Cannabinoid receptor modulators

A pharmaceutical product selected from:

• a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit;
• comprising a compound which is:
• and one or more known pharmaceutical agents selected from:
• analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.

A method for the treatment of pain in an individual in need thereof, comprising administering to said individual, a therapeutically effective amount of a compound which is:

• and one or more known pharmaceutical agents selected from:
• analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents;
• wherein the pain is chosen from:
• bone and joint pain, pain associated with osteoarthritis, hyperalgesia, allodynia, inflammatory pain, inflammatory hyperalgesia, neuropathic pain, neuropathic hyperalgesia, acute nociception, muscle pain, dental pain, migraine and other headache pain, pain that occurs as an adverse effect of therapeutics in an individual, and pain associated with a disorder selected from:
• cancer, multiple sclerosis, allergic reactions, nephritic syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV related-neuropathy, sciatica, and an autoimmune condition.

A method of modulating the activity of the cannabinoid CB2 receptor comprising contacting the cannabinoid CB2 receptor with a composition comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

• wherein:
• R1, R2, R3, R4, R5, and R6 are each independently selected from:
• H and C1-C6 alkyl;
• X is NR7 and Y is CC(O)N(R8)R9;
• or
• X is CC(O)N(R8)R9 and Y is NR7;
• R7 is —R10—R11 —R12—R13;
• wherein:
• R10 is absent;
• R11 is absent;
• R12 is absent;
• and
• R13 is selected from:
• C1-C6 alkyl, aryl, C3-C7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl;
• wherein said C1-C6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from:
• C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylsulfonyl, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, C1-C6 haloalkyl, halogen, and hydroxyl;
• R8 is —R14—R15—R16—R17;
• wherein:
• R14 is selected from:
• C1-C6 alkylene, C3-C7 cycloalkenylene, C3-C7 cycloalkylene, heteroarylene, and heterocyclylene;
• wherein said C1-C6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from:
• C1-C6 alkoxycarbonyl, C1-C6 alkyl, C3-C7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl;
• wherein said C1-C6 alkyl and aryl are optionally substituted with one substituent selected from:
• C1-C6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl;
• or R14 is absent;
• R15 is selected from:
• —C(O)NH—, —C(O)—, —C(O)O—, C1-C6 alkylene, C3-C7 cycloalkylene, heteroarylene, and heterocyclylene;
• wherein said heterocyclylene is optionally substituted with C1-C6 alkyl;
• or R15 is absent;
• R16 is C1-C6 alkylene;
• or R16 is absent;
• and
• R17 is selected from:
• H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C2-C6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C1-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C5-C11 bicycloalkyl, C3-C7 cycloalkylamino, C2-C8 dialkylamino, C2-C8 dialkylsulfonamide, C1-C6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;
• wherein said C1-C6 alkylamino, amino, aryl, arylamino, aryloxy, C5-C11 bicycloalkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from:
• C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkyl, C1-C6 alkylsulfonyl, amino, aryl, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl;
• and
• R9 is selected from:
• H, C1-C6 alkyl, and C3-C7 cycloalkyl;
• or
• R8 and R9 together with the nitrogen atom to which they are both bonded form a group selected from:
• heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from:
• Carbo-C1-C6-alkoxy, C1-C6 alkoxy, C1-C6 alkyl, aryl, carbo-C1-C6-alkoxy, C1-C6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl;
• wherein said aryl, C1-C6 alkyl, and heteroaryl are optionally substituted with one substituent selected from:
• C3-C7 cycloalkyl, C1-C6 alkoxy, halogen, and hydroxyl,
• and one or more known pharmaceutical agents selected from:
• analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.