3-(Diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives

A method tar the treatment of pain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of compound of Formula (I)

• wherein:
• R1 is selected from the group consisting of hydrogen, C1-8alkyl, halo1-3(C1-8)alkyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, C1-8alkoxy (C2-8) alkynyl, cycloalkyl, cycloalkyl (C1-8) alkyl, cycloalkylcarbonyl (C1-8) alkyl, cycloalkyl (C2-8) alkenyl, cycloalkyl (C2-8) alkynyl, heterocyclyl, heterocyclyl (C1-8)alkyl, heterocyclylcarbonyl (C1-8) alkyl, heterocyclyl (C2-8) alkenyl, heterocyclyl (C2-8)alkynyl, aryl, aryl (C1-8)alkyl, arylcarbonyl (C1-8)alkyl, aryl (C2-8)alkenyl, aryl (C2-8)alkynyl, arylaminocarbonyl (C1-8) alkyl, heteroaryl (C1-8) alkyl, heteroarylcarbonyl (C1-8) alkyl, heteroaryl (C2-8) alkenyl, heteroaryl (C2-8) alkynyl, heteroarylaminocarbonyl (C1-8) alkyl, (R1a)2—N—(C1-8) alkyl, R1a—O—(C1-8) alkyl, R1a—S—(C1-8) alkyl, R1a—SO—(C1-8) alkyl and R1a—SO2—(C1-8)alkyl;
• wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di (C1-6alkyl) amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy;
• and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di (C1-6alkyl) amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
• R1a is independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy(C1-8)alkyl, hydroxy(C1-8)alkyl, halo1-3(C1-8)alkyl, halo1-3(C1-8)alkoxy(C1-8)alkyl, C2-8alkenyl, C2-8alkynyl, cycloalkyl, cycloalkyl (C1-8) alkyl, heterocyclyl, heterocyclyl (C1-8) alkyl, heterocyclyl (C1-8) alkenyl, heterocyclyl (C1-8) alkynyl, aryl, aryl (C1-8) alkyl, aryl (C1-8)alkenyl, aryl (C1-8)alkynyl, arylcarbonyl (C1-8)alkyl, heteroaryl, heteroaryl (C1-8) alkyl, heteroaryl (C1-8) alkenyl, heteroaryl (C1-8) alkynyl and heteroarylcarbonyl (C1-8) alkyl;
• wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di (C1-6alkyl) amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy;
• and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di (C1-6alkyl) amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
• R2 selected from the group consisting of aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di (C1-6alkyl) amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
• alternatively, when aryl and heteroaryl are substituted with two substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety;
• wherein the moiety is selected from the group consisting of —(CH2)3-5— and —O(CH2)1-3O—;
• R3 is selected from the group consisting of aryl and heteroaryl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di (C1-6alkyl) amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
• alternatively, when aryl and heteroaryl are substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety;
• wherein the moiety is selected from the group consisting of —(CH2)3-5— and —O(CH2)1-3O—;
• A is selected from the group consisting of —C(═X)— and —SO2—;
• X is selected from the group consisting of O and S;
• Z is selected from the group consisting of —O(R4) and —N(R5)(R6)
• R4 is selected from the group consisting of hydrogen, C1-8alkyl (optionally substituted with one to three halogen substituents), C1-8alkoxy(C1-8)alkyl, C2-8alkenyl, cycloalkyl, cycloalkyl (C1-8)alkyl, heterocyclyl, heterocyclyl (C1-8) alkyl, aryl, aryl (C1-8) alkyl, heteroaryl, heteroaryl (C1-8) alkyl, amino (C1-8) alkyl, C1-8alkylamino (C1-8) alkyl, di (C1-8)alkylamino(C1-8)alkyl and hydroxy(C1-8)alkyl;
• wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano;
• and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, —OCH2O—, —O(CH2)2O—, trifluoromethyl, halogen, hydroxy and cyano;
• R5 and R6 are independently selected from the group consisting of hydrogen, C1-8alkyl (optionally substituted with one to three halogen substituents), C1-8alkoxy(C1-8)alkyl, C2-8alkenyl, cycloalkyl, cycloalkyl (C1-8)alkyl, heterocyclyl, heterocyclyl (C1-8)alkyl, aryl, aryl (C1-8)alkyl, heteroaryl, heteroaryl (C1-8) alkyl, amino (C1-8) alkyl, C1-8alkylamino(C1-8)alkyl, di (C1-8)alkylamino(C1-8)alkyl, aminoimino, aminocarbonyl, aminocarbonyl (C1-8) alkyl, aryloxycarbonylamino (C1-8) alkyl, heteroaryloxycarbonylamino (C1-8) alkyl, hydroxy (C1-8) alkyl and trifluoro(C1-4)alkoxy;
• wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano;
• and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, —OCH2O—, —O(CH2)2O—, trifluoromethyl, halogen, hydroxy and cyano;
• alternatively, R5 and R6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety optionally substituted with one to four substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy and cyano;
• wherein the cycloalkyl in any cycloalkyl containing substituent is a branched or unbranched cyclic aliphatic hydrocarbon chain of three to seven carbon atom members;
• wherein the heteroaryl in any heteroaryl containing substituent is an aromatic ring of five or six members wherein the ring has at least one heteroatom member selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said five-membered ring optionally contains up to two additional nitrogens, and wherein said six-membered ring optionally contains from one to three additional nitrogen atoms wherein at most two nitrogen atoms are adjacent;
• wherein the heterocyclyl in any heterocyclyl containing substituent is a nonaromatic ring of five to seven members in which one to four members are nitrogen or a nonaromatic ring of five to seven members in which zero, one or two members are nitrogen and one member is oxygen or sulfur,
• wherein the heterocyclyl optionally contains zero, one or two unsaturated bonds, and wherein optionally up to three carbon members of the hetercyclyl adjacent to nitrogen members is oxo substituted, and wherein optionally, the heterocyclyl ring is fused to a ring selected from the group consisting of a benzene ring, a 5 or 6 membered heteroaryl containing one of O, S or N wherein said heteroaryl optionally contains one additional nitrogen, a 5 to 7 membered alicyclic ring, and a 5 to 7 membered heterocyclyl ring of the same definition as above but absent the option of a further fused ring;
• and
• wherein the alkylthio of any alkylthio containing substituent is attached to the rest of the molecule through its sulfur atom;
• or enantiomers, diastereomers or pharmaceutically acceptable salts thereof.