Novel cannabinoid receptor 2 (cb2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases

A compound according to

• wherein
• D and D′ are independently H, —OH, —ORa, (C1-C6)alkyl or
• Ra, Ra″, and Ra′″ are independently selected from the group consisting of H, straight or branched chain (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C14)aryl, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, or (C3-C14)aryl(C1-C6)alkylene-;
• A, B and Q are each independently (C1-C6)alkylene, (C2-C6)alkenylene or (C2-C6)alkynylene,
• e, f and g independently are integers between 0 and 6 inclusive;
• V, W, X, Y, and Z are each independently a bond, —C(R′″)2—, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, or —S—, wherein no two adjacent members of V, W, X, Y, and Z are simultaneously —O—, —S—, or —NR′″;
• R′″ is H, —OH, —ORa, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl]2, —CN, (C3-C8)heteroaryl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl, (C3-C8)aryl, (C3-C8)heterocycloalkyl-(C1-C6)alkylene-, (C3-C8)heteroaryl-(C1-C6)alkylene-, (C3-C8)aryl(C1-C6)alkylene-, (C3-C8)aryl(C1-C6)alkenylene-, or (C1-C6)alkyl-(C3-C8)arylene;
• l, m, n, p and q independently are integers between 0 and 2 inclusive, wherein at least one of l, m, n, or p is not 0;
• represents the option of having one or more double bonds;
• wherein any alkyl, alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with halogen, oxo, —COOH, —CN, —NO2, —OH, —NRdRe, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)haloalkyl, (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)heterocycloalkyl, or (C3-C8)aryloxy;
• and
• wherein Rd and Re are each independently H, straight or branched (C1-C6)alkyl, optionally substituted (C3-C8)aryl, optionally substituted (C3-C14)aryl(C1-C6)alkylene-, and H2N(C1-C6)alkylene-,
• with the proviso that when each
• in Formula I is independently a phenyl, Bf and Qg are both methylene and e is 0, D is not 4-dimethylaminophenyl;
• wherein
• A, B′ and E are each independently a bond, —C(R′″)2—, —CR′″, —NR′″—, —N—, —O—, —C(O)—, or —S—;
• wherein no two adjacent members of A, B′ and E are simultaneously —O—, —S—, or —NR′″—;
• h, j and k independently are integers between 0 and 2 inclusive, wherein at least one of h, j or k is not 0;
• represents the option of having one or more double bonds;
• D and D″ are each independently —C(O), —CH2C(O)—, (C1-C6)alkylene, —C(O)NH—, or —NHC(O)—;
• represents the option of having a C5-C6 fused ring optionally having one or more double bonds;
• R and R1 are each independently OH, —ORa, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)heteroaryl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl, (C3-C8)aryl, (C3-C8)heterocycloalkyl-(C1-C6)alkylene-, (C3-C8)heteroaryl-(C1-C6)alkylene, or (C3-C8)aryl(C1-C6)alkylene-;
• Ra is H, straight or branched chain (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C14)aryl, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, or (C3-C14)aryl(C1-C6)alkylene-;
• wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halogen, oxo, —COOH, —CN, —NO2, —OH, —NRdRe, (C1-C6)alkoxy, or (C3-C8)aryloxy;
• and
• wherein Rd and Re are each independently H, straight or branched (C1-C6)alkyl;
• optionally substituted C3-C14)aryl(C1-C6)alkylene-, and H2N(C1-C6)alkylene;
• wherein
• X is N, N+, or —CH—;
• R′ is H, straight or branched chain (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C14)aryl, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, or (C3-C14)aryl(C1-C6)aralkylene-;
• Q′, R and T are each independently selected from a bond, —C(O)(C1-C6)alkylene-, (C1-C6)alkyl, —S(O)2—, —S(O)—, —S(O)2NHR″, —O—(C1-C6-alkylene)-O—, —OC(O)—, and —(C1-C6)alkylene)-OC(O)—;
• G, H, J, L, and M are each independently a bond, —C(R′″)2—, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, and —S—,
• no two adjacent members of G, H, J, L, or M are simultaneously —O—, —S—, or —NR′″—;
• R′″ is H, —OH, —ORa halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynl, —NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl]2, —CN, (C3-C8)heteroaryl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl, (C3-C8)aryl, (C3-C8)heterocycloalkyl-(C1-C6)alkylene-, (C3-C8)heteroaryl-(C1-C6)alkylene-, (C3-C8)aryl(C1-C6)alkylene-, or (C1-C6)alkyl-(C3-C8)arylene;
• l, m, n, p and q independently are integers between 0 and 2 inclusive, wherein at least one of l, m, n, or p is not 0;
• o is 0 when X is N or CH, and o is 1 when X is N+;
• represents the option of having one or more double bonds;
• Ra is H, straight or branched chain (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C14)aryl, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene- or (C3-C14)aryl(C1-C6)alkylene-;
• wherein any alkyl, alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halogen, oxo, —COOH, —CN, —NO2—, —OH, —NRdRe, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)haloalky, (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)heterocycloalkyl, or (C3-C8)aryloxy;
• and
• wherein Rd and Re are each independently H, straight or branched (C1-C6)alkyl, optionally substituted (C3-C8)aryl, optionally substituted (C3-C14)aryl(C1-C6)alkylene-, or H2N(C1-C6)alkylene-;
• wherein:
• R1 and R2 are independently H, alkyl, or alkenyl;
• R3 is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl;
• R4 and R5 are independently a bond, alkylenyl, or alkenylenyl;
• each R6 and R7 are independently OH, F, Cl, Br, I, (C1-C6)alkyl, alkoxy, amino, COOH, CONH2, SO3H, PO3H2, CN, SH, NO2 or CF3;
• p and q are independently 0, 1, 2, 3, 4, or 5;
• with the proviso that where R1 and R2 are both H, R4 and R5 are both methylene, p and q are 0, R3 is not 4-dimethylaminophenyl;
• or a pharmaceutically acceptable salt thereof.