ( 1.45), 1.807 (1.51), 1.818 (1.45), 1.826 (1.22), 1.834 (1.34 ), 1.843 (1.05), 1.850 (0.93), 1.855 (0.64), 1.861 ( 1.11), 1.874 (0.76), 1.877 (0.76), 1.881 (0.58), 1.892 (0.52 ), 1.898 (0.47), 2.331 (0.81), 2.518 (4.95), 2.522 ( 3.08), 2.673 (0.81), 2.874 (2.09), 2.891 (3.20), 2.908 (2.27 ), 3.052 (2.44), 3.067 (4.71), 3.082 (2.56), 3.585 ( 0.64), 3.601 (1.34), 3.604 (1.40), 3.621 (1.80), 3.639 (0.93 ), 3.728 (0.93), 3.745 (1.57), 3.761 (1.40), 3.764 ( 1.34), 3.782 (0.87), 3.811 (0.41), 3.827 (1.11), 3.843 (1.92), 3.858 (1.28), 4.020 (0.52), 4.040 (16.00), 4.063 (0.47), 4.203 (2.27), 4.220 (3.43), 4.238 (2.15), 6.568 (0.99), 6.583 (2.09), 6.5 98 (0.99), 6.985 (10.12), 7.595 (1.05), 7.599 (1.05), 7.613 (1.51), 7.615 (2.15 ), 7.633 (1.45), 7.636 (1.45), 7.710 (1.45), 7.714 ( 1.45), 7.727 (1.22), 7.731 (2.33), 7.735 (1.69), 7.749 (1.16 ), 7.752 (1.22), 7.990 (2.15), 7.997 (2.39), 8.007 ( 1.86), 8.011 (1.80), 8.018 (2.09), 8.682 (2.97), 8.687 (3.08 ), 9.362 (4.60), 9.367 (4.71). Example 114 (4‐methylpiperazin‐1‐yl)[2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazo l]‐1‐ yl]methanone (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐methylpiperazine, CAS‐RN: [109‐01‐3]) LC‐MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 404 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.175 (16.00), 2.254 (3.29), 2.266 (4.59), 2.278 (3.44), 2.327 (1.00), 2.331 (0.75), 2.518 (3.94), 2.523 (2.39), 2.6 69 (1.00), 2.673 (0.70), 2.886 (1.84), 2.903 (2.74), 2.921 (1.94), 3.262 (3.49), 3.274 (4.29), 3.287 (3.39), 4.142 (14.95), 4.197 (1.94), 4.215 (2.94), 4.232 (1.84), 6.987 (9.37), 7.596 (0.90), 7.599 (0.85), 7.613 (1.30 ), 7.616 (1.89), 7.619 (1.10), 7.633 (1.25), 7.636 ( 1.25), 7.710 (1.30), 7.714 (1.30), 7.727 (1.05), 7.731 (2.04 ), 7.735 (1.50), 7.749 (1.10), 7.752 (1.05), 7.993 ( 2.24), 7.997 (2.14), 7.999 (1.99), 8.009 (1.60), 8.014 (1.74 ), 8.018 (1.89), 8.686 (2.49), 8.692 (2.59), 9.361 ( 4.09), 9.367 (4.09). Example 115
N‐[2‐oxopyrrolidin‐3‐yl]‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐aminopyrrolidin‐2 ‐one, CAS‐RN: [2483‐65‐0]) LC‐MS (Method 1): R t = 0.78 min; MS (ESIpos): m/z = 403 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.825 (1.06) , 1.855 (1.36), 1.882 (1.13), 1.907 (0.98), 2.232 (0 .45), 2.240 (0.68), 2.252 (0.83), 2.261 (1.13), 2.269 (0.91 ), 2.274 (0.98), 2.283 (0.75), 2.291 (0.60), 2.303 ( 0.38), 2.331 (1.21), 2.336 (0.60), 2.518 (7.25), 2.522 (4.53 ), 2.539 (1.89), 2.673 (1.13), 2.678 (0.53), 2.891 ( 2.87), 2.909 (4.30), 2.926 (2.94), 3.145 (1.89), 3.157 (3.02 ), 3.168 (2.11), 3.181 (2.64), 4.036 (1.06), 4.043 ( 1.21), 4.063 (16.00), 4.083 (0.83), 4.088 (0.91), 4.182 (0.98), 4.204 (2.42), 4.212 (3.55), 4.230 (6.87), 4.247 (3.17), 5.757 (3.92), 6.760 (3.25), 6.781 (3.09), 6.986 (0.53), 7.021 (13.21), 7. 595 (1.51), 7.597 (1.51), 7.612 (2.19), 7.615 (3.17), 7.632 (2.11), 7.636 (2.11 ), 7.710 (2.04), 7.713 (2.11), 7.727 (1.74), 7.731 ( 3.32), 7.734 (2.49), 7.748 (2.19), 7.751 (2.79), 7.758 (4.08 ), 7.988 (3.02), 7.999 (3.62), 8.005 (2.87), 8.008 ( 2.64), 8.019 (3.17), 8.689 (4.45), 8.694 (4.38), 9.366 (6.49 ), 9.371 (6.34). Example 116 1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidi ne‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]azetidi ne‐3‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and azetidine‐3‐carboxa mide, CAS‐RN: [740768‐99‐4]) LC‐MS (Method 1): R t = 0.78 min; MS (ESIpos): m/z = 403 [M+H]⁺ 1 H‐NMR (400MHz, DMSO‐d 6 ): δ [ppm]= 2.90 (t, 2H), 3.24 ‐ 3.31 (m, 1H), 3.86 ‐ 4.00 (m, 4H), 4.06 ‐ 4.13 (m, 4H), 4.21 (t, 2H), 6.99 ‐ 7.02 (m, 1H), 7.02 ‐ 7.08 (m, 1H), 7.42 ‐ 7.50 (m, 1H), 7.59 7.65 (m, 1H), 7.73 (ddd, 1H), 8.01 (d, 2H), 8.68 (d, 1H), 9.36 (d, 1H ). Example 117
N‐[(1H‐pyrazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐(1H‐pyrazol‐3 yl)methanamine, CAS‐RN: [37599‐58‐9]) LC‐MS (Method 1): R t = 0.83 min; MS (ESIpos): m/z = 400 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.907 (0.44) , 2.336 (0.62), 2.518 (8.62), 2.522 (5.63), 2.539 (0 .88), 2.673 (1.32), 2.678 (0.62), 2.881 (3.16), 2.898 (5.10), 2.916 (3.43), 3.356 (2.37), 3.377 (1.14), 4.069 (16.00), 4.205 (4.48), 4.223 (7.91), 4.240 (5.36), 6. 145 (2.11), 6.944 (0.70), 6.985 (15.38), 7.003 (0.44) , 7.596 (1.93), 7.599 (2.02), 7.613 (2.99), 7.617 (4.13 ), 7.634 (2.99), 7.636 (2.99), 7.710 (2.37), 7.714 ( 2.46), 7.727 (2.02), 7.731 (3.87), 7.735 (2.81), 7.748 (2.02 ), 7.752 (2.11), 7.991 (3.60), 7.997 (4.22), 8.008 ( 3.16), 8.012 (2.99), 8.019 (3.69), 8.681 (5.10), 8.686 (5.27 ), 9.361 (8.09), 9.367 (7.65), 12.538 (0.79). Example 118 (morpholin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihy drospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and morpholine, CAS‐RN: [110‐91‐8]) LC‐MS (Method 1): R t = 0.92 min; MS (ESIpos): m/z = 391 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (3.90) , 2.885 (2.01), 2.903 (3.22), 2.920 (2.09), 3.261 (4 .38), 3.272 (6.43), 3.285 (5.27), 3.544 (5.11), 3.557 (6.23), 3.568 (4.34), 4.160 (16.00), 4.196 (2.21), 4.214 (3.42), 4.231 (2.05), 6.983 (7.32), 7.593 (0.88), 7.6 13 (1.89), 7.630 (1.25), 7.633 (1.25), 7.706 (1.13), 7.710 (1.13), 7.727 (1.85), 7.731 (1.45), 7.745 (1.01), 7.7 48 (0.96), 7.991 (3.22), 8.012 (2.65), 8.682 (2.85), 8.687 (2.85), 9.357 (3.66), 9.363 (3.66). Example 119
N‐(3‐hydroxypropyl)‐2'‐(quinolin‐3‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐aminopropan‐1‐o l, CAS‐RN: [156‐87‐6]) LC‐MS (Method 1): R t = 0.81 min; MS (ESIpos): m/z = 379 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.530 (0.62) , 1.546 (2.03), 1.563 (2.95), 1.580 (2.09), 1.596 (0 .62), 2.517 (6.09), 2.522 (3.82), 2.673 (0.86), 2.874 (1.91 ), 2.892 (2.95), 2.909 (2.03), 3.054 (1.11), 3.071 ( 2.34), 3.087 (2.34), 3.103 (0.98), 3.297 (0.62), 3.306 (0.80 ), 3.375 (0.62), 3.406 (1.35), 3.422 (3.14), 3.436 ( 3.14), 3.450 (1.23), 4.029 (16.00), 4.202 (2.03), 4.221 (3.14), 4.237 (1.91), 4.433 (1.35), 4.446 (2.89), 4.459 (1.29), 5.757 (8.74), 6.477 (0.92), 6.491 (1.91), 6.5 06 (0.92), 6.986 (8.25), 7.596 (0.86), 7.599 (0.92), 7.613 (1.35), 7.616 (1.91), 7.634 (1.29), 7.636 (1.29), 7.7 10 (1.17), 7.713 (1.23), 7.727 (1.05), 7.731 (1.91), 7.734 (1.42), 7.748 (1.05), 7.752 (0.98), 7.991 (2.03), 7.9 97 (2.28), 8.008 (1.72), 8.019 (1.97), 8.681 (2.77), 8.686 (2.83), 9.361 (4.00), 9.367 (4.00). Example 120 N‐(2‐hydroxyethyl)‐N‐methyl‐2'‐(quinolin‐3‐y l)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(methylamino)ethano l, CAS‐RN: [109‐83‐1]) LC‐MS (Method 1): R t = 0.86 min; MS (ESIpos): m/z = 378 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.331 (0.58) , 2.518 (3.26), 2.522 (1.99), 2.669 (0.78), 2.673 (0 .58), 2.854 (16.00), 2.884 (1.51), 2.902 (2.24), 2.919 (1.56), 3.229 (1.31), 3.245 (3.16), 3.260 (1.70), 3.497 (0.78), 3.512 (1.90), 3.526 (1.80), 3.541 (0.63), 4.128 (11.28), 4.204 (1.60), 4.222 (2.38), 4.239 (1.51), 4.690 (0.63), 4.703 (1.31), 4.717 (0.63), 6.976 (7.10 ), 7.597 (0.73), 7.599 (0.68), 7.614 (1.07), 7.617 ( 1.51), 7.619 (0.92), 7.634 (0.97), 7.636 (0.97), 7.710 (0.97 ), 7.714 (0.97), 7.728 (0.88), 7.731 (1.51), 7.735 ( 1.17), 7.749 (0.83), 7.752 (0.83), 7.997 (2.43), 8.018 (2.14 ), 8.687 (2.04), 8.692 (2.04), 9.364 (3.11), 9.369 ( 3.16).
Example 121 N‐(2‐oxopiperidin‐4‐yl)‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐1‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 4‐aminopiperidin‐2 one, CAS‐RN: [5513‐66‐6]) LC‐MS (Method 1): R t = 0.79 min; MS (ESIpos): m/z = 417 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.228 (0.54) , 1.564 (0.53), 1.571 (0.51), 1.577 (0.68), 1.584 (0 .54), 1.589 (0.51), 1.595 (0.89), 1.602 (0.59), 1.609 (0.69 ), 1.845 (0.73), 1.854 (0.77), 1.864 (0.54), 1.875 ( 0.61), 1.885 (0.59), 2.092 (1.11), 2.115 (1.11), 2.135 (1.46 ), 2.157 (1.53), 2.331 (0.51), 2.349 (1.05), 2.361 ( 1.07), 2.388 (0.76), 2.392 (0.78), 2.403 (0.78), 2.518 (3.58 ), 2.522 (2.21), 2.669 (0.67), 2.673 (0.50), 2.879 ( 2.01), 2.897 (3.23), 2.914 (2.15), 3.108 (0.83), 3.116 (0.75 ), 3.133 (0.76), 3.145 (0.94), 3.157 (1.01), 3.166 ( 1.03), 3.176 (0.75), 3.187 (0.45), 3.195 (0.41), 3.820 (0.56 ), 3.829 (0.58), 3.838 (0.74), 3.846 (0.70), 3.854 ( 0.58), 3.863 (0.60), 4.051 (16.00), 4.205 (2.19), 4.223 (3.45), 4.240 (2.11), 6.525 (2.18), 6.544 (2.11), 6.999 (8.87), 7.521 (1.82), 7.597 (1.05), 7.599 (1.03), 7.6 14 (1.54), 7.617 (2.20), 7.634 (1.44), 7.637 (1.43), 7.710 (1.38), 7.714 (1.39), 7.728 (1.22), 7.731 (2.20), 7.7 35 (1.62), 7.749 (1.15), 7.752 (1.16), 7.993 (2.36), 7.998 (2.61), 8.009 (1.99), 8.013 (1.96), 8.019 (2.26), 8.6 83 (3.10), 8.688 (3.16), 9.364 (4.45), 9.369 (4.43). Example 122 N‐(6‐oxopiperidin‐3‐yl)‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyr azole]‐1‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 5‐aminopiperidin‐2 one, CAS‐RN: [154148‐70‐6]) LC‐MS (Method 1): R t = 0.79 min; MS (ESIpos): m/z = 417 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.913 (0.71) , 0.932 (0.58), 0.945 (4.11), 0.951 (0.53), 0.962 (8 .26), 0.981 (4.03), 1.230 (2.63), 1.374 (2.75), 1.399 (0.61 ), 1.702 (0.41), 1.711 (0.45), 1.721 (0.53), 1.728 ( 0.65), 1.735 (0.74), 1.744 (0.42), 1.753 (0.78), 1.758 (0.55 ), 1.776 (0.43), 1.820 (0.69), 1.831 (0.78), 1.845 ( 0.53),
1.862 (0.42), 2.217 (1.17), 2.233 (1.99), 2.244 (1 .81), 2.249 (1.57), 2.256 (1.19), 2.262 (1.23), 2.332 (0.41), 2.518 (2.56), 2.522 (1.64), 2.876 (1.95), 2.893 (3.11 ), 2.910 (2.09), 2.943 (1.33), 2.962 (2.83), 2.968 ( 1.21), 2.976 (2.42), 2.980 (2.23), 2.993 (2.84), 3.011 (0.63 ), 3.226 (0.56), 3.235 (0.91), 3.244 (0.66), 3.252 ( 0.56), 3.256 (0.55), 3.264 (0.79), 3.273 (0.50), 3.791 (0.48), 3.800 (0.59), 3.810 (0.64), 4.057 (16.00), 4.204 (2.11), 4.221 (3.31), 4.239 (2.08), 5.715 (0.48), 6.5 23 (2.11), 6.542 (2.03), 6.992 (8.85), 7.388 (1.64), 7.392 (1.65), 7.597 (0.97), 7.599 (0.96), 7.614 (1.48), 7.6 17 (2.07), 7.634 (1.37), 7.637 (1.39), 7.710 (1.33), 7.714 (1.39), 7.728 (1.12), 7.731 (2.12), 7.735 (1.54), 7.7 49 (1.14), 7.752 (1.11), 7.992 (2.16), 7.998 (2.43), 8.009 (1.85), 8.013 (1.80), 8.019 (2.14), 8.680 (2.95), 8.6 85 (3.02), 9.362 (4.31), 9.368 (4.32). Example 123 N‐[2‐(1H‐imidazol‐1‐yl)ethyl]‐2'‐(quinolin‐3 ‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 ‐ b]pyrazole]‐1‐carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(1H‐imidazol‐1 yl)ethanamine, CAS‐RN: [5739‐10‐6]) LC‐MS (Method 1): R t = 0.82 min; MS (ESIpos): m/z = 415 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.229 (0.86) , 2.323 (0.75), 2.327 (1.01), 2.331 (0.75), 2.665 (0 .78), 2.669 (1.01), 2.673 (0.78), 2.874 (1.72), 2.892 (2.86), 2.909 (1.82), 4.023 (16.00), 4.039 (4.08), 4.053 (1.90), 4.202 (1.87), 4.219 (2.99), 4.236 (1.77), 6.6 87 (0.83), 6.701 (1.74), 6.715 (0.83), 6.910 (3.98), 6.984 (6.37), 7.171 (3.98), 7.600 (0.88), 7.615 (5.00), 7.6 38 (1.22), 7.712 (1.01), 7.715 (0.99), 7.732 (1.64), 7.736 (1.35), 7.751 (0.88), 7.753 (0.91), 8.000 (3.54), 8.0 21 (3.15), 8.689 (2.63), 8.693 (2.73), 9.368 (3.30), 9.373 (3.28). Example 124 N‐benzyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro [azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxam ide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and benzylamine, CAS‐RN: [100‐46‐9]) LC‐MS (Method 1): R t = 1.05 min; MS (ESIpos): m/z = 411 [M+H]
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.323 (0. 62), 2.327 (0.85), 2.332 (0.62), 2.522 (2.69), 2.665 (0.62), 2.669 (0.87), 2.673 (0.64), 2.894 (1.90), 2.911 (3.07), 2.929 (2.03), 4.088 (16.00), 4.210 (2.09), 4.228 (3.48), 4.240 (4.39), 4.255 (3.84), 5.758 (0.47), 7.0 00 (7.83), 7.096 (0.96), 7.111 (2.03), 7.126 (0.94), 7.221 (0.66), 7.238 (1.83), 7.250 (0.70), 7.255 (1.19), 7.2 59 (0.85), 7.287 (1.98), 7.304 (5.25), 7.319 (4.35), 7.324 (1.11), 7.337 (3.65), 7.355 (1.15), 7.599 (0.90), 7.6 01 (0.90), 7.618 (1.94), 7.636 (1.28), 7.639 (1.26), 7.712 (1.15), 7.715 (1.17), 7.733 (1.90), 7.736 (1.41), 7.7 50 (1.00), 7.753 (0.98), 7.993 (2.07), 8.000 (2.33), 8.010 (1.79), 8.021 (2.03), 8.685 (2.84), 8.689 (2.88), 9.3 65 (3.88), 9.371 (3.75). Example 125 N‐(2‐hydroxy‐2‐methylpropyl)‐2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐amino‐2‐methylp ropan‐2‐ol, CAS‐RN: [2854‐16‐2]) LC‐MS (Method 1): R t = 0.85 min; MS (ESIpos): m/z = 393 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.061 (16.00), 1.339 (0.44), 2.518 (1.66), 2.522 (1.07), 2.886 (0.91), 2.903 (1.39), 2.921 (0.99), 2.997 (1.86), 3.0 12 (1.90), 4.075 (7.68), 4.208 (0.95), 4.226 (1.47), 4.244 (0.91), 4.515 (3.17), 6.346 (0.40), 6.361 (0.91), 6.3 77 (0.40), 6.983 (4.51), 7.596 (0.48), 7.599 (0.48), 7.613 (0.67), 7.617 (0.99), 7.619 (0.59), 7.634 (0.63), 7.6 37 (0.63), 7.710 (0.63), 7.714 (0.63), 7.728 (0.51), 7.731 (0.99), 7.735 (0.71), 7.749 (0.55), 7.752 (0.51), 7.9 95 (1.07), 7.998 (1.11), 8.000 (1.07), 8.010 (0.83), 8.015 (0.87), 8.019 (0.99), 8.685 (1.31), 8.690 (1.35), 9.3 64 (2.14), 9.370 (2.06). Example 126 N‐[(1‐methyl‐1H‐imidazol‐4‐yl)methyl]‐2'‐(qu inolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐(1‐methyl‐1H‐ imidazol‐4‐yl)methanamine, CAS‐RN: [486414‐83‐9] ) LC‐MS (Method 1): R t = 0.83 min; MS (ESIpos): m/z = 415 [M+H]
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.332 (0. 71), 2.518 (5.52), 2.522 (3.86), 2.576 (0.55), 2.587 (0.47), 2.673 (0.71), 2.872 (1.42), 2.890 (2.21), 2.907 (1.58), 3.383 (0.95), 3.608 (16.00), 4.028 (1.02), 4.050 (11.19), 4.072 (3.07), 4.086 (2.84), 4.202 (1.58), 4.220 (2.36), 4.237 (1.50), 6.798 (0.71), 6.813 (1.50), 6.827 (0.71), 6.909 (2.52), 6.912 (2.52), 6.979 (0.71 ), 6.983 (6.94), 7.467 (2.52), 7.469 (2.52), 7.596 ( 0.79), 7.598 (0.79), 7.613 (1.10), 7.616 (1.58), 7.618 (0.95 ), 7.633 (1.10), 7.636 (1.02), 7.710 (1.02), 7.713 ( 1.10), 7.727 (0.87), 7.731 (1.66), 7.734 (1.18), 7.748 (0.95 ), 7.752 (0.87), 7.990 (1.50), 7.997 (1.73), 7.999 ( 1.73), 8.007 (1.26), 8.010 (1.26), 8.018 (1.50), 8.680 (2.05 ), 8.685 (2.13), 9.360 (3.23), 9.365 (3.39). Example 127 N‐{[5‐oxopyrrolidin‐2‐yl]methyl}‐2'‐(quinolin‐ 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1, 2‐ b]pyrazole]‐1‐carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 5‐(aminomethyl)pyrrol idin‐2‐one, CAS‐RN: [154148‐69‐3]) LC‐MS (Method 1): R t = 0.80 min; MS (ESIpos): m/z = 418 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.689 (0.72) , 1.703 (1.15), 1.719 (0.86), 1.729 (1.15), 1.740 (0 .58), 2.028 (0.72), 2.033 (0.72), 2.051 (1.15), 2.067 (2.02 ), 2.078 (0.72), 2.083 (0.86), 2.088 (0.58), 2.097 ( 2.02), 2.103 (1.15), 2.112 (3.46), 2.118 (1.73), 2.135 (1.73 ), 2.143 (1.59), 2.159 (1.59), 2.183 (0.58), 2.331 ( 1.15), 2.336 (0.58), 2.518 (7.06), 2.522 (4.32), 2.539 (0.72 ), 2.678 (0.43), 2.883 (2.59), 2.900 (4.18), 2.917 ( 2.74), 3.029 (1.73), 3.034 (1.73), 3.044 (3.17), 3.048 (3.32 ), 3.060 (1.87), 3.063 (1.87), 3.386 (0.86), 3.397 ( 0.43), 3.552 (1.15), 3.567 (1.59), 3.582 (1.15), 4.042 (1.30), 4.062 (16.00), 4.087 (1.01), 4.208 (2.88), 4.226 (4.47), 4.243 (2.74), 6.579 (1.30), 6.594 (2.74), 6.609 (1.15), 6.980 (12.54), 7. 597 (1.44), 7.600 (1.30), 7.614 (2.16), 7.617 (2.88), 7.634 (1.87), 7.637 (1.87 ), 7.681 (3.89), 7.711 (2.02), 7.715 (1.87), 7.728 ( 1.59), 7.732 (3.03), 7.736 (2.31), 7.750 (1.59), 7.753 (1.59 ), 7.997 (4.76), 8.018 (4.04), 8.681 (4.04), 8.686 ( 4.18), 9.362 (6.05), 9.368 (6.05). Example 128
