CANNABINOID DERIVATIVES

1 - 159 . (canceled)

160 . 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, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl;

R 2 is hydrogen, C 1 -C 8 alkyl, hydroxy, —CO 2 H, or —CO 2 (C 1 -C 8 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 3a and R 3b are each independently hydrogen or C 1 -C 6 alkyl;

R 4a and R 4b are independently hydrogen, —CO 2 H or —CO 2 (C 1 -C 6 alkyl);

R 5 is hydrogen or has the structure

 wherein

R 5a and R 5b are each independently:

hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, hydroxy, halo, —O(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —CO 2 H or —CO 2 (C 1 -C 4 alkyl), —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, —(C 0 -C 4 alkyl)-heterocycloalkyl, or NR 5c R 5d , wherein

R 5c and R 5d are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 alkyl);

or R 5a and R 5b come together to form a cycloalkyl or heterocycloalkyl ring;

Q 5 is Y 5 R 5e or NR 5f R 5g , wherein

Y 5 is O or S;

R 5e , R 5f and R 5g are independently hydrogen, C 1 -C 8 alkyl, —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —C(O)R 5h , —CO 2 R 5h , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(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, or R 5 and R 5g together with a nitrogen to which they are attached form a heterocycloalkyl ring, wherein each R 5h is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or —(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl); and

R 6 is hydrogen, hydroxy or has the structure

 provided that R 6 is not hydrogen or hydroxy when R 5 is hydrogen, wherein

R 6a and R 6b are each independently:

hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, hydroxy, halo, —O(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, —(C 0 -C 4 alkyl)-cycloalkyl, —(C 0 -C 4 alkyl)-heterocycloalkyl or NR 6c R 6d wherein

R 6c and R 6d are independently hydrogen, C 1 -C 4 alkyl, or —C(O)(C 1 -C 4 alkyl);

or R 6a and R 6b come together to form a cycloalkyl or heterocycloalkyl ring;

Q 6 is Y 6 R 6e or NR 6f R 6g , wherein

Y 6 is O or S,

R 6e , R 6f and R 6g are independently hydrogen, C 1 -C 8 alkyl, —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —C(O)R 6h , —CO 2 R 6h , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(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, or R 6f and R 6g together with a nitrogen to which they are attached form a heterocycloalkyl ring, wherein each R 6h is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl);

wherein

each alkyl, alkenyl and alkynyl is unsubstituted, fluorinated, 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 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 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 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 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 , —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 or —NR B S(O) 1-2 NR B R A ; 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 , —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 or —NR B S(O) 1-2 NR B R A ;

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), or R A and R B together with the nitrogen atom to which they are attached come together to form an unsubstituted heterocycloalkyl ring comprised of 3-6 ring members.

161 . The compound according to claim 160 , wherein R 1 is hydrogen, C 2 -C 6 alkyl or C 2 -C 6 alkenyl.

162 . The compound according to claim 160 , wherein R 2 is hydrogen, C 1 -C 6 alkyl, hydroxy, —CO 2 H, or —CO 2 (C 1 -C 4 alkyl).

163 . The compound according to claim 160 , 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.

164 . The compound according to claim 160 , wherein R 4a and R 4b are independently hydrogen, —CO 2 H or —CO 2 (C 1 -C 6 alkyl).

165 . The compound according to claim 160 , wherein the compound is of formula:

166 . The compound according to claim 165 , wherein R 5 is hydrogen or has the structure

167 . The compound according to claim 166 , wherein R 5a and R 5b are each independently hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, hydroxy, halo, —O(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), —(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.

168 . The compound according to claim 166 , wherein Q 5 is —NR 5f R 5g , wherein R 5f and R 5g are independently hydrogen, C 1 -C 8 alkyl, —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —C(O)R 5h , —CO 2 R 5h , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(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, or R 5f and R 5g together with a nitrogen to which they are attached form a heterocycloalkyl ring, wherein each R 5h is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl), —(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.

