NOVEL KAPPA OPIOID LIGANDS

摘要

The invention provides novel ligands of Kappa (κ) opioid receptors, such as can be used to modulate a Kappa opioid receptor. Methods of synthesis and methods of use are also provided. Compounds of the invention can be used therapeutically in the treatment of dissociative disorders or pain, or to provide neuroprotection, or to induce diuresis, or to modulate the immune system, or for treatment of one or more of an affective disorders comprising depression or stress/anxiety; an addictive disorder; alcoholism, epilepsy; a cognition deficiency; schizophrenia; Alzheimer's disease; or pain.

主权项

1. A compound of formula (I)wherein
the ring designated A can further comprise an additional nitrogen atom in any position that bears any of W, X, Y, or Z, provided that the respective group W, X, Y, or Z is absent from that position; W is H, (C1-C6)alkyl, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, or halo; X is H, halo, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, NRaRb, N(Ra)C(═O)(C1-C6)alkyl, CO2R, or heteroaryl; Y is H, halo, (C1-C6)alkyl, (C3-C9)cycloalkyl, or halo; Z is halo, hydroxy, CO2R, C(═O)NR2, CN, heteroaryl(C0-C6)alkyl, hydroxy(C1-C6)alkyl, HC(═O), HC(═O), (C1-C6)C(═O), or CR(═NOR); wherein each independently selected R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6)alkyl; or, any adjacent pair of W, X, and Y, can together with the atoms to which they are bonded form a fused cycloalkyl, heterocyclyl, or aryl, or heteroaryl, any of which can be mono- or independently multi-substituted with (C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NRaRb, N(Ra)C(═O)(C1-C6)alkyl, CO2R, or heteroaryl; wherein any alkyl, cycloalkyl, aryl, or heteroaryl of W, X, Y, or Z, can be unsubstituted or can be mono- or independently multi-substituted with (C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NRaRb, N(Ra)C(═O)(C1-C6)alkyl, CO2R, or heteroaryl; the ring system Cyc, comprising the nitrogen atom, comprises a mono-, bi-, or tri-cyclic heterocyclyl bonded to ring A via the nitrogen atom, wherein Cyc comprises a 4, 5, 6, 7, or 8 membered ring, optionally bridged with one or two bridges independently comprising 0, 1, or 2 carbon atoms, the ring system Cyc optionally containing 1 or 2 additional heteroatoms selected from NR, O, or S(O)q wherein q=0, 1, or 2; wherein R1, and optionally, m independently selected R2, are bonded to the ring system Cyc, m=0, 1, or 2; R1 is (CH2)nNRaRb, wherein Ra and Rb are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, is substituted with 0, 1, 2, 3, or 4 independently selected J, and wherein any heterocyclyl or cycloalkyl is mono-, bi-, or tri-cyclic; or Ra and Rb together with the nitrogen atom to which they are bonded form a heterocyclyl ring substituted with 0, 1, 2, 3, or 4 independently selected J, wherein n=0, 1, or 2; or R1 is (CH2)p1NRa(CH2)p2 bonded to two carbon atoms of Cyc to form a 5-, 6-, or 7-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 independently selected J, p1 and p2 are independently 0, 1, or 2, provided that p1+p2 is no less than 2; R2 is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, OR, CO2R, or halo, wherein m=0, 1, or 2; J is independently at each occurrence OR, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, CO2R, or halo; or any pharmaceutically acceptable salt thereof.