[3‐(dimethylamino)pyrrolidin‐1‐yl][2'‐(quinolin 3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1 ,2‐ b]pyrazol]‐1‐yl]methanone (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and N,N‐dimethylpyrrolidi n‐3‐amine, CAS‐RN: [69478‐75‐7]) LC‐MS (Method 1): R t = 0.94 min; MS (ESIpos): m/z = 418 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.627 (0.74) , 1.654 (1.05), 1.679 (0.84), 1.907 (0.84), 1.987 (0 .53), 2.001 (1.05), 2.017 (0.95), 2.028 (0.84), 2.042 (0.53), 2.169 (16.00), 2.318 (0.63), 2.322 (1.37), 2.326 (1.79), 2.332 (1.37), 2.336 (0.63), 2.518 (7.47), 2.5 22 (4.74), 2.539 (0.53), 2.620 (0.63), 2.660 (0.84), 2.664 (1.47), 2.669 (2.00), 2.673 (1.47), 2.678 (0.63), 2.8 88 (2.53), 2.904 (4.21), 2.907 (4.11), 2.923 (2.95), 2.997 (1.26), 3.020 (1.79), 3.043 (1.16), 3.223 (0.84), 3.2 40 (1.16), 3.248 (2.00), 3.266 (2.11), 3.274 (1.47), 3.291 (1.47), 3.299 (1.05), 3.395 (1.89), 3.401 (1.89), 3.4 22 (2.21), 3.442 (1.05), 3.448 (0.95), 3.483 (1.58), 3.501 (1.79), 3.508 (1.68), 3.526 (1.37), 4.067 (3.16), 4.0 74 (3.37), 4.088 (4.32), 4.094 (4.74), 4.173 (7.26), 4.194 (5.37), 4.202 (3.79), 4.210 (1.16), 4.219 (5.89), 4.237 (3.26), 6.988 (15.37), 7. 596 (1.58), 7.599 (1.47), 7.614 (2.32), 7.617 (3.26), 7.620 (2.00), 7.634 (2.11 ), 7.637 (2.21), 7.711 (2.21), 7.715 (2.11), 7.728 ( 1.79), 7.732 (3.26), 7.736 (2.63), 7.749 (1.79), 7.752 (1.89 ), 7.996 (5.47), 8.017 (4.84), 8.678 (4.53), 8.683 ( 4.63), 9.359 (7.26), 9.364 (7.05). Example 129 N‐{2‐[oxolan‐3‐yl]ethyl}‐2'‐(quinolin‐3‐yl) 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxamide (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydros piro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(tetrahydrofuran‐ 3‐yl)ethanamine, CAS‐RN: [770709‐01‐8]) LC‐MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 419 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.415 (1.05) , 1.425 (0.53), 1.434 (1.16), 1.444 (1.26), 1.453 (1 .37), 1.464 (1.58), 1.472 (2.84), 1.489 (2.95), 1.507 (1.16 ), 1.972 (0.42), 1.984 (0.53), 1.991 (0.74), 2.002 ( 1.05), 2.010 (0.63), 2.013 (0.53), 2.021 (1.16), 2.033 (0.74 ), 2.039 (0.53), 2.051 (0.53), 2.099 (0.53), 2.117 ( 1.16), 2.135 (1.37), 2.154 (1.05), 2.172 (0.42), 2.331 (0.84 ), 2.518 (5.37), 2.522 (3.37), 2.673 (0.84), 2.874 ( 1.89), 2.891 (2.95), 2.909 (2.00), 3.003 (0.63), 3.020 (1.47 ), 3.032 (1.58), 3.045 (1.37), 3.063 (0.63), 3.197 ( 1.79), 3.216 (2.53), 3.235 (1.89), 3.589 (0.84), 3.608 (1.89 ), 3.628 (2.42), 3.646 (1.16), 3.688 (1.05), 3.700 ( 1.16), 3.709 (1.79), 3.721 (1.79), 3.730 (0.74), 3.741 (0.74), 3.793 (1.68), 3.811 (2.32), 3.831 (1.58), 4.029 (16.00), 4.202 (2.00), 4.220 (3.16), 4.237 (1.89), 6.520 (0.95), 6.535 (1.89), 6.549 (0.95), 6.978 (8.63), 7.596 (0.95), 7.599 (0.95), 7.614 (1.37), 7.616 (2.00 ), 7.633 (1.26), 7.636 (1.26), 7.710 (1.16), 7.714 ( 1.16),
7.728 (1.05), 7.731 (1.89), 7.735 (1.47), 7.749 (1 .05), 7.752 (1.05), 7.992 (2.00), 7.997 (2.32), 8.008 (1.79), 8.012 (1.68), 8.018 (2.00), 8.679 (2.74), 8.684 (2.84 ), 9.360 (4.00), 9.365 (4.00). Example 130 N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ole]‐1‐ carboxamide Step 1: To a solution of tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihyd rospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (750 mg, 1.99 2 mmol, see example 3) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2' (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) was used in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[a zetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (109 mg , 40 % purity, 115 µmol) was dissolved in DCM (3. 0 ml) and DIPEA (200 µl, 1.1 mmol; CAS‐RN:[7087‐68‐5]) under ni trogen, isocyanatoethane (27 µl, 340 µmol) was added and the mixture was stirred overnig ht at rt. The solution was evaporated and purified by preparative HPLC to yield the title compound (21. 8 mg, 95 % purity, 54 % yield). LC‐MS (Method 1) : R t = 0.73 min; MS (ESIpos): m/z = 337 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.00 2 (7.18), 1.020 (16.00), 1.038 (7.23), 2.332 (0.66), 2.518 (3.89), 2.523 (2.52), 2.539 (1.75), 2.840 (2.47), 2.858 (3.89), 2.875 (2.68), 3.008 (0.93), 3.026 (3.01), 3.039 (3.18 ), 3.043 (3.18), 3.057 (2.85), 3.076 (0.82), 3.980 ( 1.15), 4.003 (14.14), 4.023 (1.15), 4.141 (2.63), 4.150 (0.99), 4.159 (4.11), 4.176 (2.58), 6.447 (2.85), 6.452 (3.34), 6.456 (4.16), 6.460 (3.23), 6.470 (2.68), 6.484 (1.26), 6.734 (12.71), 7. 456 (2.41), 7.463 (2.90), 7.470 (2.36), 8.272 (4.16), 8.278 (4.33), 8.656 (5.37 ), 8.661 (5.32), 11.642 (1.97). The following compounds (example 131 to example 143) were synthesized in analogy to example 130: Example 131 2'‐(2‐aminopyrimidin‐5‐yl)‐N‐ethyl‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxamide
(prepared from tert‐butyl 2'‐(2‐aminopyrimidin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1 ,2‐ b]pyrazole]‐1‐carboxylate (see example 4) and isocy anatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.58 min; MS (ESIpos): m/z = 314 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.991 (4.08) , 1.009 (9.51), 1.026 (4.12), 2.331 (0.44), 2.518 (3 .17), 2.522 (1.86), 2.673 (0.44), 2.813 (1.46), 2.831 (2.30 ), 2.848 (1.53), 2.995 (0.55), 3.013 (1.75), 3.027 ( 1.86), 3.031 (1.86), 3.044 (1.68), 3.062 (0.47), 3.327 (2.51 ), 3.371 (0.44), 3.376 (0.40), 3.945 (0.95), 3.965 ( 6.63), 3.970 (6.38), 3.990 (0.95), 4.098 (1.57), 4.107 (0.58 ), 4.116 (2.37), 4.132 (1.49), 6.444 (0.73), 6.458 ( 1.46), 6.473 (0.69), 6.621 (7.40), 6.716 (4.05), 8.595 (16.0 0). Example 132 2'‐(6‐aminopyridin‐3‐yl)‐N‐ethyl‐5',6'‐dihyd rospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide (prepared from tert‐butyl 2'‐(6‐aminopyridin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 168) and iso cyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.64 min; MS (ESIpos): m/z = 313 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.991 (5.82), 1.010 (13.28), 1.028 (6.20), 1.221 (0.42), 1.239 (1.99), 1.255 (1.91), 1.270 (1.15), 1.907 (0.88), 2.3 32 (1.22), 2.518 (7.96), 2.522 (5.01), 2.673 (1.26), 2.808 (2.33), 2.826 (3.83), 2.843 (2.49), 2.996 (0.84), 3.0 13 (2.68), 3.027 (2.99), 3.031 (2.95), 3.045 (2.60), 3.063 (0.77), 3.946 (0.88), 3.967 (16.00), 3.988 (0.96), 4.086 (2.49), 4.104 (3.90), 4.121 (2.37), 6.354 (0.80), 6.440 (1.26), 6.454 (2.45), 6.468 (1.22), 6.539 (1.84 ), 6.566 (8.57), 7.816 (1.26), 7.821 (1.26), 7.838 ( 1.22), 8.305 (3.37), 8.310 (3.33). Example 133 N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐methyl‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 11) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.81 min; MS (ESIpos): m/z = 351 [M+H]
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.932 (1.81), 0.935 (0.56), 0.948 (1.81), 1.004 (6.50), 1.021 (15.69), 1.039 (6.99), 2.270 (15.27), 2.273 (15.34), 2.331 (0.91), 2.336 (0.42), 2.518 (4.90), 2.523 (3.11 ), 2.678 (0.39), 2.844 (2.26), 2.861 (3.57), 2.879 (2.41 ), 3.010 (0.85), 3.027 (2.76), 3.041 (3.03), 3.045 ( 2.93), 3.059 (2.72), 3.077 (0.79), 3.983 (0.81), 4.004 (16.00), 4.025 (0.79), 4.139 (2.41), 4.158 (3.74), 4.174 (2.30), 5.759 (1.29), 6.456 (1.18), 6.470 (2.43), 6.484 (1.14), 6.765 (11.64), 7. 218 (2.84), 7.221 (2.86), 8.241 (3.82), 8.245 (3.86), 8.632 (5.11), 8.637 (4.94 ), 11.279 (2.03). Example 134 N‐ethyl‐2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxamide (prepared from tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin 7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxylate (see example 12) and isoc yanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.65 min; MS (ESIpos): m/z = 350 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.009 (5.21), 1.026 (11.77), 1.045 (5.25), 2.518 (4.19), 2.522 (2.63), 2.673 (0.80), 2.886 (1.84), 2.903 (2.71), 2.9 21 (1.97), 3.016 (0.67), 3.034 (2.13), 3.048 (2.30), 3.051 (2.24), 3.066 (2.13), 3.084 (0.61), 4.030 (16.00), 4.237 (1.97), 4.255 (2.87), 4.272 (1.85), 5.758 (1.54), 6.490 (0.85), 6.504 (1.74), 6.518 (0.83), 7.181 (8.95 ), 8.780 (4.08), 8.786 (4.30), 9.063 (3.54), 9.067 ( 5.12), 9.086 (6.60), 9.090 (4.39), 9.654 (4.36), 9.660 (4.34 ). Example 135 N‐ethyl‐2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐d ihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 ‐ carboxamide (prepared from tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[ azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 13) and isoc yanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.77 min; MS (ESIpos): m/z = 338 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.931 (1.78), 0.934 (0.60), 0.948 (1.82), 1.002 (5.26), 1.019 (12.08), 1.037 (5.23), 2.331 (0.61), 2.518 (3.26), 2.523 (2.08), 2.673 (0.63), 2.851 (1.89), 2.868 (2.84), 2.886 (2.01), 3.008 (0.67), 3.025 (2.19), 3.039 (2.38), 3.043 (2.32), 3.057 (2.14), 3.075 (0.61), 4.003
(16.00), 4.170 (2.01), 4.188 (3.06), 4.205 (1.92), 5.759 (2.65), 6.468 (0.85), 6.482 (1.72), 6.496 (0.85), 6.908 (9.05), 7.134 (2.87), 7.137 (2.97), 7.140 (3.02 ), 7.143 (2.90), 8.308 (5.61), 8.313 (5.71), 8.318 ( 2.94), 8.320 (3.26), 8.322 (3.22), 8.325 (2.74), 8.997 (5.04 ), 9.002 (4.88). Example 136 N‐ethyl‐2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxamide (prepared from tert‐butyl 2'‐(6‐fluoroquinolin‐3 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐1‐carboxylate (see example 16) and isoc yanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 366 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.932 (1.13), 0.948 (1.13), 1.007 (5.05), 1.025 (11.49), 1.043 (5.08), 2.327 (1.49), 2.331 (1.08), 2.336 (0.49), 2.5 18 (5.80), 2.522 (3.63), 2.669 (1.52), 2.673 (1.11), 2.678 (0.49), 2.873 (1.88), 2.891 (2.86), 2.908 (1.98), 3.0 14 (0.67), 3.032 (2.14), 3.046 (2.40), 3.050 (2.27), 3.064 (2.14), 3.082 (0.62), 4.021 (16.00), 4.205 (2.06), 4.223 (3.01), 4.240 (1.86), 5.758 (6.54), 6.476 (0.90), 6.490 (1.86), 6.504 (0.88), 6.985 (8.35), 7.610 (0.80 ), 7.617 (0.98), 7.633 (1.29), 7.640 (1.52), 7.655 ( 0.90), 7.662 (1.03), 7.780 (1.47), 7.787 (1.44), 7.804 (1.52 ), 7.811 (1.39), 8.054 (1.26), 8.068 (1.29), 8.077 ( 1.21), 8.090 (1.16), 8.685 (2.71), 8.690 (2.73), 9.338 (3.38 ), 9.343 (3.27). Example 137 N‐ethyl‐2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl] ‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]p yrazole]‐1‐ carboxamide (prepared from tert‐butyl 2'‐[5‐(pyrrolidin‐1‐y l)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4' pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 7) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 367 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.995 (5.14), 1.013 (11.74), 1.031 (5.06), 1.953 (2.20), 1.962 (2.65), 1.969 (6.37), 1.977 (2.64), 1.986 (2.33), 2.3 31 (0.42), 2.518 (2.39), 2.522 (1.51), 2.673 (0.42), 2.832 (1.84), 2.849 (2.82), 2.867 (1.95), 3.001 (0.65), 3.0 18 (2.17), 3.032 (2.33), 3.036 (2.29), 3.050 (2.08), 3.069 (0.61), 3.274 (2.28), 3.290 (5.92), 3.306 (2.35), 3.987 (16.00), 4.142 (1.95), 4.160 (2.93), 4.177 (1.85),
5.758 (2.74), 6.450 (0.89), 6.464 (1.82), 6.478 (0 .87), 6.795 (8.92), 7.189 (1.67), 7.194 (2.14), 7.196 (2.11), 7.201 (1.66), 7.843 (3.13), 7.850 (3.05), 8.246 (3.64 ), 8.250 (3.49). Example 138 N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyra zole]‐ 1‐carboxamide (prepared from tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]p yridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 10) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.65 min; MS (ESIpos): m/z = 338 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.002 (5.49), 1.020 (12.74), 1.038 (5.52), 2.331 (0.70), 2.518 (3.73), 2.522 (2.38), 2.673 (0.72), 2.850 (1.93), 2.8 67 (2.94), 2.884 (2.05), 3.008 (0.70), 3.026 (2.28), 3.040 (2.46), 3.044 (2.43), 3.058 (2.23), 3.076 (0.63), 4.005 (16.00), 4.161 (2.03), 4.179 (3.09), 4.196 (1.93), 5.758 (1.46), 6.464 (0.95), 6.478 (1.98), 6.492 (0.93 ), 6.832 (9.46), 8.156 (4.82), 8.524 (4.47), 8.529 ( 4.61), 8.977 (4.61), 8.982 (4.51), 13.669 (1.08). Example 139 N‐ethyl‐2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐methyl‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 11) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.72 min; MS (ESIpos): m/z = 352 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.003 (3.84) , 1.021 (9.00), 1.039 (4.05), 2.326 (0.74), 2.332 (0 .54), 2.516 (16.00), 2.522 (2.96), 2.669 (0.77), 2.673 (0.61), 2.851 (1.37), 2.869 (2.19), 2.886 (1.47), 3.010 (0.51), 3.027 (1.66), 3.041 (1.78), 3.045 (1.78), 3.060 (1.60), 3.077 (0.47), 4.0 06 (11.39), 4.155 (1.46), 4.173 (2.29), 4.190 (1.43), 6.466 (0.73), 6.480 (1.52 ), 6.494 (0.71), 6.846 (6.56), 8.515 (2.92), 8.520 ( 2.95), 8.936 (2.84), 8.941 (2.84), 13.212 (1.28). Example 140
N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(2‐methyl‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 14) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.82 min; MS (ESIpos): m/z = 351 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.001 (6.46), 1.019 (15.34), 1.036 (6.93), 2.332 (0.75), 2.387 (13.81), 2.518 (4.79), 2.522 (3.03), 2.539 (0.78), 2.673 (0.75), 2.834 (2.33), 2.851 (3.74), 2.869 (2.51), 3.006 (0.85), 3.024 (2.80), 3.038 (3.03), 3.041 (3.01), 3.055 (2.73), 3.073 (0.80), 3.974 (0.85), 3.995 (16.00), 4.016 (0.87), 4.129 (2.49), 4.147 (3.90), 4.164 (2.37), 6.136 (2.56), 6.138 (3.41), 6.140 (3.45), 6.143 (2.68), 6.451 (1.22), 6.464 (2.54), 6.478 (1.20), 6.696 (10.69), 8.104 (3.81), 8.109 (3.92), 8.525 (4.93), 8.530 (4.93), 11.452 (2.28). Example 141 N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1 ,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrol o[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine ‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 17) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.90 min; MS (ESIpos): m/z = 365 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.003 (6.12), 1.021 (14.47), 1.039 (6.43), 1.251 (6.78), 1.265 (1.25), 1.270 (16.00), 1.289 (6.89), 2.332 (0.87), 2.518 (4.83), 2.523 (3.27), 2.673 (0.87), 2.679 (0.42), 2.692 (1.25), 2.710 (3.58), 2.711 (3.65), 2.729 (3.48 ), 2.730 (3.51), 2.749 (1.11), 2.842 (2.12), 2.860 ( 3.34), 2.877 (2.23), 3.009 (0.77), 3.027 (2.54), 3.041 (2.75 ), 3.045 (2.71), 3.059 (2.47), 3.077 (0.73), 3.159 ( 0.70), 3.172 (0.77), 3.983 (0.94), 4.005 (12.83), 4.026 (0.94), 4.140 (2.30), 4.149 (0.94), 4.158 (3.51), 4.175 (2.12), 6.456 (1.11), 6.470 (2.33), 6.484 (1.08), 6.775 (10.78), 7.218 (2.96), 7.221 (2.71), 7.224 (2.89), 8.260 (3.55), 8.265 (3.62), 8.630 (4.73), 8.635 (4.42 ), 11.297 (1.98). Example 142
2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4 '‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(2‐chloro‐3‐ethyl 1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate (see example 169/intermediate 80) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 1.01 min; MS (ESIpos): m/z = 400 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.001 (5.48), 1.019 (12.29), 1.037 (5.57), 1.178 (4.33), 1.197 (10.08), 1.216 (4.51), 1.232 (0.53), 1.252 (0.53), 2.331 (0.97), 2.518 (6.81), 2.522 (4.42), 2.539 (0.80), 2.673 (1.59), 2.677 (1.41), 2.695 (3.09), 2.714 (3.01 ), 2.733 (0.97), 2.842 (1.94), 2.859 (3.18), 2.877 ( 2.12), 3.007 (0.71), 3.025 (2.39), 3.039 (2.65), 3.043 (2.56 ), 3.057 (2.30), 3.074 (0.71), 3.290 (0.44), 3.294 ( 0.44), 3.300 (0.44), 3.382 (0.80), 3.385 (0.62), 4.001 (16.00), 4.142 (2.03), 4.159 (3.27), 4.176 (2.03), 5.756 (4.86), 6.459 (1.06), 6.473 (2.21), 6.487 (1.06), 6.8 10 (8.84), 8.258 (3.80), 8.263 (3.89), 8.642 (4.51), 8.647 (4.33), 12.222 (2.92). Example 143 N‐ethyl‐2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3 ‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3, 4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro ‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate (see example 8) and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.61 min; MS (ESIpos): m/z = 353 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.995 (5.26), 1.013 (12.28), 1.030 (5.68), 1.230 (0.78), 2.331 (0.68), 2.518 (4.96), 2.522 (3.09), 2.673 (0.70), 2.8 27 (2.02), 2.844 (3.28), 2.862 (2.16), 2.999 (0.75), 3.017 (2.39), 3.031 (2.64), 3.034 (2.66), 3.049 (2.33), 3.067 (0.70), 3.582 (6.73), 3.9 60 (0.54), 3.980 (16.00),