169 . The compound according to claim 160 , wherein R 6 is hydrogen, hydroxy or has the structure

170 . The compound according to claim 169 , wherein R 6a and R 6b are each independently hydrogen, C 1 -C 4 alkyl, hydroxy, halo, —O(C 1 -C 4 alkyl), —C(O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), —(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.

171 . The compound according to claim 160 , wherein each alkyl is unsubstituted.

172 . The compound according to claim 160 , wherein 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 , —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 , or —NR B S(O) 1-2 R A .

173 . The compound according to claim 160 , wherein each 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 , —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 , or —NR B S(O) 1-2 R A .

174 . The compound according to claim 160 , which is:

2-(3,7-dimethylocta-2,6-dien-1-yl)-3-(methoxymethoxy)-5-pentylphenol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-3-((2-methoxypropan-2-yl)oxy)-5-pentylphenol;

3-((2,5,8,11,14-pentaoxahexadecan-15-yl)oxy)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylphenol;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl ethyl carbonate;

1-(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)ethyl ethyl carbonate;

1-(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)ethyl (2-methoxyethyl) carbonate;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl pivalate;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl 2-ethylbutanoate;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl acetate;

methyl ((2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl)(methyl)carbamate;

2-methoxyethyl ((2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl)(methyl)carbamate;

2,5,8,11-tetraoxatridecan-13-yl ((2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl)(methyl)carbamate;

methyl ((2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl)(phenyl)carbamate;

methyl ((2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-pentylphenoxy)methyl)(4-nitrophenyl)carbamate;

2-(3,7-dimethylocta-2,6-dien-1-yl)-3-((1-methoxycyclopentyl)oxy)-5-pentylphenol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-3-(ethoxymethoxy)-5-pentylphenol;

2-(3,7-dimethylocta-2,6-dien-1-yl)-3-((2-methoxyethoxy)methoxy)-5-pentylphenol;

3-((cyclohexyloxy)methoxy)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylphenol;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-propylphenoxy)methyl pivalate;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-propylphenoxy)methyl ethyl carbonate;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-(2-methyloctan-2-yl)phenoxy)methyl ethyl carbonate;

(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-hydroxy-5-(2-methyloctan-2-yl)phenoxy)methyl pivalate;

2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-bis(methoxymethoxy)-5-pentylbenzene;

2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-bis((2-methoxypropan-2-yl)oxy)-5-pentylbenzene;

15,15′-((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(2,5,8,11,14-pentaoxahexadecane);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene) diethyl bis(carbonate) (4′) ((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(ethane-1,1-diyl) diethyl bis(carbonate);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(ethane-1,1-diyl) bis(2-methoxyethyl) bis(carbonate);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene) bis(2-ethylbutanoate);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene) diacetate;

dimethyl (((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene))bis(methylcarbamate);

bis(2-methoxyethyl) (((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene))bis(methylcarbamate);

di(2,5,8,11-tetraoxatridecan-13-yl) (((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene))bis(methylcarbamate);

dimethyl (((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene))bis(phenylcarbamate);

dimethyl (((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene))bis((4-nitrophenyl)carbamate);

2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-bis((1-methoxycyclopentyl)oxy)-5-pentylbenzene;

2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-bis(ethoxymethoxy)-5-pentylbenzene;

2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-bis((2-methoxyethoxy)methoxy)-5-pentylbenzene;

((((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))bis(methylene))bis(oxy))dicyclohexane;

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-propyl-1,3-phenylene)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-propyl-1,3-phenylene)bis(oxy))bis(methylene) diethyl bis(carbonate);

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-(2-methyloctan-2-yl)-1,3-phenylene)bis(oxy))bis(methylene) diethyl bis(carbonate); or

((2-(3,7-dimethylocta-2,6-dien-1-yl)-5-(2-methyloctan-2-yl)-1,3-phenylene)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate).

175 . A pharmaceutical composition comprising a compound according to claim 160 , 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.

176 . 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 160 or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, diluent, or carrier.

177 . The method according to claim 176 , wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ or a μ-opioid receptor.

178 . 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 160 or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, diluent, or carrier, 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, tumors, or trigeminal neuralgia.