Substituted spirocyclic piperidine derivatives as histamine-3 (H3) receptor ligands

A compound of Formula (I):

• or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is C3-C8 cycloalkyl;
• W is —CH2—, —CH2CH2—, or —CH2—O—;
• k is 0, 1, or 2;
• m is 0, 1, or 2;
• and the sum of m and k is 1, 2, or 3;
• Y2═Y3 is —C(X)═CH— or —CH═C(X)—;
• X is R2, —OR2, —(C1-C3 alkyl)-R2, —O—(C1-C3 alkyl)-R2, —NHR2, —NHC(═O)R2, or —NHC(═O)NHR2;
• wherein said C1-C3 alkyl is optionally substituted with —OH or C1-C4 alkoxy;
• R2 is
• A is F, Cl, or Br;
• R3 is H, F, or C1-C4 alkyl;
• R4 is H, F, or C1-C4 alkyl;
• R4A is H, F, Cl, Br, or C1-C4 alkyl;
• R5 is H, F, or C1-C4 alkyl;
• R5A is H, F, Cl, Br, C1-C4 alkyl or phenyl;
• or, R4 and R5, together with the carbon atoms to which they are attached, form a fused C3-C6 cycloalkyl ring optionally substituted with 1, 2, or 3 R14;
• or, R4A and R5A, together with the carbon atoms to which they are attached, form a fused phenyl ring optionally substituted with 1, 2, or 3 R14;
• a C3-C6 cycloalkyl ring optionally substituted with 1, 2 or 3 R14;
• a 5 to 6 membered fused heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1, 2, or 3 R14;
• or
• a 5 to 6 membered fused heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO2, wherein said heterocycloalkyl ring system is optionally substituted with 1, 2, or 3 R14;
• R6 is H, F, or C1-C4 alkyl;
• R7 is H, F, Cl, Br, or C1-C4 alkyl;
• R8 is H, —C(═O)R27, —CO2R27, C1-C6 alkyl optionally substituted by 1-3 R20;
• C3-C8 cycloalkyl optionally substituted by 1-3 R20A;
• C6-C10 aryl optionally substituted by 1-3 R20A;
• C7-C15 arylalkyl optionally substituted by 1-3 R20A;
• or
• a 5 to 10 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1-3 R20A;
• R9, at each occurrence, is independently F, Cl, Br, C1-C4 alkyl, or C1-C4 alkoxy;
• R10 is F, Cl, Br, C1-C3 alkyl, or C1-C3 alkoxy;
• R14 at each occurrence is independently F, Cl, Br, I, —OR21, —OR22, —NR23R24, —NHOH, —NO2, —CN, —CF3, (═O), —C(═O)R21, —CO2R21, —OC(═O)R21, —C(═)NR23R24, —NR27C(═O)R21, —NR27C(═O)OR21, —OC(═O)NR23R24, —NR27C(═S)R21, —SR21, —S(O)R21, or —S(O)2R21;
• C1-C6 alkyl optionally substituted with OR26;
• C2-C6 alkenyl, or C2-C6 alkynyl;
• R20 at each occurrence is independently F, Cl, Br, I, —OR21, —OR22, —NR23R24, —NHOH, —NO2, —CN, —CF3, (═O), —C(═O)R21, —CO2R21, —C(═O)NR23R24, —NR27C(═O)R21, —NR27C(═O)OR21, —OC(═O)NR23R24, —NR27C(═S)R21, —SR21, —S(O)R21, or —S(O)2R21;
• C1-C6 alkyl optionally substituted with OR26;
• C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl group, or 5-or 6-membered heteroaryl group;
• R20A at each occurrence is independently F, Cl, Br, I, —OR21, —OR22, —NR23R24, —NHOH, —NO2, —CN, —CF3, (═O), —C(═O)R21, —CO2R21, —OC(═O)R21, —C(═O)NR23R24, —NR27C(═O)R21, —NR27C(═O)OR21, —OC(═O)NR23R24, —NR27C(═S)R21, —SR21, —S(O)R21, or —S(O)2R21;
• C1-C6 alkyl optionally substituted with OR26;
• C2-C6 alkenyl, or C2-C6 alkynyl;
• R21 at each occurrence is independently H, C1-C6 alkyl, C6-C10 aryl, or C7-C15 arylalkyl;
• R22 at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
• R23 and R24 at each occurrence are independently selected from H, C1-C6 alkyl, and C6-C10 aryl;
• or, R23 and R24, together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heterocycloalkyl ring system is optionally substituted with ═O;
• R26 is H or C1-C6 alkyl;
• R27 is H or C1-C6 alkyl;
• n is 0, 1, 2, or 3;
• and
• z is 0, 1, 2, 3, 4, 5, or 6.