Bicyclic-substituted amines as histamine-3 receptor ligands

A compound of the formula:

• or a pharmaceutically acceptable salt, ester, or amide thereof, wherein:
• Y and Y′ are each independently CH or CF;
• X, X′, Z and Z′ are each independently C;
• Z is N;
• one of R1 and R2 is selected from the group consisting of halogen, cyano, and L2R6;
• the other of R1 and R2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy;
• R3 is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;
• R3a is absent;
• R3b is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, and thioalkoxy;
• R4 and R5 are each independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NRARB)alkyl, or R4 and R5 taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:
• R6 is selected from the group consisting of aryl, heteroaryl, heterocycle, and cycloalkyl,
• wherein each R6 is optionally substituted with 1, 2 or 3 substituents selected from the group consisting alkyl, cyano, halo, —NRARB, alkoxy, alkoxyimino, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, (NRARB)carbonyl, cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, and thioalkoxy;
• R7, R8, R9, and R10 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl;
• or one of the pair R7 and R8 or the pair R9 and R10 is taken together to form a C3-C6 ring, wherein 0, 1, or 2 heteroatoms selected from O, N, or S replace a carbon atom in the ring;
• R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro;
• Q is selected from the group consisting of a bond, O, S, and NR15;
• L is —[C(R16)(R17)]n— or —[C(R16)(R17)]pO—;
• L2 is selected from the group consisting of a bond, —O—, —C(═O)—, —S—, —[C(R18)(R19)]q—, —O—[C(R18)(R19)]q—, —NH— and —N(alkyl)-;
• R15 is selected from the group consisting of hydrogen, alkyl, acyl, amido, and formyl;
• R16 and R17 at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and fluoro;
• R18 and R19 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro;
• Rx and Ry at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, dialkylamino, and fluoro, or one of Rx or Ry represents a covalent bond when taken together with Rx or Ry on an adjacent carbon atom such that a double bond is represented between the adjacent carbon atoms;
• m is an integer from 1 to 5;
• n is an integer from 1 to 6;
• p is an integer from 2 to 6;
• and
• q is an integer from 1 to 4.