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
• the
• moiety is
• R1 is hydrogen, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —CO2H, —(C0-C4 alkyl)-C(O)O(C1-C6 alkyl), —(C0-C4 alkyl)-OC(O)O—(C1-C6 alkyl), —OR1a, —(C1-C4 alkyl)OR1a, —SR1a, —(C1-C4 alkyl)SR1a, —NR1bR1c, —(C1-C4 alkyl)NR1bR1c, —(C1-C4 alkyl)C(O)NR1bR1c, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or oxo when attached to a ring of appropriate saturation, wherein
• R1a, R1b, and R1c are independently hydrogen, C1-C4 alkyl, or —C(O)(C1-C4) alkyl;
• R2 is hydrogen, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —CO2H, —(C0-C4 alkyl)-C(O)O(C1-C6 alkyl), —(C0-C4 alkyl)-OC(O)O—(C1-C6 alkyl), —OR2a, —(C1-C4 alkyl)OR2a, —SR2a, —(C1-C4 alkyl)SR2a, —NR2bR2c, —(C1-C4 alkyl)NR2bR2c, —(C1-C4 alkyl)C(O)NR2bR2c, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or oxo when attached to a ring of appropriate saturation, wherein
• R2a, R2b, and R2e are independently hydrogen, C1-C4 alkyl, or —C(O)(C1-C4) alkyl;
• R3 is hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, —(OCH2CH2)0-6O(C1-C8 alkyl), —(C0-C4 alkyl)-NR3aR3b, —(C0-C4 alkyl)-aryl, —(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,
• wherein
• Q1 is O or S;
• R4a is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR4c, —(C1-C4 alkyl)OR4c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R4c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)0-6(NR4cR4d), —(C1-C4 alkyl)NR4cR4d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0-C4 alkyl)-heterocycloalkyl,
• R4b is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR4c, —(C1-C4 alkyl)OR4c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R4c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)0-6(NR4cR4d), —(C1-C4 alkyl)NR4cR4d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0-C4 alkyl)-heterocycloalkyl,
• wherein R4c and R4d are hydrogen or C1-C6 alkyl,
• or R4a and R4b together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring,
• R4e is hydrogen, C1-C8 alkyl, cycloalkyl or aryl,
• R4f is —OR4g C1-C8 alkyl, cycloalkyl or NR4hR4i,
• wherein R4g is C1-C8 alkyl, cycloalkyl, or aryl, and
• wherein R4h and R4i are C1-C8 alkyl, or R4h and R4i together with a nitrogen to which they are attached form a heterocyloalkyl ring or heteroaryl ring, and
• R4j and R4k are each independently hydrogen or C1-C8 alkyl;
• R5 is hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)-O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —C(O)O(C1-C4 alkyl), —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —(C1-C4 alkyl)C(O)O(C1-C4 alkyl), or —(C1-C4 alkyl)OC(O)(C1-C4 alkyl);
• R6 is hydrogen or —OR6a, wherein R6a is hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)-O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —C(O)O(C1-C4 alkyl), —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —(C1-C4 alkyl)C(O)O(C1-C4 alkyl), or —(C1-C4 alkyl)OC(O)(C1-C4 alkyl);
• and
• R7 is hydrogen,
• provided R7 is not hydrogen when R4 is hydrogen, wherein
• Q2 is O or S;
• R7a is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR7c, —(C1-C4 alkyl)OR7c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R7c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)0-6(NR7cR7d), —(C1-C4 alkyl)NR7cR7d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0-C4 alkyl)-heterocycloalkyl,
• R7b is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR7c, —(C1-C4 alkyl)OR7c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R7c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)0-6(NR7cR7d), —(C1-C4 alkyl)NR7cR7d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0-C4 alkyl)-heterocycloalkyl,
• wherein R7c and R7d are hydrogen or C1-C6 alkyl,
• or R7a and R7b together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring,
• R7e is H, C1-C8 alkyl, cycloalkyl, or aryl,
• R7f is —OR7g, C1-C8 alkyl, cycloalkyl, or NR7hR7i,
• wherein R7g is C1-C8 alkyl, cycloalkyl, or aryl, and
• wherein R7h and R7i are C1-C8 alkyl, or R7h and R7i together with a nitrogen to which they are attached form a heterocyloalkyl ring or heteroaryl ring, and
• R7j and R7k are each independently hydrogen or C1-C8 alkyl;
• wherein
• each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, substituted with one or two hydroxyl groups, one or two C1-C6 alkoxy groups, one or two —C(O)O(C1-C4 alkyl) groups, or 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 R8;
• 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 R8;
• 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 R9;
• 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 R9,
• in which
• each R8 is independently oxo, C1-C4 alkyl, —Cl, —F, —Br, —CN, —SF5, —N3, nitro, —SRA, —S(O)1-2RA, —ORA, —(C0-C3 alkyl)-ORB, —NRBRA, —C(O)RA, —C(O)NRBRA, —NRBC(O)RA, —C(S)NRBRA, —NBC(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, —NRBS(O)1-2NRBRA, phenyl, C3-C8 cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl;
• and
• each R9 is independently optionally-substituted C1-C4 alkyl, —Cl, —F, —Br, —CN, —SF5, —N3, nitro, —SRA, —S(O)1-2RA, —ORA, —(C0-C3 alkyl)-ORB, —NRBRA, —C(O)RA, —C(O)NRBRA, —NRBC(O)RA, —C(S)NRBRA, —NRBC(S)RA, —CO2RA, —OC(O)RA, —SO3H, —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, —NRBS(O)1-2NRBRA, phenyl, C3-C8 cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl;
• 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).