4.120 (2.13), 4.138 (3.33), 4.155 (2.05), 6.450 (1 .09), 6.464 (2.21), 6.478 (1.09), 6.702 (8.80), 7.898 (2.86), 7.900 (2.72), 7.902 (2.94), 8.467 (3.13), 8.472 (3.09 ), 11.030 (2.24). Example 144 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3, 4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide (45.0 mg, 128 µmol, see example 140) was dissolved in DMF (450 µl), NCS (18.9 mg, 141 µmol; CAS‐RN:[128‐09‐6]) and diph enylperoxyanhydride (34.2 mg, 141 µmol; CAS‐RN:[94 36‐0]) were added and the mixture was stirred over night at rt. The mixture was quenched with an aq. Na 2 S 2 O 3 solution and extracted 3x with EtOAc. The com bined organic layers were dried and evaporated. The residue was purified by preparative HPLC to yiel d the title compound (15.0 mg, 95 % purity, 29 % yield). LC‐MS (Method 1): R t = 0.94 min; MS (ESIpos): m/z = 385 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.002 (3.80), 1.020 (9.10), 1.035 (8.56), 1.03 8 (4.47), 1.052 (16.00), 1.070 (8.72), 2.336 (0.43), 2.388 (10.99), 2.518 (5.71), 2.523 (3.91), 2.678 (0.43), 2.844 (1.24), 2.862 (1.93), 2.879 (1.33), 3.008 (0.47), 3.025 (1.57), 3.039 (1.66), 3.043 (1.66), 3.0 57 (1.51), 3.076 (0.45), 3.405 (1.17), 3.417 (1.21), 3.422 (3.62), 3.435 (3.64), 3.440 (3.64), 3.452 (3.75), 3.4 57 (1.10), 3.469 (1.03), 3.979 (0.63), 4.000 (6.52), 4.002 (6.90), 4.023 (0.63), 4.146 (1.33), 4.164 (2.04), 4.1 81 (1.28), 4.344 (2.27), 4.356 (4.45), 4.369 (2.18), 6.457 (0.67), 6.471 (1.42), 6.485 (0.65), 6.818 (6.49), 8.089 (2.61), 8.094 (2.52), 8.648 (2.90), 8.653 (2.88), 11.900 (1.39). The following example was prepared in analogy to exa mple 144: Example 145 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole]‐1‐carboxamide (prepared from N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyri din‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrr olo[1,2‐ b]pyrazole]‐1‐carboxamide (see example 130) LC‐MS (Method 1): R t = 0.87 min; MS (ESIpos): m/z = 371 [M+H]
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.003 (7.01), 1.021 (16.00), 1.035 (7.62), 1.039 (7.68), 1.052 (12.22), 1.070 (6.30), 2.322 (0.52), 2.326 (0.72), 2.331 (0.51), 2.522 (2.46), 2.664 (0.57), 2.668 (0.76), 2.673 (0.55), 2.850 (2.62), 2.867 (4.33), 2.884 (2.80 ), 3.009 (0.96), 3.027 (3.11), 3.041 (3.49), 3.044 ( 3.38), 3.059 (3.02), 3.077 (0.89), 3.404 (0.93), 3.417 (1.07 ), 3.422 (2.73), 3.435 (2.89), 3.439 (2.66), 3.452 ( 2.63), 3.457 (1.00), 3.469 (0.90), 3.983 (1.40), 4.004 (14.0 6), 4.006 (14.18), 4.027 (1.46), 4.155 (2.77), 4.172 (4.41), 4.189 (2.72), 4.344 (1.61), 4.356 (3.10), 4.3 69 (1.51), 6.461 (1.35), 6.475 (2.74), 6.489 (1.33), 6.855 (10.96), 7.687 (7.08), 8.223 (5.87), 8.228 (5.85), 8. 760 (5.40), 8.765 (5.30), 12.002 (0.91). Example 146 N‐ethyl‐2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5 ',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyraz ole]‐1‐ carboxamide To a solution of 1‐(ethylcarbamoyl)‐5',6'‐dihydrospiro[azetidine‐3,4' ‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl trifluoromethanesulfonate (100 mg, 271 µmol, intermedi ate 9) in 1,4‐dioxane (4.3 ml) were added 6‐ (4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H ‐pyrrolo[3,2‐b]pyridine (133 mg, 543 µmol), K 3 PO 4 (1.6 ml, 0.50 M, 810 µmol; CAS‐RN:[7778‐53‐2]) and XPhos Pd G2 (32.0 mg, 40.7 µmol; CAS‐RN:[14221‐0 1‐ 3]). The mixture was stirred overnight at 100°C. Th e mixture was diluted with EtOAc, washed with sat. NaCl solution and the organic phase was dried and c oncentrated under reduced pressure. The mixture was purified by preparative HPLC to yield the title compound (41.0 mg, 95 % purity, 43 % yield). LC‐ MS (Method 1): R t = 0.69 min; MS (ESIpos): m/z = 337 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.90 4 (0.41), 1.004 (4.79), 1.021 (11.41), 1.039 (4.97), 1. 751 (0.64), 2.518 (4.18), 2.523 (2.72), 2.540 (16.00) , 2.728 (0.74), 2.846 (1.61), 2.863 (2.52), 2.881 (1.76 ), 2.888 (1.12), 3.009 (0.61), 3.027 (1.96), 3.041 ( 2.09), 3.044 (2.06), 3.059 (1.94), 3.077 (0.58), 3.981 (1.51 ), 4.002 (6.14), 4.011 (6.75), 4.032 (1.65), 4.151 ( 1.74), 4.161 (0.66), 4.170 (2.68), 4.186 (1.71), 6.457 (0.81 ), 6.471 (1.66), 6.485 (0.79), 6.530 (1.47), 6.533 ( 1.55), 6.536 (1.55), 6.593 (0.43), 6.596 (0.43), 6.599 (0.44 ), 6.786 (8.07), 7.621 (1.50), 7.629 (2.14), 7.636 ( 1.53), 7.673 (0.44), 7.680 (0.61), 7.687 (0.43), 8.018 (0.74 ), 8.021 (0.76), 8.023 (0.81), 8.026 (0.72), 8.052 ( 2.44), 8.054 (2.67), 8.057 (2.83), 8.059 (2.52), 8.661 (1.32), 8.666 (1.28), 8.774 (4.46), 8.779 (4.46), 11.347 (1.35). Example 147 ethyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6' dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] 1‐ carboxylate
To a solution of ethyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[ azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (66.0 mg, 179 µmol, see intermediate 19) in 1,4‐dioxane (2.8 ml) was added under nitrogen at ambient temperature 5‐(4,4,5,5‐te tramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[2, 3‐ b]pyridine (87.2 mg, 357 µmol), potassium phosphate solution (1.1 ml, 0.50 M, 540 µmol; CAS‐RN:[7778 ‐ 53‐2]) and 2 nd generation XPhos Pd (21.1 mg, 26.8 µmol; CAS ‐RN:[14221‐01‐3]). The reaction mixture was stirred at 100°C overnight, cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfa te and the solvent was removed under reduced pressure. The crude product was purified via HPLC chromatography to yield the title compound 15.0 mg (95 % purity, 24 % yield). LC‐MS (Method 1): R t = 0.93 min; MS (ESIpos): m/z = 338 [M+H] + . ¹H‐ NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.177 (7.10), 1.1 95 (16.00), 1.213 (7.36), 2.074 (0.69), 2.518 (4.35), 2.523 (2.84), 2.674 (0.69), 2.870 (2.23), 2.888 (3.45 ), 2.905 (2.35), 4.029 (1.99), 4.047 (6.21), 4.065 ( 6.08), 4.082 (1.92), 4.138 (4.62), 4.147 (4.71), 4.155 (6.19 ), 4.172 (2.96), 6.452 (2.02), 6.455 (2.12), 6.460 ( 2.14), 6.464 (1.99), 6.780 (10.22), 7.460 (1.71), 7.466 (2.00), 7.474 (1.71), 8.264 (3.99), 8.269 (4.09), 8.649 (4.55), 8.654 (4.45), 11.650 (1.45). The following compounds (example 148 and example 149) were prepared in analogy to example 147: Example 148 ethyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐1‐carboxylate (prepared from ethyl 2'‐[(trifluoromethanesulfonyl)oxy] ‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see intermediate 19) and 3‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐ dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridine, CAS ‐RN: [1111637‐95‐6]) LC‐MS (Method 1): R t = 1.00 min; MS (ESIneg): m/z = 350 [M‐H] ⁻ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.036 (1.01), 1.053 (2.24), 1.071 (1.05), 1.178 (7.14), 1.195 (16.00), 1.213 (7.53), 2.271 (14.25), 2.274 (14.68), 2.518 (2.13), 2.523 (1.39), 2.872 (2.22), 2.889 (3.53 ), 2.906 (2.36), 4.031 (2.10), 4.048 (6.68), 4.066 (6.55 ), 4.084 (2.04), 4.136 (4.01), 4.154 (6.95), 4.170 ( 3.27),
4.358 (0.44), 6.809 (11.10), 7.222 (2.71), 7.225 (2.72), 8.230 (3.61), 8.235 (3.73), 8.626 (4.62), 8.631 (4.60), 11.290 (1.86). Example 149 ethyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2 b]pyrazole]‐1‐carboxylate (prepared from prepared from ethyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[ azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermediate 19) and 3‐chloro‐5‐(4,4,5,5‐tetramethyl‐ 1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridi ne, CAS‐RN: [1111638‐73‐3]) LC‐MS (Method 1): R t = 1.05 min; MS (ESIneg): m/z = 370 [M‐H] ⁻ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.905 (0.40), 1.178 (7.28), 1.196 (16.00), 1.213 (7.52), 1.232 (0.48), 2.337 (0.50), 2.518 (6.04), 2.523 (4.00), 2.5 40 (0.79), 2.678 (0.50), 2.878 (2.25), 2.895 (3.63), 2.912 (2.44), 4.030 (2.07), 4.048 (6.54), 4.066 (6.46), 4.0 84 (2.01), 4.151 (6.09), 4.168 (5.03), 4.186 (2.75), 5.759 (1.30), 6.897 (10.25), 7.692 (8.08), 8.089 (0.66), 8.211 (5.09), 8.216 (5.30), 8.752 (4.58), 8.756 (4.53), 12.015 (1.43). Example 150 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo [1,2‐ b]pyrazole] Step 1: To a solution of tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate (234 mg, 585 µmol, see example 170/intermediate 72) in dichloromethane (20 mL) was a dded under nitrogen at ambient temperature trifluoro acetic acid (1.5 ml, 19 mmol; CAS‐RN:[76‐05‐1]) and the reaction was stirred at room temperature for four hours. The reaction was evaporated, toluene was added and evaporated again (repeated twice). The residue was dissolved in toluene, dried over sodium sulfate and evaporated to obtain crude trifluoroacetic acid—2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] ( 1/1) (412mg > 100%). This material was used in t he following step without further purification. LC‐MS ( Method 1): R t = 0.83 min; MS (ESIpos): m/z = 300
[M+H] + . Step 2: To a solution of formaldehyde (20 l, 37 % in water, 270 µmol; CAS‐RN:[50‐00‐0]) and trifluoroacetic acid—2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5 yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] (1/1) (127 mg, 59 % purity, 181 µmol) in THF (2.5 ml) was added under nitroge n at room temperature sodium triacetoxyborohydride (86.4 mg, 407 µmol; CAS‐RN:[76‐05‐1]) and acetic acid (10 µl). The reaction was stirred at ambient temperature overnight, the solvent was removed under reduced pressure and the crude product was purified by HPLC chromatography to yield the title compound (6,0mg, 10,03%). 1 H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.229 (0.48), 1.750 (0.99), 1.907 (0.45), 2.315 (16.00), 2.326 (3.19), 2.331 (1.92), 2.336 (0.96), 2.518 (6.64), 2.522 (4.44), 2.539 (1.41), 2.659 (0.67), 2.664 (1.44), 2.668 (1.92), 2.673 (1.41 ), 2.678 (0.67), 2.795 (3.86), 2.812 (5.65), 2.831 ( 4.02), 3.436 (3.93), 3.453 (2.87), 4.113 (4.31), 4.122 (1.44 ), 4.131 (6.04), 4.139 (1.44), 4.148 (4.12), 4.552 ( 2.01), 5.758 (1.12), 6.792 (15.55), 7.682 (6.74), 7.689 (6.87), 8.212 (5.68), 8.216 (5.94), 8.742 (0.42), 8.752 (7.57), 8.757 (7.50), 11.995 (2.52). The following compounds (example 151 and example 152) were prepared in analogy to example 150: Example 151 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[ 1,2‐ b]pyrazole] (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 170/intermediate 72) and acetaldehyde, CAS‐RN: [75‐07‐0]) LC‐MS (Method 1): R t = 1.02 min; MS (ESIpos): m/z = 328 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.896 (6.24), 0.915 (15.16), 0.932 (6.50), 2.422 (1.67), 2.439 (5.66), 2.458 (5.82), 2.475 (2.28), 2.518 (4.15), 2.5 23 (2.78), 2.795 (3.29), 2.813 (4.82), 2.831 (3.59), 3.254 (5.32), 3.273 (7.08), 3.368 (6.95), 3.386 (5.15), 4.1 21 (3.59), 4.130 (1.15), 4.138 (5.10), 4.146 (1.15), 4.155 (3.46), 6.770 (16.00), 7.681 (4.95), 7.687 (4.97), 8.216 (5.73), 8.221 (5.88), 8.754 (6.59), 8.760 (6.52), 11.993 (2.13). Example 152
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4 '‐ pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidin e‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 170/intermediate 72) and aceton, CAS‐RN: [67‐64‐ 1]) LC‐MS (Method 1): R t = 1.09 min; MS (ESIpos): m/z = 342 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.889 (15.82 ), 0.904 (16.00), 2.295 (0.42), 2.310 (1.11), 2.318 (0.60), 2.326 (2.36), 2.331 (1.16), 2.337 (0.69), 2.3 41 (1.11), 2.518 (4.62), 2.523 (3.10), 2.660 (0.42), 2.665 (0.92), 2.669 (1.29), 2.673 (0.88), 2.678 (0.42), 2.7 90 (2.22), 2.807 (3.24), 2.825 (2.40), 3.257 (3.42), 3.276 (4.49), 3.371 (4.62), 3.389 (3.33), 4.124 (2.36), 4.1 33 (0.88), 4.141 (3.42), 4.148 (0.92), 4.158 (2.31), 6.759 (10.08), 7.683 (3.93), 8.217 (4.67), 8.222 (4.76), 8. 754 (4.39), 8.759 (4.30), 11.992 (1.39). The following compound (example 153) was prepared in analogy to example 84: Example 153 N N N NH N Cl H N CH 3 N 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(2‐chloro‐3‐ethyl 1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate (see example 169/intermediate 80) and 1H‐imidazole‐ 2‐carbaldehyde, CAS‐RN: [10111‐08‐7)] LC‐MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 408 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.832 (0.41) , 0.851 (0.82), 0.867 (0.70), 0.886 (0.45), 0.905 (0 .78), 1.182 (6.93), 1.201 (16.00), 1.219 (7.59), 1.232 (4.84), 1.256 (0.78), 1.278 (0.66), 1.296 (0.53), 1.352 (0.49), 1.395 (15.18), 1.420 (5.05), 2.318 (0.78), 2.323 (1.76), 2.327 (2.54), 2.332 (1.76), 2.337 (0.78), 2.518 (10.63), 2.523 (7.18), 2.660 (0.94), 2.665 (2.46), 2.669 (2.79), 2.674 (2.13), 2.683 (2.30), 2.702 (4.39), 2.721 (4.10), 2.740 (1.27), 2.796 (2.54), 2.8 13 (3.98), 2.831 (2.67), 3.436 (2.71), 3.454 (4.84), 3.482 (4.80), 3.499 (2.67), 3.672 (7.38), 3.853 (0.66), 3.8 70 (0.98), 3.887 (0.62), 3.977 (0.62), 3.992 (0.66), 4.106
(2.87), 4.124 (4.27), 4.141 (2.75), 5.453 (2.71), 6.731 (13.42), 6.845 (0.90), 6.954 (4.02), 8.088 (1.35), 8.237 (5.95), 8.242 (6.15), 8.255 (0.45), 8.260 (0.45 ), 8.629 (7.79), 8.634 (7.59), 8.640 (0.70), 8.645 ( 0.62), 12.221 (3.45). The following compounds (example 154 to example 156) were synthesized in analogy to example 1: Example 154 tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from tert‐butyl 2'‐[(trifluoromethanesulfon yl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermedi ate 17) and 1H‐pyrrolo[2,3‐b]pyridin‐5‐ylboronic acid, CAS‐RN: [944059‐24‐9]) LC‐MS (Method 1): R t = 1.16 min; MS (ESIpos): m/z = 394 [M+H] ¹H‐NMR (500 MHz, DMSO‐d6) δ [ppm]: 1.430 (16.00), 1.622 (0.47), 2.422 (0.57), 2.436 (0.84), 2.450 (0.62), 2.514 (0.99), 2.518 (0.97), 2.522 (0.79), 4.1 64 (0.58), 4.179 (0.95), 4.192 (0.57), 5.758 (1.71), 6.440 (0.65), 6.443 (0.69), 6.447 (0.71), 6.450 (0.66), 6.7 66 (2.36), 7.451 (0.56), 7.456 (0.66), 7.462 (0.56), 8.273 (0.84), 8.276 (0.86), 8.661 (1.19), 8.665 (1.16), 11. 622 (0.41). Example 155 tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from tert‐butyl 2'‐[(trifluoromethanesulfon yl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermedi ate 17) and 2‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3 ,2‐ dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridine, CAS ‐RN: [1111638‐03‐9]) LC‐MS (Method 1): R t = 1.21 min; MS (ESIpos): m/z = 408 [M+H]
