Cannabinoid derivatives

A compound having structural formula:

• or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, wherein
• R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl;
• R2 is hydrogen, C1-C8 alkyl, hydroxy, —CO2H, or —CO2(C1-C8 alkyl);
• R3 is hydrogen, C2-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, —(OCH2CH2)0-6O(C1-C8 alkyl), —(C0-C4 alkyl)-NR3aR3b, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl or —(C0-C4 alkyl)-heterocycloalkyl, wherein R3a and R3b are each independently hydrogen or C1-C6 alkyl;
• R4 is hydrogen, —CO2H or —CO2(C1-C6 alkyl);
• R5a and R5b are independently:
• hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, hydroxy, halo, —(C0-C4 alkyl)O(C1-C6 alkyl), —(CH2CH2O)1-8(C1-C4 alkyl), —(C0-C4 alkyl)C(O)(C1-C8 alkyl), —CO2H, —CO2(C1-C8 alkyl), —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or —NR5cR5d, wherein
• R5c and R5d are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or —(C0-C4 alkyl)C(O)1-2(C1-C6 alkyl);
• or R5a and R5b together with a carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring;
• Q5 is O, S, or NR5, wherein
• R5e is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(CH2CH2O)1-8(C1-C4 alkyl), —C(O)R5f, —CO2R5f, —(C1-C4 alkyl)-aryl, —(C1-C4 alkyl)-heteroaryl, —(C1-C4 alkyl)-cycloalkyl or —(C1-C4 alkyl)-heterocycloalkyl, wherein each R5f is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or —(CH2CH2O)1-6(C1-C4 alkyl);
• and
• R6 is hydrogen, hydroxy or
• wherein
• R6a and R6b are each independently:
• hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydroxy, halo, —O(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —CO2H, —CO2(C1-C4 alkyl), —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl or —NR6cR6d, wherein:
• R6c and R6d are independently hydrogen, C1-C4 alkyl, or —C(O)(C1-C4 alkyl), or R6c and R6d together with a carbon atom to which they are attached form a heterocycloalkyl ring;
• or R6a and R6b together with a carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring;
• Q6 is —Y6R6e or —NR6fR6g, wherein
• Y6 is O or S,
• R6e, R6f and R6g are independently hydrogen, C1-C8 alkyl, —(CH2CH2O)1-8(C1-C4 alkyl), —C(O)R6h, —CO2R6h, C2-C8 alkenyl, C2-C8 alkynyl, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl or —(C0-C4 alkyl)-heterocycloalkyl, or R6f and R6g together with the nitrogen to which they are attached form a heterocyclic ring, wherein each R6h is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or —(CH2CH2O)1-6(C1-C4 alkyl);
• wherein
• each alkyl, alkenyl and alkynyl is unsubstituted, fluorinated, chlorinated, substituted with one or two hydroxyl or C1-C6 alkoxy groups, or substituted with one or two oxo groups;
• each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3-8 ring members, and is substituted with 0-6 R7;
• each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms where each is independently nitrogen, oxygen or sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3-8 ring members, and is substituted with 0-6 R7;
• each aryl is a phenyl or a naphthyl, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R8;
• each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, where each is independently nitrogen, oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms where each is independently nitrogen, oxygen or sulfur, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R8,
• in which
• each R7 is independently oxo, C1-C4 alkyl, —Cl, —F, —Br, —CN, —SF5, —N3, nitro, —SRA, —S(O)1-2RA, —ORA, —NRBRA, —C(O)RA, —C(O)NRBRA, —NRBC(O)RA, —C(S)NRBRA, —NRBC(S)RA, —CO2RA, —OC(O)RA, —C(O)SRA, —SC(O)RA, —C(S)ORA, —OC(S)RA, —C(S)SRA, —SC(S)RA, —S(O)1-2ORA, —OS(O)1-2RA, —S(O)1-2NRBRA, —NRBS(O)1-2RA, —OCO2RA, —OC(O)NRBRA, —NRBCO2RA, —NRBC(O)NRBRA, —SCO2RA, —OC(O)SRA, —SC(O)SRA, —SC(O)NRBRA, —NRBC(O)SRA, —OC(S)ORA, —OC(S)NRBRA, —NRBC(S)ORA, —NRBC(S)NRBRA, —SC(S)ORA, —OC(S)SRA, —SC(S)SRA, —SC(S)NRBRA, —NRBC(S)SRA, —NRBC(NRB)NRBRA or —NRBS(O)1-2NRBRA;
• and
• each R8 is independently optionally-substituted C1-C4 alkyl), —Cl, —F, —Br, —CN, —SF5, —N3, nitro, —SRA, —S(O)1-2RA, —ORA, —NRBRA C(O)RA, —C(O)NRBRA, —NRBC(O)RA, —C(S)NRBRA, —NRBC(S)RA, —CO2RA, —OC(O)RA, —C(O)SRA, —SC(O)RA, —C(S)ORA, —OC(S)RA, —C(S)SRA, —SC(S)RA, —S(O)1-2ORA, —OS(O)1-2RA, —S(O)1-2NRBRA, —NRBS(O)1-2RA, —OCO2RA, —OC(O)NRBRA, —NRBCO2RA, —NRBC(O)NRBRA, —SCO2RA, —OC(O)SRA, —SC(O)SRA, —SC(O)NRBRA, —NRBC(O)SRA, —OC(S)ORA, —OC(S)NRBRA, —NRBC(S)ORA, —NRBC(S)NRBRA, —SC(S)ORA, —OC(S)SRA, —SC(S)SRA, —SC(S)NRBRA, —NRBC(S)SRA, —NRBC(NRB)NRBRA or —NRBS(O)1-2NRBRA;
• wherein each RA is independently H or C1-C3 alkyl, and each RB is independently H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, —S(O)1-2(C1-C3 alkyl), —C(O)(C1-C3 alkyl) or —CO2(C1-C3 alkyl), or RA and RB together with the nitrogen atom to which they are attached come together to form an unsubstituted heterocycloalkyl ring comprised of 3-6 ring members;
• and
• which is:
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-pentyl-2-phenyl -4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-5-pentyl-2-(4(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-2-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxin-2-carboxylic acid;
• ethyl 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-pentyl-4H-spiro[benzo[d][1,3]dioxine-2,1′-cyclopentan]-4-one;
• 2-(3-chloropropyl)-8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-methyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-2-(4-fluorophenyl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 2-butyl-8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-2-ethyl-7-hydroxy-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-(4-methoxyphenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one;
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-5-propyl-4H-benzo[d][1,3]dioxin-4-one;
• or
• 8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, provided that the compound is not