Granted Patent B2

US 12,617,765 · App. 17/783,290 · Granted May 5, 2026

Inventors: Patrick Thomas Gunning (Mississauga, CA); Jeffrey Alan Omeara (Halton Hills, CA); Quang Huy To (Hamilton, CA)

Assignee: Canopy Growth Corporation

C07D319/08A61K31/366C07D327/06

Abstract

Claims (55)

1 . 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 2 -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)-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 4 is hydrogen, —CO 2 H or —CO 2 (C 1 -C 6 alkyl);

R 5a and R 5b are independently:

hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, hydroxy, halo, —(C 0 -C 4 alkyl)O(C 1 -C 6 alkyl), —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —(C 0 -C 4 alkyl)C(O)(C 1 -C 8 alkyl), —CO 2 H, —CO 2 (C 1 -C 8 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 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or —(C 0 -C 4 alkyl)C(O) 1-2 (C 1 -C 6 alkyl);

or R 5a and R 5b together with a carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring;

Q 5 is O, S, or NR 5 , wherein

R 5e is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CH 2 CH 2 O) 1-8 (C 1 -C 4 alkyl), —C(O)R 5f , —CO 2 R 5f , —(C 1 -C 4 alkyl)-aryl, —(C 1 -C 4 alkyl)-heteroaryl, —(C 1 -C 4 alkyl)-cycloalkyl or —(C 1 -C 4 alkyl)-heterocycloalkyl, wherein each R 5f 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

 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 6c and R 6d together with a carbon atom to which they are attached form a heterocycloalkyl ring;

or R 6a and R 6b together with a carbon atom to which they are attached 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 the nitrogen to which they are attached form a heterocyclic ring, wherein each R 6h 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);

wherein

each alkyl, alkenyl and alkynyl is unsubstituted, fluorinated, chlorinated, 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; 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

2 . A pharmaceutical composition comprising a compound to claim 1 , or an enantiomer, diastereomer, racemate, tautomer, a pharmaceutically acceptable salt, solvate or hydrate together with a pharmaceutically acceptable excipient, diluent, or carrier.

3 . 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 1 or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, diluent, or carrier.

4 . The method according to claim 3 , wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ or a μ-opioid receptor.

5 . The method according to claim 4 , wherein the cannabinoid receptor is CB1 or CB2.

6 . 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 1 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.

Assignments (6)

Continuity (4)

References Cited (36)