1 H‐NMR (500 MHz, DMSO‐d6) δ [ppm]: 1.039 (0.97), 1.053 (2.06), 1.067 (1.04), 1.428 (16.00), 1.615 (0.56), 1.680 (0.48), 1.691 (0.40), 2.384 (3.68), 2.4 14 (0.64), 2.428 (1.01), 2.442 (0.70), 2.518 (1.33), 2.522 (1.01), 3.411 (0.42), 3.421 (0.40), 3.425 (0.64), 3.4 35 (0.59), 3.439 (0.54), 3.449 (0.50), 3.561 (0.46), 4.151 (0.63), 4.165 (1.07), 4.179 (0.62), 4.358 (0.61), 6.1 32 (0.88), 6.728 (2.20), 8.104 (0.93), 8.108 (0.97), 8.530 (1.14), 8.535 (1.18), 11.432 (0.61). Example 156 tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospir o[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbox ylate (prepared from tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[ piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermediate 17) and quinolin‐3‐ylboronic acid, CAS‐RN: [191162‐39‐7]) LC‐MS (Method 1): R t = 1.29 min; MS (ESIpos): m/z = 405 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.035 (1.19), 1.052 (2.20), 1.070 (1.28), 1.436 (16.00), 1.648 (0.46), 1.712 (0.45), 1.987 (0.52), 2.454 (0.63), 2.4 72 (0.99), 2.518 (0.75), 2.523 (0.51), 3.423 (0.62), 3.435 (0.61), 3.440 (0.60), 3.452 (0.53), 4.226 (0.58), 4.2 44 (0.93), 4.261 (0.57), 4.357 (0.46), 7.019 (2.26), 7.609 (0.40), 7.612 (0.56), 7.707 (0.41), 7.724 (0.59), 7.7 28 (0.46), 7.975 (0.51), 7.978 (0.53), 7.996 (1.29), 8.017 (0.52), 8.664 (0.79), 8.668 (0.79), 9.364 (1.25), 9.3 69 (1.23). Example 157 tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razole]‐1‐ carboxylate (60.0 mg, 152 µmol, see example 154) wa s dissolved in DMF (610 µl), NCS (22.4 mg, 168 µmol; CAS‐RN:[128‐09‐6]) and diphenylperoxyanhydri de (40.6 mg, 168 µmol; CAS‐RN:[94‐36‐0]) were added and the mixture was stirred overnight at rt. The mixture was quenched with an aq. Na 2 S 2 O 3 solution and extracted 3x with EtOAc. The combined o rganic layers were dried and evaporated. The
residue was purified by preparative HPLC and prepa rative TLC to yield the title compound (12.0 mg, 95 % purity, 17 % yield). LC‐MS (Method 1): R t = 1.27 min; MS (ESIpos): m/z = 429 [M+H] + . ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.431 (16.00), 1.623 (0.48), 1.688 (0.50), 2.421 (0.60), 2.439 (0.96), 2.456 (0.78), 2.518 (3.08), 2.523 (2.05), 3.603 (0.43), 4.1 72 (0.57), 4.190 (0.95), 4.208 (0.57), 6.915 (2.17), 7.678 (2.17), 8.234 (1.48), 8.239 (1.52), 8.771 (1.21), 8.7 76 (1.19). The following compound (example 158) was synthesized in analogy to example 157: Example 158 tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2 ,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine 4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (prepared from tert‐butyl 2'‐(2‐methyl‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example15 5). LC‐MS (Method 1): R t = 1.33 min; MS (ESIpos): m/z = 443 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.430 (16.00), 1.619 (0.45), 1.682 (0.52), 1.906 (1.19), 2.336 (0.61), 2.387 (5.02), 2.416 (0.58), 2.434 (0.87), 2.4 51 (0.74), 2.518 (8.27), 2.523 (5.70), 2.678 (0.61), 3.594 (0.42), 4.164 (0.55), 4.181 (0.90), 4.199 (0.55), 6.8 76 (2.35), 8.088 (0.42), 8.101 (1.26), 8.106 (1.26), 8.659 (1.22), 8.664 (1.26). The following compounds (example 159 to example 162) were prepared in analogy to example 64: Example 159 N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[ piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxam ide (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5' ,6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyraz ole]‐1‐ carboxylate (see example 156) and and isocyanatoethane , CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.96 min; MS (ESIpos): m/z = 376 [M+H]
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.916 (0.82), 0.930 (5.87), 0.947 (5.85), 1.015 (7.47), 1.033 (16.00), 1.051 (7.64), 1.591 (0.93), 1.601 (1.24), 1.624 (2.72), 1.634 (2.24), 1.646 (2.33), 1.655 (1.93), 1.688 (2.77), 1.701 (2.28), 1.726 (1.35), 2.323 (0.86 ), 2.326 (1.15), 2.331 (0.89), 2.385 (0.42), 2.403 ( 0.97), 2.421 (1.18), 2.451 (4.50), 2.469 (8.22), 2.665 (0.84 ), 2.668 (1.13), 2.673 (0.87), 2.940 (0.40), 2.956 ( 0.53), 3.045 (1.11), 3.063 (3.39), 3.076 (3.74), 3.080 (3.81 ), 3.094 (3.28), 3.112 (1.00), 3.355 (1.68), 3.364 ( 1.80), 3.378 (1.60), 3.388 (2.53), 3.398 (2.10), 3.411 (1.97 ), 3.419 (1.66), 3.535 (2.46), 3.548 (1.95), 3.557 ( 1.53), 3.573 (1.69), 4.225 (3.41), 4.243 (5.54), 4.260 (3.26 ), 5.758 (0.73), 6.527 (1.49), 6.541 (2.86), 6.554 ( 1.48), 6.982 (10.19), 7.592 (1.42), 7.610 (3.04), 7.629 (2.15), 7.701 (1.71), 7.704 (1.95), 7.722 (2.92), 7.725 (2.42), 7.739 (1.40), 7.742 (1.62), 7.976 (3.32), 7.9 94 (6.85), 8.015 (3.17), 8.672 (4.67), 8.677 (4.79), 9.368 (5.70), 9.374 (5.72). Example 160 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and isocyanatoethane, CAS‐RN: [109‐90‐ 0]) LC‐MS (Method 1): R t = 0.93 min; MS (ESIpos): m/z = 399 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.010 (7.20), 1.028 (16.00), 1.046 (7.53), 1.565 (0.73), 1.574 (0.93), 1.597 (2.13), 1.607 (1.67), 1.621 (1.73), 1.6 29 (1.47), 1.662 (2.13), 1.700 (1.07), 2.084 (0.60), 2.418 (2.73), 2.436 (4.40), 2.453 (3.20), 2.518 (10.27), 2.523 (6.67), 2.540 (1.00), 3.039 (0.93), 3.057 (2.93), 3.070 (3.20), 3.074 (3.13), 3.088 (2.87), 3.105 (0.87 ), 3.375 (2.73), 3.385 (1.87), 3.398 (1.67), 3.531 ( 1.87), 3.544 (1.47), 3.552 (1.13), 3.568 (1.33), 4.171 (2.67 ), 4.189 (4.33), 4.206 (2.60), 6.509 (1.27), 6.523 ( 2.47), 6.537 (1.20), 6.877 (9.67), 7.676 (9.53), 8.237 (6.40), 8.242 (6.47), 8.773 (5.53), 8.778 (5.47), 11.985 (1.00). Example 161 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4 ,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐2‐methyl ‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole] 1‐carboxylate (see example 158) and and isocyanatoethane, CAS‐RN: [109‐90‐0]) LC‐MS (Method 1): R t = 0.99 min; MS (ESIpos): m/z = 413 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.009 (5.25), 1.027 (11.79), 1.045 (5.50), 1.570 (0.76), 1.592 (1.76), 1.603 (1.37), 1.615 (1.44), 1.658 (1.80), 1.6 94 (0.90), 2.084 (0.43), 2.323 (1.44), 2.327 (1.94), 2.331 (1.44), 2.386 (16.00), 2.413 (2.27), 2.431 (3.67), 2.449 (2.59), 2.522 (6.51), 2.539 (1.62), 2.665 (1.40), 2.669 (1.94), 2.673 (1.40), 3.038 (0.72), 3.055 (2.27 ), 3.069 (2.52), 3.073 (2.44), 3.086 (2.19), 3.104 ( 0.68), 3.374 (1.91), 3.384 (1.47), 3.398 (1.33), 3.524 (1.58 ), 3.561 (1.11), 4.162 (2.09), 4.180 (3.42), 4.197 ( 2.01), 6.506 (1.01), 6.519 (1.98), 6.532 (0.97), 6.837 (6.87 ), 8.103 (3.88), 8.108 (3.88), 8.661 (4.10), 8.666 ( 3.92), 11.877 (2.23). Example 162 N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin 5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo [1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐methyl‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 171) and and isocyanatoethane, CAS‐RN: [109‐90‐ 0]) ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.010 (6.52), 1.028 (14.61), 1.046 (6.86), 1.232 (1.78), 1.565 (0.71), 1.574 (0.94), 1.597 (2.12), 1.607 (1.69), 1.6 20 (1.78), 1.629 (1.48), 1.662 (2.17), 1.676 (1.82), 1.700 (1.07), 2.084 (0.45), 2.271 (15.68), 2.273 (16.00), 2 .322 (0.97), 2.326 (1.33), 2.331 (0.99), 2.415 (2.53) ,
2.432 (4.35), 2.449 (2.96), 2.522 (5.02), 2.539 (1 .31), 2.664 (0.97), 2.668 (1.31), 2.673 (0.99), 3.039 (0.86), 3.057 (2.75), 3.070 (3.05), 3.074 (3.00), 3.088 (2.70 ), 3.105 (0.82), 3.366 (1.42), 3.377 (2.08), 3.386 ( 1.67), 3.400 (1.57), 3.527 (1.91), 3.539 (1.52), 3.547 (1.20 ), 3.563 (1.37), 4.157 (2.60), 4.175 (4.27), 4.192 ( 2.53), 6.509 (1.22), 6.522 (2.38), 6.535 (1.20), 6.764 (8.77 ), 7.211 (3.35), 8.240 (4.10), 8.245 (4.29), 8.644 ( 4.20), 8.649 (4.12), 11.258 (2.42). The following compounds (example 163 to example 167) were prepared in analogy to example 101: Example 163 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]ethan‐1‐one (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[ piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see ex ample 157) and acetic acid, CAS‐RN: [64‐19‐7]) LC‐MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 370 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.595 (0.74) , 1.605 (0.51), 1.618 (0.56), 1.628 (0.47), 1.682 (0 .88), 1.693 (0.79), 1.704 (0.98), 1.716 (0.98), 1.726 (0.88), 1.738 (0.84), 1.753 (0.88), 1.764 (0.60), 2.053 (16.00), 2.323 (0.60), 2.327 (0.88), 2.331 (0.65), 2.439 (1.72), 2.457 (2.79), 2.475 (2.74), 2.523 (3.67), 2.665 (0.65), 2.669 (0.88), 2.673 (0.65), 3.394 (0.56 ), 3.402 (0.56), 3.426 (0.79), 3.436 (0.51), 3.450 ( 0.47), 3.552 (0.65), 3.561 (0.60), 3.574 (0.65), 3.585 (0.60 ), 3.591 (0.56), 3.604 (0.84), 3.616 (0.56), 3.801 ( 0.56), 3.813 (0.47), 3.821 (0.42), 3.835 (0.51), 4.186 (1.77 ), 4.203 (3.02), 4.220 (1.72), 6.903 (5.91), 7.678 ( 2.51), 7.685 (2.56), 8.227 (2.93), 8.231 (3.02), 8.768 (3.21 ), 8.773 (3.30), 11.990 (1.26). Example 164 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]‐2‐methylpropan‐1‐one
(prepared from tert‐butyl 2'‐(3‐chloro‐1H‐py rrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spi ro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see ex ample 157) and 2‐methylpropanoic acid, CAS‐RN: [79‐31‐2]) LC‐MS (Method 1): R t = 1.05 min; MS (ESIpos): m/z = 398 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.971 (0.77), 0.988 (0.88), 0.993 (0.77), 1.025 (16.00), 1.041 (15.89), 1.230 (0.44), 1.572 (0.55), 1.595 (1.21), 1.620 (0.99), 1.690 (2.19), 1.714 (1.64), 1.752 (1.42), 1.789 (0.77), 2.322 (1.32), 2.327 (1.86), 2.332 (1.32 ), 2.443 (2.96), 2.462 (5.15), 2.522 (6.79), 2.539 ( 1.10), 2.665 (1.42), 2.669 (1.86), 2.673 (1.42), 2.899 (0.77 ), 2.916 (1.86), 2.933 (2.52), 2.949 (1.86), 2.966 ( 0.66), 3.292 (0.55), 3.385 (1.21), 3.423 (1.32), 3.449 (0.88 ), 3.568 (0.66), 3.594 (1.10), 3.618 (0.88), 3.703 ( 1.21), 3.738 (0.77), 3.852 (0.99), 3.887 (0.88), 4.185 (3.51), 4.202 (6.36), 4.220 (3.40), 5.757 (3.84), 6.937 (11.40), 7.675 (5.59), 7.682 (5.70), 8.232 (5.37), 8. 236 (5.48), 8.773 (6.36), 8.778 (6.36), 11.983 (2.63) . Example 165 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carbonyl]cyclopropane‐1‐carbonitrile (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[ piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see ex ample 157) and 1‐cyanocyclopropanecarboxylic acid, CAS‐RN: [6914‐79‐0]) LC‐MS (Method 1): R t = 1.02 min; MS (ESIpos): m/z = 421 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.170 (0.73) , 1.186 (0.73), 1.405 (0.88), 1.524 (4.40), 1.630 (8 .51), 1.637 (6.17), 1.817 (2.20), 1.907 (0.73), 2.323 (2.06), 2.327 (2.79), 2.331 (2.06), 2.522 (10.42), 2.665 (2.20), 2.669 (2.94), 2.673 (2.20), 3.466 (0.88), 3.8 58 (1.17), 3.989 (0.88), 4.201 (5.14), 4.219 (8.95), 4.236 (4.84), 5.758 (0.59), 6.987 (16.00), 7.681 (8.81), 7.688 (8.95), 8.234 (8.37), 8.238 (8.51), 8.779 (9.69), 8.784 (9.69), 9.430 (0.44), 11.997 (4.55). Example 166
[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razol]‐ 1‐yl](phenyl)methanone (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrro lo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[ piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see ex ample 157) and benzoic acid, CAS‐RN: [65‐85‐0]) LC‐MS (Method 1): R t = 1.10 min; MS (ESIpos): m/z = 432 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.711 (2.09), 2.326 (2.20), 2.331 (1.62), 2.336 (0.81), 2.518 (14.14), 2.522 (9.28), 2.668 (2.20), 2.673 (1.62), 2.678 (0.81), 3.493 (1.86), 3.580 (0.81), 4.037 (0.70), 4.207 (2.67), 5.758 (0.58), 6.978 (12.75), 7.423 (1.97), 7.430 (2.90), 7.440 (4.52), 7.445 (4.75), 7.448 (7.77), 7.455 (4.64), 7.457 (5.22), 7.463 (16.00), 7.470 (8.23), 7.475 (3.83), 7.480 (4.29), 7.488 (1.04), 7.685 (7.07), 8.226 (7.77), 8.231 (8.12), 8.771 (7.19 ), 8.776 (7.30), 11.993 (2.43). Example 167 [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razol]‐ 1‐yl](oxan‐4‐yl)methanone (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and tetrahydro‐2H‐pyran‐4‐carboxylic acid, CAS‐RN: [5337‐03‐1]) LC‐MS (Method 1): R t = 0.95 min; MS (ESIpos): m/z = 440 [M+H] ¹H‐NMR (600 MHz, DMSO‐d6) δ [ppm]: 0.850 (0.55) , 1.230 (2.22), 1.531 (1.06), 1.552 (2.48), 1.575 (2 .06), 1.593 (1.35), 1.599 (2.38), 1.620 (2.87), 1.628 (1.74 ), 1.640 (1.74), 1.647 (1.13), 1.662 (0.71), 1.670 ( 0.90), 1.677 (0.80), 1.692 (2.61), 1.699 (2.03), 1.708 (1.77 ), 1.714 (1.67), 1.759 (1.29), 1.782 (0.74), 2.378 ( 0.58), 2.381 (1.38), 2.384 (1.96), 2.387 (1.42), 2.390 (0.61 ), 2.447 (2.90), 2.449 (2.74), 2.458 (4.89), 2.462 ( 4.96), 2.472 (3.35), 2.515 (5.51), 2.518 (5.76), 2.521 (4.57 ), 2.606 (0.61), 2.609 (1.38), 2.612 (1.90), 2.615 ( 1.32), 2.618 (0.58), 2.919 (0.58), 2.925 (1.13), 2.932 (0.68 ), 2.938 (1.26), 2.944 (2.22), 2.950 (1.13), 2.956 ( 0.71), 2.963 (1.09), 2.969 (0.52), 3.387 (2.58), 3.390 (2.61 ), 3.406 (5.76), 3.410 (5.54), 3.425 (4.02), 3.429 ( 3.64), 3.445 (0.84), 3.590 (0.74), 3.607 (1.26), 3.614 (0.93 ), 3.624 (0.90), 3.736 (1.16), 3.744 (0.93), 3.752 ( 0.74), 3.761 (0.87), 3.845 (3.61), 3.849 (4.06), 3.852 (3.80 ), 3.861 (3.38), 3.865 (3.41), 3.868 (3.54), 4.192 ( 4.22), 4.198 (1.09), 4.204 (8.82), 4.210 (1.13), 4.216 (4.25 ), 6.934 (16.00), 7.683 (14.45), 8.088 (0.68), 8.229 (9.95), 8.232 (10.78), 8.772 (9.21), 8.775 (8.92), 11 .999 (2.51). The following compounds (intermediate 168 to intermediate 171) were prepared in analogy to example 1: Example 168 tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dih ydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1 carboxylate (prepared from intermediate 6 and (6‐aminopyridin‐3 ‐yl)boronic acid, CAS‐RN: [851524‐96‐4]) LC‐MS (Method 1): R t = 0.98 min; MS (ESIpos): m/z = 342 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.383 (4.76), 1.394 (16.00), 2.518 (0.86), 2.522 (0.58), 2.807 (0.58), 2.824 (0.86), 2.833 (0.43), 2.841 (0.58), 4.0 31 (0.86), 4.041 (1.01), 4.045 (1.01), 4.055 (1.15), 4.072 (1.15), 4.089 (0.58), 5.712 (9.80), 5.962 (1.44), 6.2 20 (0.43), 6.451 (0.72), 6.453 (0.72), 6.473 (0.72), 6.474 (0.72), 6.545 (3.03), 7.706 (0.58), 7.712 (0.58), 7.7 27 (0.58), 7.733 (0.58), 8.290 (0.72), 8.296 (0.72). Example 169/Intermediate 80 tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2, 3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3 ,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate
(prepared from intermediate 6 and 2‐chloro‐3‐e thyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 ‐yl)‐ 1H‐pyrrolo[2,3‐b]pyridine, (preparation described in WO 2018/167147)) LC‐MS (Method 1): R t = 1.31 min; MS (ESIpos): m/z = 428 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.180 (0.69), 1.199 (1.60), 1.218 (0.70), 1.394 (16.00), 1.419 (7.84), 2.518 (1.28), 2.523 (0.84), 2.665 (0.83), 2.6 69 (0.49), 2.673 (0.41), 2.681 (1.03), 2.698 (0.96), 2.716 (0.42), 2.872 (0.45), 3.853 (0.69), 3.870 (1.00), 3.8 87 (0.65), 3.976 (0.62), 3.991 (0.71), 4.150 (0.46), 5.452 (3.21), 6.845 (1.45), 8.255 (0.62), 8.260 (0.64), 8.6 40 (0.77), 8.645 (0.77), 9.651 (0.41). Example 170/Inermediate 72 tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxylate (prepared from intermediate 6 and and 3‐chloro‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborol an‐2‐yl)‐1H‐ pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111638‐73‐3]) LC‐MS (Method 1): R t = 1.21 min; MS (ESIpos): m/z = 400 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.065 (2.29), 1.172 (0.54), 1.394 (2.93), 1.420 (16.00), 1.987 (0.87), 2.518 (1.35), 2.522 (0.89), 2.862 (0.56), 2.8 79 (0.87), 2.896 (0.59), 4.089 (0.97), 4.144 (0.62), 4.162 (0.95), 4.179 (0.57), 5.451 (0.52), 6.890 (3.02), 7.6 89 (0.79), 7.692 (0.80), 8.217 (1.21), 8.222 (1.26), 8.756 (1.24), 8.760 (1.22), 12.010 (0.41). Example 171 tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrro lo[1,2‐ b]pyrazole]‐1‐carboxylate
