CANNABINOID DERIVATIVES

1 - 104 . (canceled)

105 . 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

R 1 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-OC(O)O—(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-N(R 1b )—C(O)—O—(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-O—C(O)—NR 1b R 1c , —(C 0 -C 4 alkyl)-N(R 1b )—C(O)—NR 1b R 1c , —OR 1a , —(C 1 -C 4 alkyl)OR 1a , —SR 1a , —(C 1 -C 4 alkyl)S(O) 0-2 R 1a , —NR 1b R 1c , —(C 1 -C 4 alkyl)NR 1b R 1c , —(C 1 -C 4 alkyl)C(O)NR 1b R 1c , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein

R 1a , R 1b , and R 1c are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 ) alkyl;

R 2 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-OC(O)O—(C 1 -C 6 alkyl), —(C 1 -C 4 alkyl)OR 2a , —(C 1 -C 4 alkyl)SR 2a , —NR 2b R 2c , —(C 1 -C 4 alkyl)NR 2b R 2c , —(C 1 -C 4 alkyl)C(O)NR 2b R 2c , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein

R 2a , R 2b , and R 2c are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 ) alkyl;

R 3 is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —(OCH 2 CH 2 ) 0-6 O(C 1 -C 8 alkyl), —(C 0 -C 4 alkyl)-NR 3a R 3b , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl or —(C 0 -C 4 alkyl)-heterocycloalkyl, wherein R 1a and R 3b are each independently hydrogen or C 1 -C 6 alkyl;

R 4 is —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl or —(C 0 -C 4 alkyl)-heterocycloalkyl;

R 5 is hydrogen, C 1 -C 8 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —(C 1 -C 4 alkyl)C(O)O(C 1 -C 4 alkyl), or —(C 1 -C 4 alkyl)OC(O)(C 1 -C 4 alkyl); and

R 6 is hydrogen or —OR 6a , wherein R 6a is hydrogen, C 1 -C 8 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —(C 1 -C 4 alkyl)C(O)O(C 1 -C 4 alkyl), or —(C 1 -C 4 alkyl)OC(O)(C 1 -C 4 alkyl)

wherein

each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, substituted with one or two hydroxyl or C 1 -C 6 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 R 7 ;

each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms where each is independently boron, nitrogen, oxygen or sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl or aryl rings, each having 3-8 ring members, and is substituted with 0-6 R 7 ;

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 R 8 ;

each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, where each is independently boron, nitrogen, oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms where each is independently boron, 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 R 8 ;

in which

each R 7 is independently oxo, C 1 -C 4 alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —C 1 -C 4 alkyl-OR A , —NR B R A , —C 1 -C 4 alkyl-NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , —OCO 2 R A , —OC(O)NR B R A , —NR B CO 2 R A , —NR B C(O)NR B R A , —SCO 2 R A , —OC(O)SR A , —SC(O)SR A , —SC(O)NR B R A , —NR B C(O)SR A , —OC(S)OR A , —OC(S)NR B R A , —NR B C(S)OR A , —NR B C(S)NR B R A , —SC(S)OR A , —OC(S)SR A , —SC(S)SR A , —SC(S)NR B R A , —NR B C(S)SR A , —NR B C(NR B )NR B R A , —NR B S(O) 1-2 NR B R A , unsubstituted phenyl, or a five to six-membered unsubstituted heteroaryl; and

each R 8 is independently optionally-substituted C 1 -C 4 alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —C 1 -C 4 alkyl-OR A , —NR B R A , —C 1 -C 4 alkyl-NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , —OCO 2 R A , —OC(O)NR B R A , —NR B CO 2 R A , —NR B C(O)NR B R A , —SCO 2 R A , —OC(O)SR A , —SC(O)SR A , —SC(O)NR B R A , —NR B C(O)SR A , —OC(S)OR A , —OC(S)NR B R A , —NR B C(S)OR A , —NR B C(S)NR B R A , —SC(S)OR A , —OC(S)SR A , —SC(S)SR A , —SC(S)NR B R A , —NR B C(S)SR A , —NR B C(NR B )NR B R A , —NR B S(O) 1-2 NR B R A , unsubstituted phenyl, or a five to six-membered unsubstituted heteroaryl.

wherein each R A is independently H or C 1 -C 3 alkyl, and each R B is independently H, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 hydroxyalkyl, —S(O) 1-2 (C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkyl) or —CO 2 (C 1 -C 3 alkyl).

106 . The compound according to claim 105 , wherein R 1 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-N(R 1b )—C(O)—O—(C 1 -C 6 alkyl), —(C 0 -C 4 alkyl)-O—C(O)—NR 1b R 1c , —(C 0 -C 4 alkyl)-N(R 1b )—C(O)—NR 1b R 1c , —OR 1a , —(C 1 -C 4 alkyl)OR 1a , —SR 1a , —(C 1 -C 4 alkyl)SR 1a , —NR 1b R 1c , —(C 1 -C 4 alkyl)NR 1b R 1c , —(C 1 -C 4 alkyl)C(O)NR 1b R 1c , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl.