(prepared from tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[ piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermediate 17) and and 3‐methyl‐5‐(4,4,5,5‐tet ramethyl‐ 1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridi ne, CAS‐RN: [1111637‐95‐6]) LC‐MS (Method 1): R t = 1.19 min; MS (ESIpos): m/z = 408 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.431 (16.00), 1.622 (0.51), 1.645 (0.42), 1.685 (0.54), 1.697 (0.42), 2.272 (3.89), 2.275 (3.87), 2.416 (0.62), 2.4 34 (1.01), 2.451 (0.74), 2.518 (2.23), 2.522 (1.61), 2.539 (0.55), 3.594 (0.47), 4.157 (0.60), 4.175 (0.99), 4.1 93 (0.60), 5.758 (0.40), 6.804 (2.09), 7.211 (0.77), 7.214 (0.76), 8.237 (0.97), 8.242 (1.00), 8.642 (1.25), 8.6 47 (1.22), 11.259 (0.54). The following compounds (example 172 to example 175) were prepared in analogy to example 111: Example 172 [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) 5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]py razol]‐ 1‐yl](morpholin‐4‐yl)methanone (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and morpholine, CAS‐RN: [110‐91‐8]) LC‐MS (Method 1): R t = 0.96 min; MS (ESIpos): m/z = 441 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.644 (1.02) , 1.654 (1.40), 1.676 (3.48), 1.688 (2.95), 1.698 (3 .14), 1.710 (3.96), 1.724 (4.21), 1.735 (3.00), 1.758 (1.60 ), 1.906 (0.77), 2.336 (0.92), 2.428 (4.59), 2.446 ( 7.44), 2.463 (6.04), 2.518 (10.39), 2.522 (7.15), 2.539 (3.7 7), 2.678 (0.97), 3.146 (7.35), 3.158 (10.49), 3.169 (8.02), 3.295 (1.89), 3.379 (3.96), 3.391 (2.66), 3.414 (1.84), 3.577 (8.41), 3.5 89 (10.54), 3.599 (7.44), 4.175 (4.50), 4.193 (7.01), 4.210 (4.30), 5.758 (2.95), 6.898 (16.00), 7.676 (6.53), 7.681 (6.57), 8.233 (8.99), 8.238 (9.18), 8.771 (9.52), 8.775 (9.38), 11. 984 (3.00). Example 173
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) ‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4' pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and N‐methylmethanamine, CAS‐RN: [124‐ 40‐3]) LC‐MS (Method 1): R t = 1.00 min; MS (ESIpos): m/z = 399 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.681 (0.59) , 1.692 (0.49), 1.701 (0.56), 1.713 (0.79), 1.725 (0 .75), 1.737 (0.52), 2.430 (0.81), 2.447 (1.28), 2.465 (1.06), 2.518 (1.18), 2.522 (0.79), 2.765 (16.00), 3.266 (0.56), 3.276 (0.50), 3.288 (0.62), 3.297 (0.83), 3.3 09 (0.90), 4.174 (0.81), 4.192 (1.22), 4.209 (0.76), 6.891 (2.92), 7.678 (1.91), 8.241 (1.98), 8.246 (1.99), 8.7 76 (1.65), 8.781 (1.63), 11.982 (0.58). Example 174 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(2‐hydroxy‐2‐methylpropyl)‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole] 1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and 1‐amino‐2‐methylpropan 2‐ol, CAS‐ RN: [2854‐16‐2]) LC‐MS (Method 1): R t = 0.89 min; MS (ESIpos): m/z = 443 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.054 (16.00), 1.616 (0.75), 1.626 (0.60), 1.639 (0.60), 1.648 (0.50), 1.683 (0.75), 1.695 (0.65), 2.426 (0.89), 2.4 44 (1.49), 2.461 (1.09), 2.518 (2.68), 2.523 (1.74), 3.041 (1.84), 3.055 (1.84), 3.159 (1.59), 3.171 (1.59), 3.3 14 (0.70), 3.393 (0.75), 3.406 (0.60), 3.417 (0.84), 3.427 (0.60), 3.440 (0.55), 3.582 (0.65), 3.594 (0.50), 3.6 03 (0.40), 3.618 (0.50), 4.176 (0.94), 4.194 (1.54), 4.211 (0.89), 4.687 (2.34), 6.452 (0.40), 6.467 (0.84), 6.8 89 (3.38), 7.675 (3.58), 8.240 (2.34), 8.245 (2.43), 8.776 (1.99), 8.781 (1.99). Example 175 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐methyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and methanamine, CAS‐RN: [74‐89‐5]) LC‐MS (Method 1): R t = 0.87 min; MS (ESIpos): m/z = 385 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.229 (0.40) , 1.564 (1.00), 1.574 (1.20), 1.596 (2.80), 1.606 (2 .20), 1.619 (2.40), 1.628 (1.80), 1.660 (2.80), 1.673 (2.20 ), 1.697 (1.40), 2.331 (1.40), 2.336 (0.60), 2.416 ( 3.60), 2.434 (6.00), 2.452 (4.60), 2.518 (8.40), 2.522 (5.60 ), 2.539 (1.20), 2.586 (16.00), 2.596 (15.80), 2.673 (1.60), 2.678 (0.60), 3.400 (3.00), 3.519 (2.60), 3.5 32 (2.00), 3.541 (1.60), 3.556 (1.80), 4.168 (3.60), 4.187 (5.60), 4.204 (3.40), 5.755 (6.40), 6.470 (1.00), 6.480 (2.60), 6.491 (2.60), 6.5 01 (0.80), 6.872 (13.40), 7.673 (12.80), 8.233 (8.80), 8.238 (9.00), 8.770 (7.4 0), 8.775 (7.20), 11.983 (1.00). The following compounds (example 176 and example 177) were prepared in analogy to example 70: Example 176 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and 1,1,1‐trifluoro‐2‐isocyanatoethane, CAS‐RN: [371‐92‐6]) LC‐MS (Method 1): R t = 1.00 min; MS (ESIpos): m/z = 453 [M+H]⁺ ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.588 (1.10) , 1.597 (1.66), 1.619 (3.59), 1.629 (2.76), 1.643 (2 .76), 1.651 (2.48), 1.688 (3.59), 1.725 (1.93), 2.428 (4.69), 2.446 (8.00), 2.464 (7.45), 2.518 (12.14), 2.522 (8.00), 3.394 (3.03), 3.397 (3.31), 3.407 (3.03), 3.4 33 (3.86), 3.442 (3.03), 3.457 (2.76), 3.612 (3.31), 3.624
(2.48), 3.633 (1.93), 3.647 (2.48), 3.811 (1.10), 3.835 (3.03), 3.851 (3.31), 3.860 (3.03), 3.875 (3.03 ), 3.899 (0.83), 4.175 (4.41), 4.193 (7.17), 4.210 (4.14), 6.907 (15.45), 7.192 (1.93), 7.207 (4.14), 7.222 (1.93), 7.674 (16.00), 8.237 (9.93), 8.242 (10.21), 8.773 (9. 10), 8.778 (8.83), 11.983 (1.10). Example 177 N‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin ‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrol o[1,2‐ b]pyrazole]‐1‐carboxamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and (isocyanatomethyl)benzene, CAS‐RN: [3173‐56‐6]) LC‐MS (Method 1): R t = 1.07 min; MS (ESIpos): m/z = 461 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.594 (1.08) , 1.604 (1.36), 1.627 (2.98), 1.636 (2.17), 1.650 (2 .44), 1.658 (1.90), 1.691 (2.98), 1.703 (2.44), 1.729 (1.36 ), 2.337 (0.81), 2.432 (3.80), 2.450 (5.97), 2.467 ( 5.15), 2.518 (10.85), 2.523 (7.32), 2.679 (0.81), 3.299 (1.08), 3.391 (1.36), 3.399 (1.90), 3.410 (2.17), 3.425 (1.90), 3.434 (2.71), 3.444 (2.17), 3.457 (1.90), 3.6 02 (2.44), 3.614 (1.90), 3.623 (1.63), 3.638 (1.90), 4.177 (3.80), 4.195 (5.97), 4.213 (3.80), 4.266 (6.78), 4.281 (6.78), 6.895 (15.46), 7. 136 (1.63), 7.151 (3.53), 7.166 (1.63), 7.196 (0.81), 7.200 (1.63), 7.204 (0.81 ), 7.211 (1.08), 7.218 (4.07), 7.230 (1.63), 7.235 ( 2.71), 7.238 (1.63), 7.268 (4.07), 7.285 (10.31), 7.289 (7.59), 7.303 (9.49), 7.309 (2.44), 7.321 (7.86), 7.336 (1.08), 7.340 (2.71), 7.676 (16.00), 8.240 (10.85), 8 .245 (11.12), 8.777 (8.68), 8.782 (8.41), 11.985 (0.8 1). The following compounds (example 178 and example 179) were prepared in analogy to example 101: Example 178 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]‐2‐hydroxyethan‐1‐one
(prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and hydroxyacetic acid, CAS‐RN: [79‐14‐ 1]) LC‐MS (Method 1): R t = 386.00 min; MS (ESIpos): m/z = 1 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.052 (0.71) , 1.230 (0.57), 1.608 (0.57), 1.631 (1.29), 1.641 (1 .00), 1.655 (1.14), 1.665 (1.14), 1.720 (2.43), 1.731 (2.71 ), 1.744 (2.29), 2.443 (3.86), 2.461 (6.14), 2.479 ( 5.71), 2.518 (7.57), 2.523 (5.29), 2.539 (5.86), 2.679 (0.57 ), 3.159 (4.57), 3.171 (4.71), 3.305 (1.14), 3.310 ( 1.29), 3.393 (1.29), 3.401 (0.71), 3.446 (1.29), 3.471 (2.57 ), 3.481 (2.43), 3.495 (2.57), 3.537 (0.57), 3.833 ( 1.14), 3.844 (0.86), 3.867 (0.86), 4.094 (0.57), 4.107 (1.00 ), 4.130 (3.00), 4.140 (5.00), 4.151 (3.00), 4.186 ( 4.29), 4.204 (6.29), 4.221 (3.86), 4.554 (1.29), 4.567 (2.43 ), 4.580 (1.14), 6.911 (16.00), 7.679 (15.29), 8.224 (10.29), 8.229 (10.43), 8.767 (8.14), 8.772 (8.14), 1 1.995 (0.71). Example 179 1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐y l)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]‐2‐(pyridin‐3‐yl)ethan‐1‐one (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and pyridin‐3‐ylacetic acid, CAS‐RN: [5 01‐ 81‐5]) LC‐MS (Method 1): R t = 0.93 min; MS (ESIpos): m/z = 447 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.230 (0.62) , 1.588 (0.62), 1.598 (0.82), 1.621 (1.64), 1.631 (1 .44), 1.644 (1.85), 1.655 (1.44), 1.667 (1.64), 1.677 (1.23 ), 1.700 (1.85), 1.740 (2.26), 1.774 (0.82), 2.318 ( 0.62), 2.439 (3.90), 2.456 (6.15), 2.474 (5.13), 2.518 (9.23 ), 2.523 (6.36), 2.539 (0.62), 2.679 (0.62), 3.159 ( 1.23), 3.171 (1.23), 3.290 (0.41), 3.309 (1.23), 3.324 (3.08 ), 3.391 (1.44), 3.396 (0.82), 3.404 (0.82), 3.418 ( 0.41), 3.444 (1.03), 3.468 (1.64), 3.478 (1.03), 3.492 (1.03 ), 3.501 (0.82), 3.618 (0.82), 3.643 (1.23), 3.653 ( 1.03), 3.667 (1.03), 3.758 (1.44), 3.783 (0.82), 3.795 (1.03), 3.825 (14.77), 3.848 (1.44), 3.861 (1.03), 3.883 (1.03), 4.185 (4.10), 4.202 (6.77), 4.219 (3.90), 5.756 (5.13), 6.915 (16.00), 7. 340 (2.87), 7.342 (2.87), 7.352 (3.08), 7.354 (3.08), 7.359 (3.28), 7.361 (3.28 ), 7.371 (3.49), 7.373 (3.49), 7.646 (2.26), 7.651 ( 3.49), 7.656 (2.46), 7.665 (2.05), 7.671 (3.28), 7.675 (2.87 ), 7.681 (14.56), 8.229 (10.87), 8.234 (10.87), 8.440 (4.51), 8.445 (4.92), 8.452 (4.92), 8.457 (5.54), 8.461 (5.95), 8.466 (5.54), 8.770 (9.03), 8.775 (9.03), 11.992 (1.64). The following compounds (example 180 to example 184) were prepared in analogy to example 62:
Example 180 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(phenylmethanesulfonyl)‐5',6'‐dihydrospiro[piperidin e‐ 4,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and phenylmethanesulfonyl chloride, CAS‐ RN: [1939‐99‐7]) LC‐MS (Method 1): R t = 1.19 min; MS (ESIpos): m/z = 482 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.231 (0.60) , 1.659 (1.13), 1.669 (1.49), 1.691 (3.66), 1.702 (2 .96), 1.715 (3.16), 1.724 (2.78), 1.749 (4.35), 1.784 (1.91 ), 2.075 (0.85), 2.327 (1.21), 2.399 (4.05), 2.416 ( 7.00), 2.434 (4.43), 2.669 (1.23), 3.186 (1.99), 3.209 (3.80 ), 3.233 (2.52), 3.349 (4.23), 3.361 (2.96), 3.382 ( 2.64), 4.172 (4.15), 4.189 (6.92), 4.207 (4.03), 4.526 (16.0 0), 6.763 (12.02), 7.369 (1.07), 7.386 (3.52), 7.394 (1.69), 7.404 (4.67), 7.408 (3.70), 7.415 (6.14), 7.4 33 (8.47), 7.450 (3.42), 7.508 (8.75), 7.525 (5.88), 7.694 (6.92), 7.701 (7.02), 8.218 (6.66), 8.222 (6.82), 8.7 89 (7.37), 8.794 (7.31), 12.021 (3.94). Example 181 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(propane‐1‐sulfonyl)‐5',6'‐dihydrospiro[piperidi ne‐4,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and propane‐1‐sulfonyl chloride, CAS‐RN: [10147‐36‐1]) LC‐MS (Method 1): R t = 1.10 min; MS (ESIpos): m/z = 435 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.009 (0.79), 1.014 (0.65), 1.021 (6.96), 1.033 (1.42), 1.040 (16.00), 1.051 (0.91), 1.058 (7.39), 1.705 (0.74), 1.723 (2.27), 1.729 (1.34), 1.742 (3.98), 1.747 (2.04), 1.761 (4.91), 1.774 (2.39), 1.780 (3.14), 1.784 (2.48 ), 1.796 (1.94), 1.805 (1.74), 1.816 (2.39), 1.829 ( 1.90), 1.838 (1.02), 1.853 (1.02), 1.861 (0.79), 2.075 (10.67), 2.444 (2.74), 2.461 (4.41), 2.479 (3.43), 2.518 (2.28), 2.523 (1.47), 3.091 (3.65), 3.105 (2.65), 3.1 11 (3.72), 3.116 (2.76), 3.130 (3.45), 3.269 (0.93), 3.277 (1.13), 3.299 (2.26), 3.309 (1.77), 3.361 (1.35), 3.3 73 (2.22), 3.385 (1.65), 3.406 (1.18), 3.417 (0.68), 4.186 (2.77), 4.204 (4.40), 4.221 (2.72), 6.230 (0.52), 6.875 (10.12), 7.684 (5.11), 7.691 (5.09), 8.225 (4.36), 8.229 (4.48), 8.788 (5.48), 8.792 (5.39), 12.003 (2.1 6), 12.008 (2.16). Example 182 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐sulfonamide (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and dimethylsulfamyl chloride, CAS‐RN: [13360‐57‐1]) LC‐MS (Method 1): R t = 1.07 min; MS (ESIpos): m/z = 435 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.766 (0.43) , 1.784 (0.44), 1.799 (0.56), 2.448 (0.52), 2.466 (0 .82), 2.484 (0.75), 2.518 (0.44), 2.796 (16.00), 3.340 (0.54), 3.351 (0.70), 3.360 (1.01), 3.371 (0.58), 4.180 (0.52), 4.198 (0.81), 4.215 (0.50), 6.859 (1.94), 7.6 80 (0.84), 7.686 (0.84), 8.238 (0.86), 8.243 (0.89), 8.787 (1.05), 8.792 (1.03). Example 183
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl) ‐1‐(pyridine‐3‐sulfonyl)‐5',6'‐dihydrospiro[pipe ridine‐4,4'‐ pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and pyridine‐3‐sulfonyl chloride, CAS‐RN : [16133‐25‐8]) LC‐MS (Method 1): R t = 1.04 min; MS (ESIpos): m/z = 469 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.230 (0.43) , 1.723 (1.35), 1.737 (2.67), 1.755 (3.67), 1.772 (4 .62), 1.786 (2.74), 1.813 (2.63), 1.825 (4.97), 1.839 (3.50 ), 1.859 (2.76), 1.872 (1.39), 2.075 (4.41), 2.323 ( 1.22), 2.327 (1.95), 2.335 (5.47), 2.352 (8.29), 2.370 (5.36 ), 2.522 (4.86), 2.665 (0.96), 2.669 (1.32), 2.673 ( 1.00), 2.796 (0.76), 3.195 (6.60), 3.208 (10.85), 3.222 (6.47), 4.124 (5.19), 4.142 (8.34), 4.159 (5.06), 6.347 (16.00), 7.690 (7.47), 7.696 (7.69), 7.745 (3.69), 7.757 (3.84), 7.763 (3.82), 7.765 (3.93), 7.777 (3.95), 8.078 (9.20), 8.083 (9.62), 8.248 (3.19), 8.253 (4.19 ), 8.258 (3.36), 8.268 (3.00), 8.274 (3.93), 8.278 ( 3.06), 8.662 (9.99), 8.667 (9.99), 8.952 (5.69), 8.956 (5.97 ), 8.964 (5.84), 8.968 (5.67), 9.008 (7.55), 9.012 ( 7.51), 12.007 (3.91). Example 184 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐ 1‐(morpholine‐4‐sulfonyl)‐5',6'‐dihydrospiro[piper idine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole] (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridi n‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and morpholine‐4‐sulfonyl chloride, CAS‐ RN: [1828‐66‐6]) LC‐MS (Method 1): R t = 1.05 min; MS (ESIpos): m/z = 477 [M+H] ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.231 (0.60) , 1.722 (1.26), 1.734 (1.91), 1.755 (4.37), 1.768 (4 .84), 1.786 (6.17), 1.799 (6.25), 1.810 (4.28), 1.834 (2.23 ), 2.075 (2.57), 2.323 (1.03), 2.327 (1.35), 2.332 ( 1.07), 2.454 (5.55), 2.472 (10.17), 2.540 (12.51), 2.665 (1. 01), 2.669 (1.35), 2.673 (1.01), 3.140 (10.92), 3.151 (14.65), 3.162 (11.91), 3.209 (0.62), 3.351 (1.80), 3 .374 (4.90), 3.386 (8.10), 3.399 (9.98), 3.433 (1.46) , 3.648 (12.10), 3.660 (14.37), 3.671 (11.05), 4.142 (0 .41), 4.182 (5.23), 4.200 (8.65), 4.217 (5.08), 6.348
(0.56), 6.879 (16.00), 7.682 (7.75), 7.688 (8.14), 8.235 (8.63), 8.240 (8.97), 8.785 (9.47), 8.789 (9.40), 11.999 (4.31). The following compounds (example 185 to example 200) were prepared in analogy to example 64: Example 185 2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)- 5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 0.91 min; MS (ESIpos): m/z = 365 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.042 (0.42), 1.058 (15.83), 1.075 (16.00), 1.136 (0.42), 1.153 (0.42), 2.270 (10.99), 2.273 (11.14), 2.322 (0.45), 2.326 (0.61), 2.331 (0.46), 2.522 (1.59), 2.665 (0.45), 2.669 (0.63), 2.673 (0.47), 2.839 (1.68), 2.857 (2.74), 2.874 (1.80), 3.707 (0.63), 3.724 (0.91), 3.744 (0.92), 3.760 (0.64), 3.976 (0.45), 3.997 (13.49), 4.017 (0.46), 4.139 (1.78), 4.157 (2.85), 4.174 (1.72), 6.232 (1.80), 6.252 (1.78), 6.769 (7.74), 7.219 (2.24), 7.221 (2.23), 8.243 (2.86), 8.247 (3.01), 8.634 (3.52), 8.639 (3.52), 11.284 (1.59). Example 186 N-tert-butyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5', 6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.01 min; MS (ESIpos): m/z = 379 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.198 (0.54), 1.241 (0.48), 1.268 (16.00), 2.271 (3.86), 2.274 (4.07), 2.539 (0.59), 2.827 (0.61), 2.845 (1.00), 2.862 (0.65), 3.993 (4.19), 4.137 (0.65), 4.155 (1.04), 4.172 (0.64), 5.830 (1.36), 6.756 (2.73), 7.219 (0.81), 7.221 (0.81), 8.247 (1.02), 8.251 (1.06), 8.637 (1.26), 8.642 (1.25), 11.285 (0.59).
Example 187 2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2- yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.06 min; MS (ESIpos): m/z = 403 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.058 (15.94), 1.075 (16.00), 1.885 (0.56), 1.914 (0.75), 1.984 (0.54), 2.007 (1.00), 2.031 (0.94), 2.052 (0.48), 2.057 (0.54), 2.084 (1.71), 2.157 (1.29), 2.164 (1.21), 2.180 (1.60), 2.186 (1.85), 2.202 (0.88), 2.209 (1.25), 2.331 (0.94), 2.337 (0.85), 2.344 (0.75), 2.357 (1.17), 2.364 (1.75), 2.372 (0.96), 2.378 (0.98), 2.385 (1.60), 2.392 (0.92), 2.399 (0.42), 2.406 (0.52), 2.518 (3.83), 2.522 (2.46), 2.837 (1.65), 2.855 (2.71), 2.872 (1.73), 3.674 (0.87), 3.695 (1.37), 3.707 (0.71), 3.715 (0.92), 3.723 (1.00), 3.743 (0.92), 3.759 (0.60), 3.975 (0.79), 3.997 (10.25), 4.018 (0.77), 4.141 (1.73), 4.159 (2.79), 4.176 (1.67), 6.230 (1.87), 6.250 (1.83), 6.783 (7.56), 7.270 (2.37), 7.274 (2.33), 8.240 (2.90), 8.245 (2.94), 8.628 (3.56), 8.633 (3.46), 11.342 (1.65). Example 188 N-tert-butyl-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl) -5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m/z = 837 [2M+H] + ¹H-NMR (400 MHz, DMSO- d6) δ [ppm]: 1.239 (0.65), 1.267 (16.00), 2.159 (0.52), 2.164 (0.51), 2.181 (0.66), 2.187 (0.73), 2.209 (0.50), 2.359 (0.57), 2.365 (0.77), 2.373 (0.51), 2.379 (0.52), 2.386 (0.72), 2.394 (0.50), 2.539 (0.95), 2.825 (0.68), 2.843 (1.10), 2.860 (0.68), 3.697 (0.51), 3.969 (0.45), 3.991 (3.61), 4.140 (0.71), 4.157 (1.12), 4.175 (0.66), 5.825 (1.26), 6.772 (2.36), 7.274 (0.95), 7.278 (0.94), 8.249 (1.08), 8.253 (1.09), 8.630 (1.25), 8.635 (1.20), 11.356 (0.68). Example 189
2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl )-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 0.97 min; MS (ESIpos): m/z = 379 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.058 (15.92), 1.075 (16.00), 1.251 (4.86), 1.260 (0.60), 1.270 (10.93), 1.289 (4.97), 2.522 (1.24), 2.692 (1.05), 2.711 (3.04), 2.730 (2.94), 2.748 (0.96), 2.838 (1.75), 2.855 (2.93), 2.872 (1.87), 3.707 (0.64), 3.724 (0.94), 3.743 (0.96), 3.759 (0.65), 3.976 (0.63), 3.997 (13.06), 4.017 (0.62), 4.139 (1.86), 4.157 (3.01), 4.174 (1.79), 6.231 (1.91), 6.251 (1.88), 6.779 (7.21), 7.218 (2.36), 7.221 (2.31), 7.224 (2.40), 8.263 (3.00), 8.267 (3.10), 8.632 (3.56), 8.637 (3.48), 11.302 (1.77). Example 190 N-tert-butyl-2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6 '-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m/z = 393 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.239 (1.07), 1.252 (2.90), 1.267 (16.00), 1.289 (1.77), 2.539 (0.48), 2.693 (0.44), 2.711 (1.18), 2.730 (1.14), 2.826 (0.71), 2.843 (1.22), 2.860 (0.73), 3.990 (4.57), 4.137 (0.74), 4.155 (1.22), 4.172 (0.70), 5.829 (1.31), 6.768 (1.96), 6.961 (0.73), 7.089 (0.77), 7.219 (1.33), 8.270 (1.15), 8.273 (1.15), 8.634 (1.19), 8.638 (1.15), 11.308 (0.78). Example 191 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)- 5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
LC-MS (Method 1): R t = 0.94 min; MS (ESIpos): m/z = 385 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.058 (15.81), 1.074 (16.00), 1.228 (0.52), 1.266 (0.46), 2.522 (0.84), 2.846 (1.72), 2.863 (2.80), 2.881 (1.81), 3.708 (0.63), 3.724 (0.91), 3.744 (0.95), 3.760 (0.64), 3.978 (0.76), 4.000 (11.19), 4.021 (0.79), 4.154 (1.82), 4.172 (2.92), 4.188 (1.77), 6.238 (1.83), 6.257 (1.81), 6.858 (7.39), 7.684 (2.55), 7.689 (2.69), 8.226 (3.19), 8.231 (3.43), 8.763 (3.32), 8.767 (3.41), 12.005 (1.32). Example 192 N-tert-butyl-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5', 6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.04 min; MS (ESIpos): m/z = 399 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.253 (2.17), 1.267 (16.00), 2.518 (0.46), 2.834 (0.65), 2.851 (0.97), 2.868 (0.63), 3.955 (0.57), 3.994 (3.31), 4.151 (0.63), 4.170 (1.01), 4.186 (0.61), 5.836 (1.37), 6.844 (2.56), 7.687 (2.35), 8.226 (1.44), 8.231 (1.48), 8.762 (1.26), 8.767 (1.24). Example 193 (rac)-6'-methyl-N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dih ydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.02 min; MS (ESIpos): m/z = 376 [M+H] + Example 194 (rac)-N-tert-butyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydr ospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide LC-MS (Method 1): R t = 1.12 min; MS (ESIpos): m/z = 390 [M+H] + Example 195 N-ethyl-2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[ piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide LC-MS (Method 2): R t = 1.00 min; MS (ESIpos): m/z = 420 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (0.44), 0.946 (0.45), 1.018 (4.22), 1.036 (10.22), 1.054 (4.54), 1.638 (0.86), 1.672 (1.30), 1.753 (0.68), 1.763 (0.79), 1.790 (1.02), 1.814 (0.53), 1.824 (0.43), 1.877 (0.90), 1.885 (1.08), 1.891 (1.12), 1.905 (1.31), 2.024 (0.99), 2.034 (1.05), 2.518 (0.60), 3.048 (0.74), 3.062 (1.38), 3.065 (1.97), 3.079 (2.43), 3.083 (2.58), 3.097 (2.20),
3.115 (1.19), 3.744 (1.18), 3.754 (0.68), 3.768 (0.62), 3.779 (1.07), 3.897 (16.00), 4.124 (1.16), 4.140 (2.28), 4.155 (1.12), 6.481 (0.70), 6.495 (1.41), 6.509 (0.68), 6.929 (5.65), 7.334 (1.45), 7.341 (2.10), 7.356 (0.84), 7.363 (3.82), 7.367 (3.15), 7.373 (1.39), 7.883 (2.20), 7.905 (1.97), 8.577 (2.14), 8.581 (2.20), 9.176 (3.64), 9.181 (3.49). Example 196 N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro -5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 2): R t = 1.13 min; MS (ESIpos): m/z = 448 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.70), 0.947 (0.70), 1.017 (3.93), 1.035 (9.01), 1.053 (3.97), 1.348 (16.00), 1.363 (15.49), 1.636 (0.77), 1.670 (1.17), 1.751 (0.63), 1.761 (0.71), 1.787 (0.93), 1.812 (0.48), 1.884 (0.97), 1.891 (1.00), 1.905 (1.19), 2.024 (0.90), 2.034 (0.95), 2.518 (0.79), 2.523 (0.53), 3.048 (0.59), 3.065 (1.89), 3.079 (2.00), 3.083 (2.27), 3.089 (1.46), 3.097 (2.14), 3.115 (0.96), 3.741 (1.06), 3.765 (0.56), 3.776 (0.96), 4.122 (1.03), 4.137 (2.04), 4.152 (1.00), 4.750 (0.88), 4.765 (1.22), 4.780 (0.90), 6.480 (0.64), 6.494 (1.30), 6.507 (0.63), 6.917 (4.70), 7.293 (1.39), 7.300 (1.63), 7.316 (1.35), 7.322 (1.83), 7.361 (2.23), 7.368 (1.76), 7.865 (2.07), 7.888 (1.89), 8.553 (1.94), 8.558 (1.99), 9.158 (3.12), 9.163 (3.18). Example 197 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)- 6',7'-dihydro-5'H-spiro[piperidine- 4,4'-pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 2): R t = 1.11 min; MS (ESIpos): m/z = 427 [M+H] +
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.069 (15.80), 1.085 (16.00), 1.618 (0.91), 1.652 (1.30), 1.754 (0.61), 1.763 (0.78), 1.789 (1.05), 1.814 (0.57), 1.824 (0.47), 1.866 (1.11), 1.871 (1.14), 1.886 (1.35), 2.008 (1.02), 2.018 (1.08), 2.521 (0.69), 2.526 (0.49), 3.034 (0.69), 3.061 (1.31), 3.089 (0.72), 3.751 (0.76), 3.763 (1.30), 3.767 (1.30), 3.784 (1.46), 3.801 (1.44), 3.819 (0.62), 4.085 (1.17), 4.101 (2.32), 4.115 (1.15), 6.156 (1.45), 6.175 (1.41), 6.861 (5.82), 7.673 (2.35), 7.679 (2.37), 8.239 (3.17), 8.244 (3.25), 8.766 (3.41), 8.770 (3.37), 11.975 (1.19). Example 198 N-tert-butyl-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6', 7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 2): R t = 1.23 min; MS (ESIpos): m/z = 441 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.188 (0.95), 1.255 (0.83), 1.281 (16.00), 1.654 (0.52), 1.799 (0.42), 1.857 (0.44), 1.863 (0.46), 1.877 (0.54), 2.005 (0.40), 2.015 (0.43), 3.033 (0.51), 3.738 (0.49), 3.773 (0.44), 4.085 (0.46), 4.101 (0.92), 4.116 (0.45), 5.758 (1.16), 6.845 (2.22), 7.678 (0.90), 8.237 (1.36), 8.242 (1.42), 8.764 (1.31), 8.769 (1.32), 11.978 (0.40). Example 199 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-6',7'-d ihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 1.11 min; MS (ESIpos): m/z = 461 [M+H] +
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.707 (2.33), 1.741 (3.30), 1.849 (1.56), 1.859 (2.02), 1.885 (2.88), 1.921 (3.84), 1.942 (3.66), 2.037 (2.72), 2.048 (2.75), 2.329 (2.48), 2.334 (1.78), 2.338 (0.78), 2.520 (10.16), 2.525 (6.54), 2.676 (1.78), 2.680 (0.81), 3.224 (1.78), 3.251 (3.34), 3.279 (2.07), 3.375 (0.48), 3.936 (3.06), 3.970 (2.75), 4.105 (2.93), 4.120 (5.74), 4.135 (2.85), 5.760 (1.49), 6.916 (16.00), 6.934 (5.04), 6.950 (1.77), 6.952 (2.92), 6.955 (1.59), 7.218 (5.63), 7.223 (2.09), 7.239 (7.77), 7.253 (1.95), 7.258 (5.61), 7.484 (7.46), 7.486 (8.41), 7.505 (7.37), 7.508 (5.68), 7.674 (11.07), 8.244 (9.68), 8.249 (9.68), 8.522 (7.16), 8.770 (8.27), 8.774 (8.08), 11.976 (3.27). Example 200 N-ethyl-2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidin e-4,4'-pyrazolo[1,5-a]pyridine]-1- carboxamide LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m/z = 390 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (5.49), 1.017 (7.15), 1.036 (16.00), 1.054 (7.42), 1.641 (1.63), 1.675 (2.51), 1.758 (1.18), 1.768 (1.49), 1.794 (1.95), 1.819 (1.00), 1.829 (0.83), 1.890 (2.05), 1.896 (2.14), 1.910 (2.54), 2.029 (1.88), 2.038 (2.02), 2.518 (4.56), 2.523 (2.87), 3.048 (1.52), 3.061 (2.34), 3.065 (3.40), 3.079 (4.67), 3.083 (5.11), 3.097 (3.79), 3.114 (2.19), 3.159 (0.85), 3.172 (0.92), 3.751 (2.25), 3.776 (1.19), 3.786 (2.04), 4.132 (2.20), 4.147 (4.34), 4.162 (2.14), 6.480 (1.27), 6.494 (2.54), 6.507 (1.24), 6.974 (9.70), 7.585 (1.30), 7.588 (1.26), 7.603 (1.93), 7.606 (2.74), 7.623 (1.81), 7.626 (1.79), 7.699 (1.73), 7.703 (1.77), 7.716 (1.48), 7.720 (2.78), 7.723 (2.04), 7.737 (1.48), 7.740 (1.44), 7.983 (2.71), 7.991 (3.11), 8.000 (2.50), 8.012 (2.70), 8.676 (3.91), 8.681 (3.96), 9.356 (5.69), 9.361 (5.65). The following compounds (examples 201 to example 212) were prepared in analogy to example 146: Example 201 N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-6',7'-dihydro- 5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide
LC-MS (Method 2): R t = 1.17 min; MS (ESIpos): m/z = 458 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.022 (6.72), 1.040 (16.00), 1.058 (6.92), 1.650 (1.24), 1.684 (1.93), 1.760 (0.92), 1.769 (1.17), 1.796 (1.51), 1.820 (0.77), 1.830 (0.62), 1.892 (1.30), 1.900 (1.57), 1.906 (1.62), 1.920 (1.95), 2.039 (1.44), 2.048 (1.53), 2.522 (1.46), 2.526 (0.95), 3.052 (0.88), 3.070 (3.42), 3.084 (3.01), 3.089 (3.36), 3.102 (3.66), 3.120 (1.16), 3.125 (1.14), 3.752 (1.75), 3.762 (0.99), 3.776 (0.91), 3.787 (1.57), 4.151 (1.71), 4.167 (3.40), 4.181 (1.67), 6.491 (1.04), 6.505 (2.11), 6.518 (1.01), 7.004 (8.44), 7.949 (1.73), 7.954 (1.69), 7.971 (2.02), 7.976 (2.03), 8.200 (2.31), 8.222 (2.06), 8.505 (2.74), 8.903 (3.03), 8.907 (3.07), 9.510 (4.54), 9.515 (4.53). Example 202 N-ethyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6 ',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 2): R t = 1.04 min; MS (ESIpos): m/z = 421 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (4.24), 1.030 (9.60), 1.049 (4.28), 1.307 (15.88), 1.324 (16.00), 1.621 (0.88), 1.654 (1.26), 1.756 (0.57), 1.766 (0.73), 1.793 (0.98), 1.818 (0.55), 1.828 (0.45), 1.865 (1.04), 1.871 (1.08), 1.885 (1.29), 2.002 (0.96), 2.011 (1.01), 2.521 (1.33), 2.525 (0.93), 3.027 (0.67), 3.042 (0.81), 3.055 (1.87), 3.059 (2.38), 3.073 (1.93), 3.078 (2.04), 3.091 (2.03), 3.109 (0.54), 3.138 (0.76), 3.155 (0.99), 3.171 (0.71), 3.759 (1.13), 3.783 (0.62), 3.793 (1.04), 4.074 (1.08), 4.089 (2.16), 4.104 (1.09), 6.460 (0.69), 6.474 (1.41), 6.487 (0.69), 6.772 (5.29), 7.176 (1.96), 7.181 (1.97), 8.279 (2.33), 8.284 (2.45), 8.624 (3.20), 8.629 (3.14), 11.272 (1.30), 11.277 (1.32). Example 203
N-ethyl-2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7' -dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 1.00 min; MS (ESIpos): m/z = 393 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (6.52), 1.029 (14.77), 1.047 (6.80), 1.614 (1.65), 1.648 (2.42), 1.736 (1.12), 1.745 (1.45), 1.772 (1.97), 1.797 (1.14), 1.807 (0.88), 1.863 (2.32), 1.878 (2.48), 1.996 (2.00), 2.006 (2.04), 2.333 (1.35), 2.384 (16.00), 2.524 (6.00), 2.542 (1.12), 2.675 (1.30), 3.025 (1.28), 3.039 (1.41), 3.056 (4.45), 3.070 (3.45), 3.074 (3.57), 3.088 (3.63), 3.106 (0.87), 3.736 (2.14), 3.770 (1.95), 4.057 (2.47), 4.072 (4.25), 4.087 (2.05), 5.760 (4.78), 6.127 (3.88), 6.460 (1.26), 6.474 (2.52), 6.487 (1.21), 6.615 (0.77), 6.679 (8.30), 8.107 (4.12), 8.111 (4.19), 8.510 (0.63), 8.519 (5.13), 8.524 (4.96), 11.423 (2.90). Example 204 N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-di hydrospiro[azetidine-3,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxamide LC-MS (Method 1): R t = 0.80 min; MS (ESIpos): m/z = 367 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (6.87), 1.035 (16.00), 1.052 (7.07), 1.176 (0.61), 1.231 (0.83), 2.118 (0.42), 2.278 (15.24), 2.281 (15.64), 2.518 (1.85), 2.522 (1.21), 2.539 (1.61), 2.673 (0.46), 3.027 (0.91), 3.045 (2.86), 3.059 (3.10), 3.063 (3.05), 3.077 (2.74), 3.095 (0.83), 4.021 (2.64), 4.045 (7.40), 4.064 (7.55), 4.086 (2.77), 4.113 (2.94), 4.117 (2.76), 4.125 (3.10), 4.152 (3.31), 4.159 (2.59), 4.164 (2.88), 6.543 (1.25), 6.557 (2.59), 6.571 (1.22), 6.946 (10.35), 7.230 (3.07), 7.231 (3.06), 8.295 (4.19), 8.300 (4.56), 8.673 (5.20), 8.678 (5.05), 11.306 (2.14). Example 205