107 . The compound according to claim 105 , wherein R 2 is hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, —CO 2 H, —(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), —(C 1 -C 4 alkyl)OR 2a , —(C 1 -C 4 alkyl)SR 2a , —NR 2b R 2c , —(C 1 -C 4 alkyl)NR 2b R 2c , —(C 1 -C 4 alkyl)C(O)NR 2b R 2c , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, or —(C 0 -C 4 alkyl)-heterocycloalkyl.

108 . The compound according to claim 105 , wherein R 3 is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —(OCH 2 CH 2 ) 0-6 OCH 3 , —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl or —(C 0 -C 4 alkyl)-heterocycloalkyl.

109 . The compound according to claim 105 , wherein the compound is of formula:

110 . The compound according to claim 105 , wherein R 5 is hydrogen, C 1 -C 6 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), or —C(O)N(C 1 -C 4 alkyl) 2 .

111 . The compound according to claim 105 , wherein R 6 is hydrogen or —OR 6a , wherein R 6a is hydrogen, C 1 -C 6 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), or —C(O)N(C 1 -C 4 alkyl) 2 .

112 . The compound according to claim 105 , wherein R 4 is -aryl, -heteroaryl, -cycloalkyl or -heterocycloalkyl.

113 . The compound according to claim 105 , wherein R 7 is independently oxo, C 1 -C 4 alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —C 1 -C 4 alkyl-OR A , —NR B R A , —C 1 -C 4 alkyl-NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , unsubstituted phenyl, or a five to six-membered unsubstituted heteroaryl.

114 . The compound according to claim 105 , wherein R 8 is independently C 1 -C 4 alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —C 1 -C 4 alkyl-OR A , —NR B R A , —C 1 -C 4 alkyl-NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , unsubstituted phenyl, or a five to six-membered unsubstituted heteroaryl.

115 . The compound according to claim 105 , wherein each alkyl is unsubstituted.

116 . The compound according to claim 105 , which is:

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(3-methyl-1,2,4-oxadiazol-5-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(1H-tetrazol-5-yl)benzene-1,3-diol;

5-(3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)-1,3,4-oxadiazol-2(3H)-one;

5-(3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)-1,3,4-oxadiazol-2(3H)-one;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(1H-pyrrol-3-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(1H-pyrrol-2-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyridin-2-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyrimidin-4-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyrazin-2-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyrimidin-2-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyridin-3-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyrimidin-5-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyridin-4-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(furan-2-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(thiophen-2-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(thiophen-3-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(thiazol-5-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(thiazol-4-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(indolin-2-yl)-5-pentylbenzene-1,3-diol;

4-(1H-benzo[d]imidazol-2-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(9H-purin-8-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(oxetan-2-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(oxetan-3-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(oxiran-2-yl)-5-pentylbenzene-1,3-diol;

4-(aziridin-2-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

4-(aziridin-1-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(1H-indol-2-yl)-5-pentylbenzene-1,3-diol;

3-(3,7-dimethylocta-2,6-dien-1-yl)-6-pentyl-4′-(pyridin-3-yl)-[1,1′-biphenyl]-2,4-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(isoxazol-5-yl)-5-pentylbenzene-1,3-diol;

4-(4,5-dihydrooxazol-2-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

4-(benzofuran-2-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

4-(benzo[b]thiophen-2-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(4-methylthiophen-2-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(1-methyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol;

3-(3,7-dimethylocta-2,6-dien-1-yl)-3′-morpholino-6-pentyl-[1,1′-biphenyl]-2,4-diol;

4-(3,5-dimethylisoxazol-4-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(1H-pyrazol-4-yl) benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(2-methylpyridin-4-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(quinoxalin-6-yl)benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(1H-indazol-5-yl)-5-pentylbenzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(quinolin-3-yl) benzene-1,3-diol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-5-propyl-4-(thiophen-3-yl) benzene-1,3-diol; or

4-(benzofuran-2-yl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-propylbenzene-1,3-diol.

117 . A pharmaceutical composition comprising a compound according to claim 105 , 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, together with a pharmaceutically acceptable excipient, diluent, or carrier.

118 . A method of treating a disease associated with a cannabinoid receptor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 105 or a pharmaceutical composition thereof.

119 . The method according to claim 118 , wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ or a μ-opioid receptor.

120 . The method according to claim 118 , wherein the cannabinoid receptor is CB1 or CB2.

121 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 105 or a pharmaceutical composition thereof, wherein the disease is acute pain, ADHD/ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's, anorexia, anxiety disorders, arthritis, atherosclerosis, autism, bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathies, chronic pain, chronic allograft nephropathy, cocaine use disorder, complex regional pain syndrome, congestive heart failure, depression, fibromyalgia, fragile X syndrome/FXTAS, frontotemporal dementias, gingivitis pyrexia, glaucoma, glioblastoma, glomerulonephropathy, Huntington's disease, hypertrophic scars, IBD/IBS, inflammation, Inflammatory myopathies, ischemia, kidney fibrosis, keloids, leukodystrophies, liver fibrosis, liver cirrhosis, lung fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea, neuropathic pain, nightmare disorder, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, Parkinson's, post-concussion syndrome/traumatic brain injury, psychosis/schizophrenia, PTSD, regulation of bone mass, REM sleep behaviour disorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skin conditions, sleep disorders, spinocerebellar ataxias, systemic fibrosis, systemic sclerosis, thermal injury, tobacco use disorder/nicotine dependence, Tourette's, or tumors, trigeminal neuralgia.