2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7' -dihydrospiro[azetidine-3,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxamide LC-MS (Method 1): R t = 1.26 min; MS (ESIpos): m/z = 387 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.54), 1.016 (7.23), 1.034 (16.00), 1.052 (7.34), 1.065 (0.40), 1.137 (1.45), 1.232 (2.73), 1.295 (0.49), 2.084 (0.49), 2.115 (0.58), 2.451 (0.45), 2.456 (0.60), 2.518 (4.70), 2.522 (2.86), 2.539 (3.38), 3.027 (0.92), 3.045 (3.00), 3.058 (3.11), 3.062 (3.09), 3.077 (2.82), 3.095 (0.81), 4.020 (3.02), 4.043 (7.12), 4.068 (7.18), 4.091 (3.16), 4.118 (3.13), 4.130 (3.00), 4.164 (3.09), 4.178 (3.04), 6.542 (1.25), 6.556 (2.60), 6.570 (1.23), 7.056 (11.30), 7.701 (5.12), 8.285 (5.84), 8.290 (6.13), 8.798 (5.10), 8.803 (5.08), 12.028 (1.07). Example 206 N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-di hydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxamide LC-MS (Method 1): R t = 0.88 min; MS (ESIpos): m/z = 395 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (5.72), 1.033 (12.82), 1.051 (5.91), 1.232 (0.57), 1.753 (0.68), 1.764 (0.82), 1.786 (1.59), 1.795 (1.51), 1.819 (1.19), 1.829 (0.98), 1.925 (2.54), 1.958 (1.64), 2.273 (14.43), 2.523 (0.88), 2.985 (1.19), 3.014 (2.18), 3.044 (1.94), 3.062 (2.53), 3.076 (2.63), 3.079 (2.62), 3.093 (2.34), 3.111 (0.71), 3.846 (1.75), 3.879 (1.59), 4.125 (16.00), 6.516 (1.12), 6.530 (2.20), 6.543 (1.07), 6.742 (8.02), 7.23 (2.91), 8.231 (3.76), 8.236 (3.82), 8.626 (4.47), 8.631 (4.34), 11.290 (2.15). Example 207
N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7' -dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 1.01 min; MS (ESIpos): m/z = 393 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (3.52), 1.011 (6.34), 1.028 (14.52), 1.046 (6.78), 1.231 (1.29), 1.618 (1.69), 1.651 (2.48), 1.745 (1.14), 1.754 (1.46), 1.781 (1.98), 1.805 (1.04), 1.816 (0.87), 1.869 (2.19), 1.883 (2.52), 2.002 (1.94), 2.012 (2.06), 2.270 (15.56), 2.272 (16.00), 2.331 (1.32), 3.039 (2.03), 3.057 (4.16), 3.070 (4.67), 3.074 (4.20), 3.089 (3.56), 3.106 (1.29), 3.159 (0.44), 3.171 (0.46), 3.742 (2.18), 3.777 (2.00), 4.068 (2.06), 4.083 (4.07), 4.098 (2.08), 6.463 (1.25), 6.476 (2.50), 6.490 (1.26), 6.746 (8.40), 7.206 (3.39), 8.232 (4.23), 8.236 (4.33), 8.629 (5.01), 8.633 (4.99), 11.251 (2.52). Example 208 N-ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H -spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m/z = 379 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.010 (0.45), -0.002 (16.00), 0.006 (0.51), 1.011 (4.30), 1.017 (0.64), 1.029 (10.12), 1.047 (4.45), 1.620 (0.91), 1.654 (1.32), 1.742 (0.62), 1.751 (0.96), 1.779 (1.02), 1.803 (0.56), 1.812 (0.46), 1.868 (1.15), 1.883 (1.33), 2.001 (1.02), 2.011 (1.06), 2.518 (3.61), 2.523 (2.37), 2.540 (0.49), 3.027 (0.73), 3.039 (0.75), 3.057 (2.80), 3.070 (2.00), 3.074 (2.00), 3.088 (2.15), 3.105 (0.51), 3.159 (1.72), 3.172 (1.81), 3.739 (1.18), 3.764 (0.62), 3.774 (1.06), 4.067 (1.22), 4.083 (2.36), 4.098 (1.50), 4.111 (0.45), 6.432 (1.56), 6.436 (1.72), 6.440 (1.80), 6.444 (1.66), 6.462 (0.75), 6.476 (1.44), 6.489 (0.68), 6.717 (5.59), 7.442 (1.40), 7.449 (1.68), 7.457 (1.40), 8.273 (2.59), 8.278 (2.66), 8.650 (3.32), 8.655 (3.23), 11.611 (1.26).
Example 209 N-ethyl-2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dih ydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 1.09 min; MS (ESIpos): m/z = 407 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (3.84), 1.010 (6.79), 1.028 (15.79), 1.046 (6.96), 1.249 (7.22), 1.268 (16.00), 1.286 (7.52), 1.617 (1.40), 1.651 (2.04), 1.748 (0.94), 1.757 (1.21), 1.784 (1.59), 1.808 (0.87), 1.819 (0.70), 1.869 (1.75), 1.883 (2.08), 2.001 (1.56), 2.011 (1.64), 2.336 (0.44), 2.518 (5.31), 2.523 (3.60), 2.679 (0.48), 2.692 (1.27), 2.709 (3.69), 2.711 (3.79), 2.728 (3.65), 2.730 (3.70), 2.748 (1.16), 3.033 (1.14), 3.039 (1.19), 3.057 (4.15), 3.071 (3.53), 3.075 (3.09), 3.088 (3.61), 3.106 (0.85), 3.159 (0.55), 3.172 (0.58), 3.747 (1.85), 3.781 (1.67), 4.069 (1.78), 4.085 (3.56), 4.099 (1.86), 6.460 (1.11), 6.473 (2.26), 6.487 (1.09), 6.754 (8.52), 7.204 (2.95), 7.207 (2.82), 7.210 (2.96), 8.249 (3.99), 8.254 (4.08), 8.626 (5.16), 8.631 (5.02), 11.265 (2.11), 11.269 (2.12). Example 210 N-ethyl-2'-(1H-pyrazolo[3,4-b]pyridin-5-yl)-6',7'-dihydro-5' H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 0.88 min; MS (ESIpos): m/z = 380 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (1.70), 1.012 (6.67), 1.029 (16.00), 1.047 (7.24), 1.623 (1.44), 1.657 (2.17), 1.738 (1.01), 1.749 (1.33), 1.775 (1.73), 1.799 (0.98), 1.810 (0.74), 1.875 (2.04), 1.889 (2.20), 2.007 (1.75), 2.017 (1.78), 2.332 (0.87), 2.518 (5.02), 2.523 (3.19), 2.540 (2.94), 2.673 (0.88), 3.039 (1.62), 3.057 (3.95), 3.064 (2.68), 3.071 (4.12), 3.075 (3.53),
3.089 (3.45), 3.106 (1.00), 3.159 (6.78), 3.172 (7.41), 3.739 (1.96), 3.764 (1.03), 3.774 (1.77), 4.086 (2.84), 4.099 (4.68), 4.112 (2.78), 4.125 (0.79), 6.468 (1.16), 6.481 (2.35), 6.495 (1.13), 6.751 (0.80), 6.820 (8.72), 8.140 (9.79), 8.515 (0.64), 8.524 (5.81), 8.529 (5.90), 8.964 (0.73), 8.971 (6.47), 8.976 (6.11), 13.644 (1.44). Example 211 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-di hydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m/z = 413 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (7.10), 1.032 (16.00), 1.049 (7.34), 1.234 (0.44), 1.619 (1.55), 1.653 (2.23), 1.752 (0.99), 1.762 (1.31), 1.788 (1.76), 1.812 (0.96), 1.823 (0.81), 1.873 (1.97), 1.888 (2.35), 2.008 (1.74), 2.018 (1.85), 2.520 (5.24), 2.525 (3.40), 3.042 (2.05), 3.060 (3.81), 3.073 (4.52), 3.078 (4.00), 3.091 (3.27), 3.096 (2.35), 3.109 (1.15), 3.161 (1.37), 3.174 (1.44), 3.747 (2.00), 3.756 (1.29), 3.770 (1.08), 3.781 (1.83), 4.084 (1.94), 4.099 (4.14), 4.113 (2.13), 6.463 (1.21), 6.477 (2.42), 6.490 (1.16), 6.844 (0.79), 6.856 (8.97), 7.674 (8.19), 7.719 (0.65), 8.108 (0.45), 8.113 (0.49), 8.235 (6.34), 8.240 (6.59), 8.684 (0.41), 8.689 (0.41), 8.736 (0.46), 8.741 (0.43), 8.762 (5.30), 8.766 (5.26), 11.967 (0.57). Example 212 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-di hydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxamide LC-MS (Method 1): R t = 0.94 min; MS (ESIpos): m/z = 415 [M+H] +
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (7.08), 1.033 (16.00), 1.050 (7.17), 1.230 (0.47), 1.757 (0.73), 1.768 (0.91), 1.791 (1.77), 1.800 (1.68), 1.822 (1.34), 1.833 (1.11), 1.923 (2.85), 1.957 (1.81), 2.074 (1.19), 2.518 (1.72), 2.522 (1.15), 2.986 (1.36), 3.014 (2.41), 3.044 (2.14), 3.061 (2.94), 3.075 (3.05), 3.079 (3.01), 3.093 (2.72), 3.110 (0.82), 3.847 (1.94), 3.879 (1.78), 4.133 (11.41), 6.516 (1.24), 6.530 (2.47), 6.543 (1.21), 6.848 (9.89), 7.688 (3.58), 7.693 (3.60), 8.224 (4.98), 8.229 (5.22), 8.754 (5.30), 8.759 (5.33), 12.010 (1.89). Example 213 N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydro spiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro [azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxamide (75.0 mg, 206 µmol), 2-bromopropane (30.5 mg, 248 µmol) and NaOH (9.91 mg, 248 µmol) were solubilised in DMF (300 µl) and the mixture was stirred overnight at 70°C. Water was added and the mixture was extracted 3x with EtOAc, dried with a silicone filter and evaporated. The residue was purified by preparative HPLC to give 2.30 mg (96 % purity, 3 % yield) of the title compound. LC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m/z = 446 [M+H] + Example 214 2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospi ro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro [azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxamide (75.0 mg, 206 µmol), bromocyclohexane (40.4 mg, 248 µmol) and NaOH (9.91 mg, 248 µmol) were solubilised in DMF (300 µl) and the mixture was stirred overnight at 70°C. Water was added and the mixture was extracted 3x with EtOAc, dried with a silicone filter and evaporated. The residue was purified by preparative HPLC to give 1.10 mg (98 % purity, 1 % yield) of the title compound. LC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m/z = 446 [M+H] + Example 215 cyclopentyl (rac)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetid ine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate Trifluoroacetic acid—(rac)-6’-methyl-2’-(quinolin-3-yl)-5’,6’-dihy drospiro[azetidine-3,4’- pyrrolo[1,2-b]pyrazole] (1/1) (75.0 mg, 185 µmol), cyclopentyl carbonochloridate (55.1 mg, 371 µmol) and N,N-diisopropylethylamine (97 µl, 560 µmol) were solubilised in dichloromethane (1.3 ml) and the mixture was stirred for 1 h at rt. It was evaporated and the residue was purified by preparative HPLC to give 6.70 mg (100 % purity, 9 % yield) of the title compound. LC-MS (Method 1): R t = 1.27 min; MS (ESIpos): m/z = 403 [M+H] + Example 216 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(5-methyl-1H- imidazol-2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1,4]oxazine] Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7 -dihydrospiro[azetidine-3,4’- pyrazolo[5,1-c][1,4]oxazine] (1/1) (30.0 mg, 69.8 µmol) and 5-methyl-1H-imidazole-2- carbaldehyde (11.5 mg, 105 µmol) were solubilized in THF (1.0 ml), sodium triacetoxyborohydride (33.4 mg, 158 µmol) and acetic acid (4.0 µl, 70 µmol) were added and the mixture was stirred overnight at rt.5-methyl-1H-imidazole-2-carbaldehyde (11.5 mg, 105 µmol)
and sodium triacetoxyborohydride (33.4 mg, 158 µmol) were added an dthe mixture was stirred for 4 h at rt. It was poured into sat. NaHCO3 soultion and extracted 3x with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3.00 mg (97 % purity, 10 % yield) of the title compound. LC-MS (Method 2): R t = 0.86 min; MS (ESIpos): m/z = 410 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.170 (0.56), 1.186 (0.61), 1.231 (1.22), 2.106 (3.76), 2.327 (2.68), 2.331 (1.98), 2.518 (8.94), 2.523 (5.69), 2.539 (0.56), 2.669 (2.73), 2.673 (1.93), 3.493 (3.62), 3.513 (8.28), 3.538 (6.49), 3.558 (3.01), 3.577 (0.99), 3.670 (16.00), 4.037 (3.06), 4.049 (6.96), 4.061 (5.65), 4.120 (5.88), 4.133 (6.92), 4.144 (3.15), 6.489 (0.42), 6.547 (0.61), 6.753 (0.66), 6.919 (15.44), 7.708 (7.76), 7.714 (7.62), 8.238 (9.04), 8.243 (8.99), 8.783 (10.07), 8.788 (9.84), 11.560 (0.71), 11.677 (0.56), 12.034 (3.86). The following compounds (example 217 to example 229) were prepared in analogy to example 216: Example 217 2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2 -yl)methyl]-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 0.85 min; MS (ESIpos): m/z = 374 [M+H] + Example 218 1-[(4-chloro-1H-pyrazol-5-yl)methyl]-2'-(3-ethyl-1H-pyrrolo[ 2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 1.03 min; MS (ESIpos): m/z = 408 [M+H] + Example 219 (rac)-1-[(4-chloro-1H-pyrazol-5-yl)methyl]-6'-methyl-2'-(qui nolin-3-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m/z = 405 [M+H] + Example 220 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol- 2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1,4]oxazine] LC-MS (Method 2): R t = 0.82 min; MS (ESIpos): m/z = 396 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.170 (0.68), 1.186 (0.78), 1.231 (1.14), 2.327 (3.01), 2.331 (2.13), 2.518 (10.29), 2.523 (6.49), 2.669 (3.06), 2.673 (2.18), 3.499 (4.26), 3.519 (10.03), 3.542 (10.13), 3.562 (4.21), 3.578 (1.71), 3.747 (16.00), 4.038 (2.34), 4.050 (5.56), 4.063 (4.42), 4.123 (4.68), 4.136 (5.45), 4.148 (2.44), 6.834 (3.32), 6.983 (15.01), 7.074 (3.12), 7.707 (6.34), 7.713 (6.29), 8.249 (7.01), 8.254 (7.17), 8.787 (8.16), 8.792 (7.95), 11.902 (2.18), 12.032 (3.12). Example 221 (rac)-1-[(1H-imidazol-2-yl)methyl]-6'-methyl-2'-(quinolin-3- yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 0.90 min; MS (ESIpos): m/z = 371 [M+H] + Example 222 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1-methyl-1H- imidazol-2-yl)methyl]-6',7'-dihydro- 5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine] LC-MS (Method 2): R t = 1.08 min; MS (ESIpos): m/z = 436 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.650 (0.92), 1.684 (1.14), 1.812 (0.85), 1.826 (1.06), 1.840 (1.23), 1.871 (0.51), 1.881 (0.64), 1.909 (0.98), 1.933 (0.57), 1.942 (0.48), 1.979 (0.94), 1.989 (1.02), 2.285 (0.61), 2.309 (1.16), 2.325 (0.41), 2.330 (0.51), 2.338 (0.70), 2.521 (0.93), 2.526 (0.65), 2.626 (1.19), 2.646 (0.64), 2.656 (1.00), 2.667 (0.59), 2.672 (0.44), 3.593 (5.07), 3.697 (16.00), 4.066 (1.10), 4.081 (2.20), 4.096 (1.09), 6.761 (4.44), 6.764 (4.67), 6.818 (5.25), 7.089 (3.75), 7.092 (3.70), 7.674 (2.59), 7.681 (2.66), 8.213 (2.42), 8.218 (2.46), 8.753 (3.08), 8.757 (3.00), 11.976 (1.16), 11.982 (1.15). Example 223 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol- 2-yl)methyl]-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine]
LC-MS (Method 2): R t = 0.98 min; MS (ESIpos): m/z = 422 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.654 (2.73), 1.687 (3.28), 1.784 (2.60), 1.791 (2.99), 1.797 (3.15), 1.812 (3.60), 1.897 (1.52), 1.907 (2.18), 1.933 (2.96), 1.958 (2.69), 1.969 (3.53), 1.985 (3.11), 2.308 (1.85), 2.331 (3.88), 2.335 (3.74), 2.360 (1.88), 2.521 (2.13), 2.526 (1.50), 2.543 (1.92), 2.662 (3.52), 2.668 (2.56), 2.672 (2.62), 2.678 (2.12), 2.691 (2.96), 3.576 (16.00), 4.067 (3.27), 4.082 (6.54), 4.097 (3.26), 6.730 (15.88), 6.828 (0.91), 7.042 (0.91), 7.684 (7.34), 8.195 (9.94), 8.200 (10.35), 8.741 (9.31), 8.747 (9.15), 11.886 (1.48), 11.997 (2.77). Example 224 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3,3,3-trifluo ropropyl)-5',6'-dihydrospiro[piperidine- 4,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 1.21 min; MS (ESIpos): m/z = 424 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.55), 1.230 (4.75), 1.696 (5.85), 1.714 (5.66), 1.757 (7.02), 1.769 (5.82), 1.791 (3.87), 2.040 (3.67), 2.054 (3.19), 2.302 (0.46), 2.322 (1.40), 2.327 (1.89), 2.331 (1.43), 2.391 (7.80), 2.409 (12.88), 2.427 (8.39), 2.522 (12.81), 2.539 (8.62), 2.557 (7.74), 2.585 (6.60), 2.644 (6.24), 2.664 (6.96), 2.668 (6.73), 3.582 (0.65), 3.761 (0.42), 4.156 (8.52), 4.174 (13.69), 4.191 (8.72), 4.213 (1.85), 4.231 (1.14), 6.794 (8.78), 6.939 (1.17), 7.026 (2.76), 7.555 (0.46), 7.678 (14.86), 7.685 (16.00), 7.693 (2.15), 8.156 (1.14), 8.225 (13.01), 8.230 (12.98), 8.280 (0.94), 8.285 (0.91), 8.767 (1.89), 8.772 (2.08), 8.782 (15.67), 8.787 (15.54), 8.850 (0.68), 8.855 (0.68), 11.995 (7.22).
Example 225 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol- 2-yl)methyl]-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 0.85 min; MS (ESIpos): m/z = 409 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.664 (1.47), 1.686 (3.53), 1.696 (2.90), 1.707 (3.21), 1.746 (3.55), 1.778 (1.73), 2.323 (0.75), 2.327 (1.03), 2.331 (0.77), 2.379 (4.35), 2.397 (7.28), 2.414 (4.83), 2.578 (2.91), 2.598 (3.45), 2.665 (0.98), 2.669 (1.22), 2.673 (0.95), 3.602 (16.00), 4.148 (4.66), 4.166 (7.59), 4.183 (4.73), 6.672 (9.44), 6.835 (0.88), 7.036 (0.87), 7.683 (7.18), 7.689 (7.06), 8.206 (8.36), 8.211 (8.24), 8.764 (9.31), 8.769 (9.09), 11.889 (2.08), 11.998 (3.85). Example 226 1-benzyl-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-d ihydrospiro[piperidine-4,4'-pyrrolo[1,2- b]pyrazole] LC-MS (Method 1): R t = 1.30 min; MS (ESIpos): m/z = 418 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (3.58), 1.696 (3.00), 1.716 (2.99), 1.755 (3.28), 2.074 (4.45), 2.327 (0.57), 2.390 (3.39), 2.408 (5.88), 2.425 (4.10), 2.668 (0.65), 3.574 (10.60), 4.148 (3.36), 4.165 (5.60), 4.182 (3.21), 6.710 (5.94), 7.250 (1.62), 7.260 (2.36), 7.270 (2.36), 7.280 (1.48), 7.339 (16.00), 7.350 (14.82), 7.685 (5.71), 8.209 (5.25), 8.213 (5.27), 8.767 (5.25), 8.771 (5.19), 11.995 (3.08).
Example 227 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(cyclohexylmet hyl)-5',6'-dihydrospiro[piperidine- 4,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 1.57 min; MS (ESIpos): m/z = 424 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.807 (1.65), 0.832 (4.78), 0.861 (5.28), 0.890 (2.27), 1.123 (1.86), 1.174 (6.58), 1.201 (5.49), 1.231 (4.22), 1.262 (1.45), 1.487 (1.86), 1.496 (2.07), 1.505 (2.30), 1.514 (2.66), 1.523 (2.21), 1.533 (1.95), 1.541 (1.77), 1.653 (11.39), 1.676 (9.68), 1.687 (9.27), 1.743 (11.13), 1.760 (7.85), 1.771 (7.97), 2.163 (12.96), 2.181 (12.01), 2.323 (1.74), 2.327 (2.24), 2.331 (1.80), 2.379 (10.39), 2.397 (15.88), 2.414 (11.28), 2.459 (3.19), 2.464 (4.07), 2.468 (5.08), 2.518 (8.71), 2.523 (6.23), 2.530 (3.19), 2.535 (2.45), 2.539 (1.77), 2.544 (1.24), 2.548 (0.92), 2.665 (1.33), 2.669 (1.80), 2.673 (1.27), 4.146 (8.44), 4.164 (13.02), 4.181 (7.97), 6.729 (15.91), 7.678 (14.61), 8.220 (15.26), 8.225 (16.00), 8.768 (15.97), 8.773 (15.50), 11.984 (4.99). Example 228 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)- 5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m/z = 370 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.018 (15.67), 1.035 (16.00), 1.635 (0.60), 1.643 (0.74), 1.653 (0.77), 1.665 (1.38), 1.675 (1.18), 1.684 (1.32), 1.693 (1.04), 1.750 (1.32), 1.760 (1.21),
1.768 (1.31), 1.782 (0.74), 1.791 (0.73), 2.074 (1.48), 2.378 (2.10), 2.395 (3.27), 2.413 (2.26), 2.518 (2.07), 2.523 (1.45), 2.593 (1.12), 2.612 (1.42), 2.632 (0.73), 2.703 (0.41), 2.719 (1.04), 2.735 (1.38), 2.752 (1.00), 4.148 (2.22), 4.165 (3.36), 4.182 (2.16), 6.668 (5.98), 7.678 (2.90), 7.681 (2.90), 8.210 (3.98), 8.215 (4.04), 8.768 (4.08), 8.773 (4.01), 11.993 (1.46). Example 229 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1-methyl-1H- pyrazol-4-yl)methyl]-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): R t = 0.95 min; MS (ESIpos): m/z = 422 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.665 (1.04), 1.684 (0.91), 1.694 (0.75), 1.733 (0.99), 1.746 (0.85), 1.765 (0.51), 2.368 (1.50), 2.385 (2.41), 2.403 (1.74), 2.518 (1.61), 2.523 (1.37), 3.410 (4.66), 3.809 (16.00), 4.142 (1.51), 4.160 (2.36), 4.177 (1.46), 6.649 (3.91), 7.322 (4.22), 7.587 (3.94), 7.684 (4.23), 8.200 (3.27), 8.205 (3.26), 8.757 (2.99), 8.762 (2.94), 11.995 (1.07). Example 230 [2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5 'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-1-yl](4-fluorophenyl)methanone Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7 -dihydro-5’H- spiro[piperidine-4,4’-pyrazolo[1,5-a]pyridine] (1/1) (80.0 mg, 175 µmol) was solubilised in DMF (2.0 ml), 4-fluorobenzoic acid (29.5 mg, 211 µmol), N,N-diisopropylethylamine (92 µl, 530 µmol) and T3P (120 µl, 50 % purity in DMF, 210 µmol) were added and the mixture was stirred
overnight at rt. It was evaporated and purified by preparative HPLC to give 27.0 mg (99 % purity, 33 % yield) of the title compound. LC-MS (Method 2): R t = 1.24 min; MS (ESIpos): m/z = 464 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.942 (0.95), 0.956 (0.90), 1.673 (0.90), 1.801 (0.91), 1.909 (3.51), 2.024 (2.96), 2.078 (0.72), 2.521 (2.65), 2.526 (1.67), 3.503 (0.79), 4.111 (4.59), 4.205 (0.76), 6.993 (16.00), 7.278 (0.68), 7.285 (6.03), 7.290 (2.05), 7.302 (2.69), 7.307 (12.32), 7.313 (2.61), 7.324 (2.20), 7.329 (6.90), 7.519 (0.88), 7.526 (6.84), 7.532 (2.71), 7.540 (7.50), 7.548 (6.46), 7.557 (2.33), 7.562 (5.68), 7.686 (7.91), 7.693 (7.89), 8.227 (8.48), 8.231 (8.47), 8.774 (9.94), 8.779 (9.61), 11.991 (3.94). The following compound (example 231) was prepared in analogy to example 230: Example 231 [2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5 'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-1-yl](oxan-4-yl)methanone LC-MS (Method 2): R t = 1.07 min; MS (ESIpos): m/z = 454 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.938 (0.83), 0.954 (0.82), 1.519 (0.83), 1.551 (1.95), 1.574 (1.62), 1.604 (3.12), 1.631 (1.80), 1.659 (2.29), 1.692 (2.65), 1.721 (1.88), 1.734 (2.24), 1.748 (2.31), 1.782 (0.64), 1.833 (1.09), 1.861 (1.51), 1.907 (3.20), 1.921 (3.55), 2.018 (2.77), 2.029 (2.91), 2.521 (3.24), 2.526 (2.25), 2.889 (0.62), 2.898 (1.04), 2.916 (1.28), 2.926 (2.08), 2.936 (1.10), 2.943 (0.83), 2.953 (1.06), 2.964 (0.50), 3.056 (0.79), 3.084 (1.44), 3.111 (0.84), 3.379 (2.28), 3.409 (4.58), 3.438 (2.55), 3.849 (3.06), 3.863 (3.45), 4.096 (4.25), 4.110 (7.11), 4.125 (3.94), 6.777 (0.41), 6.903 (16.00), 7.679 (6.78), 8.229 (10.03), 8.234 (10.15), 8.766 (9.37), 8.771 (9.28), 11.980 (2.75). Example 232 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(methanesulfon yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole]
Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5’,6 -dihydrospiro[piperidine- 4,4’-pyrrolo[1,2-b]pyrazole] (1/1) (100 mg, 69 % purity, 156 µmol) was solubilised in DMSO (1.0 ml), methanesulfonyl chloride (17.9 mg, 156 µmol) and triethylamine (65 µl, 470 µmol) were added and the mixture was stirred overnight at rt. It was filtered and purified by preparative HPLC to give 33.0 mg (99 % purity, 52 % yield) of the title compound. LC-MS (Method 1): R t = 0.98 min; MS (ESIpos): m/z = 406 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.770 (0.48), 1.782 (0.43), 1.793 (1.27), 1.803 (1.04), 1.816 (1.16), 1.827 (1.39), 1.840 (1.49), 1.853 (1.09), 1.862 (0.50), 1.877 (0.54), 2.075 (0.85), 2.443 (1.69), 2.461 (2.68), 2.478 (1.96), 2.518 (0.76), 2.523 (0.51), 2.539 (0.76), 2.999 (16.00), 3.195 (0.50), 3.204 (0.67), 3.225 (1.34), 3.234 (0.94), 3.248 (0.86), 3.256 (0.73), 3.344 (1.40), 3.356 (0.93), 3.377 (0.82), 3.387 (0.46), 4.191 (1.72), 4.209 (2.65), 4.226 (1.66), 6.879 (6.37), 7.686 (2.29), 7.691 (2.31), 8.222 (3.35), 8.228 (3.43), 8.792 (3.44), 8.797 (3.44), 12.010 (1.13). Example 233 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-6', 7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-sulfonamide Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7 -dihydro-5’H- spiro[piperidine-4,4’-pyrazolo[1,5-a]pyridine] (1/1) (80.0 mg, 175 µmol) was solubilised in DMSO (2.0 ml), dimethylsulfamyl chloride (27.7 mg, 193 µmol) and N,N-diisopropylethylamine (92 µl, 530 µmol) were added and the mixture was stirred overnight at rt. It was filtered and purified by preparative HPLC to give 30.0 mg (99 % purity, 38 % yield) of the title compound.
LC-MS (Method 2): R t = 1.21 min; MS (ESIpos): m/z = 449 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.789 (0.47), 1.900 (0.63), 1.906 (0.66), 2.806 (16.00), 3.140 (0.45), 3.459 (0.44), 4.089 (0.41), 4.105 (0.82), 4.120 (0.40), 6.888 (1.94), 7.680 (0.83), 7.686 (0.85), 8.230 (0.95), 8.235 (0.97), 8.768 (1.09), 8.772 (1.10). Example 234 2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl -6',7'-dihydro-5'H-spiro[piperidine- 4,4'-pyrazolo[1,5-a]pyridine]-1-carboxamide N-Ethyl-2’-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7 ’-dihydro-5’H-spiro[piperidine-4,4’- pyrazolo[1,5-a]pyridine]-1-carboxamide (39.0 mg, 99.4 µmol) was solubilised in DMF (500 µl), NCS (14.6 mg, 109 µmol) and benzoyl peroxide (35.3 mg, 75 % purity, 109 µmol) were added and the mixture was stirred for 3 h at rt. It was diluted with half conc. Na2S2O3 solution, extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4 and evaporated. The residue was purified by preparative HPLC to give 21.2 mg (95 % purity, 47 % yield) of the title compound. LC-MS (Method 1): R t = 0.99 min; MS (ESIpos): m/z = 427 [M+H] + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (5.42), 1.027 (12.33), 1.045 (5.60), 1.612 (1.28), 1.645 (1.85), 1.745 (0.86), 1.754 (1.09), 1.781 (1.47), 1.805 (0.80), 1.816 (0.64), 1.867 (1.64), 1.881 (1.89), 2.000 (1.46), 2.010 (1.53), 2.331 (0.91), 2.383 (16.00), 2.518 (4.99), 2.522 (3.14), 2.673 (0.91), 3.032 (1.08), 3.038 (1.14), 3.056 (3.63), 3.069 (3.20), 3.073 (2.81), 3.087 (3.15), 3.105 (0.77), 3.742 (1.68), 3.776 (1.54), 4.072 (1.61), 4.087 (3.15), 4.102 (1.59), 6.460 (1.01), 6.473 (1.99), 6.487 (0.97), 6.813 (6.77), 8.099 (3.36), 8.104 (3.39), 8.644 (4.08), 8.649 (4.02), 11.868 (2.79).
EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS Biological in vitro assays The in vitro activity of the compounds of the present invention can be demonstrated in the following assays: The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. Biological Evaluation In order that this invention may be better understoo d, the following examples are set forth. These examples are for the purpose of illustration only, a nd are not to be construed as limiting the scope o f the invention in any manner. All publications mention ed herein are incorporated by reference in their entirety. Demonstration of the activity of the compounds of th e present invention may be accomplished through in vitro and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent to inhibit and be selective against something the following assays may be used. Binding competition assay The ability of the compounds of the present inventio n to inhibit the binding of an Alexa647‐labelled ATP‐competitive kinase inhibitor to a Glutathione‐S ‐transferase‐ (GST‐) fusion protein was quantifie d employing the TR‐FRET‐based binding competition a ssay as described in the following paragraphs. A recombinant fusion protein of N‐terminal GST and full‐length human , expressed by baculovirus infected SF9 insect cells and purified by Glutathione Sepharose affinity chromatography, was used as GST‐ fusion protein. Tracer 222 from Invitrogen (ca talogue no. PR9198A) was used as Alexa647‐ labelled ATP‐competitive kinase inhibitor. For the assay 50 nl of a 100fold concentrated solut ion of the test compound in DMSO was pipetted into either a black low volume 384well microtiter pl ate or a black 1536well microtiter plate (both Greiner Bio‐One, Frickenhausen, Germany), 3 µL solu tion of Tracer 222 (25 nM => final concentration in 5 µL assay volume is 15 nM) in aqueous assay buffer [25 mM Tris/HCl pH 7.5, 10 mM MgCl 2 , 5 mM β‐glycerolphosphate, 2.5 mM dithiothreitol, 0.5 mM ethylene glycol‐bis(2‐aminoethylether)‐N,N,N′,N′ tetraacetic acid [EGTA], 0.5 mM sodium ortho‐vanadat e, 0.01 % (w/v) bovine serum albumin [BSA], 0.005% (w/v) Pluronic F‐127 (Sigma)] were added. Th en the binding competition was started by the addition of 2 µL of a solution of the GST‐ fusi on protein (2.5 nM => final conc. in the 5 µL assay volume is 1 nM) and of Anti‐GST‐Tb (1.25 nM => fina l conc. in the 5 µL assay volume is 0.5 nM), a Lumi4®‐Tb Cryptate‐conjugated anti‐GST‐antibody from Cisbio Bioassays (France), in assay buffer. The resulting mixture was incubated 30 min at 22°C to allow the formation of a complExample between the Tracer 222, the fusion protein and Anti GST‐Tb. Subsequently the amount of this complex was evaluated by measurement of the resonance energy transfer from the Tb‐cryptate to the Tracer 222. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR‐FRET reader, e.g. a Pherastar (BM G Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin‐Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of the complex. The data were normal ised (assay reaction without inhibitor = 0 % inhibition, all other assay components but GST‐ fus ion protein = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 µM to 0.07 nM (20 µM, 5.7 µM, 1.6 µM, 0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0. 25 nM and 0.07 nM, the dilution series prepared separatel y before the assay on the level of the 100fold concentrated solutions in DMSO by serial dilutions, e xact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata Screener™ software. Table 1: Measured IC 50 values of compounds regarding inhibition of MA P4K1 (HPK1):
Phosphorylation assay in human cell line using HTRF Assay Phosphorylation assays were carried out in Jurkat E6.1 cells from American Type Culture Collection (ATCC) stably overexpressing human FLAG‐tagged SLP‐ 76 (proprietary). Cultured cells were kept in RPMI 1640 medium supplemented with 1% FCS at a cell dens ity of 2x 10e6/mL 24h prior compound testing. Starved cells were transferred to a 384 well format plate at a cell density of 140.000 cells/well and simultaneously treated with 1 µg/mL a‐CD3 antibody (clone OKT3. ebioscience #16‐0037‐85) and 4 µg/mL anti‐IgG crosslinking antibody (Invitrogen goa t anti‐mouse IgG (H+L) 2 #31160) together with t he test compound for 30 min at 37 ⁰C. Applied compou nds were tested at either fixed concentration of 10 µmol/L and 20 µmol/L or in a 8 point dose respon se titration of increase compound concentration with 10 nmol/L. 50 nmol/L. 100 nmol/L. 500 nmol/L. 1 μmol/L. 5 μmol/L. 10 μmol/L and 20 μmol/L in triplicates. The cells were washed once in phosphate buffered saline (pH 7.4). The detection of pSer376 SLP76 levels in the proprietary Jurkat cell lines wa s carried out utilizing an adapted protocol of the HTRF pSLP76 Assay (Cisbio # 63ADK076PEG). Cells were lysed using 4 µl of the supplemented lysis buffer (Cisbio # 63ADK076PEG) for 60 min at room temperatur e. Subsequently 4 µl of the premixed antibody solution (Cisbio # 63ADK076PEG) was added and incubat ed over night at room temperature. Read‐out and analyses was carried out using a Pherastar and the MARS software (BMG Labtechnologies, Offenburg, Germany). Inhibition constant (IC 50 ) values were calculated by concentration‐respo nse curve fitting applying four‐parameter nonlinear regression analyse. As control for maximal effect (max control which rep resent the maximally possible inhibition of pSer376‐SLP‐76 by a test compound) cells with no a‐CD3 (clone OKT3. ebioscience #16‐0037‐85) and no test compound treatment were used. Cells with a CD3 treatment only were used as negative control (min control. which represent the minimally p ossible inhibition of pSer376‐SLP‐76 by a test compound).