cannabinoid derivatives

Abstract

The present disclosure relates to karmavinoid derivatives, pharmaceutical compositions containing same, and their use in treating and preventing diseases associated with karmavinoid receptors, such as acute pain, ADHD / ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's disease, anorexia, etc., in subjects in need thereof. The karmavinoid derivatives have the formula: [Formula 1] TIFF2022539401000099.tif46170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 870,744, filed July 4, 2019, U.S. Provisional Patent Application No. 62 / 928,838, filed October 31, 2019, and U.S. Provisional Patent Application No. 62 / 966,411, filed January 27, 2020, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to cannabinoid derivatives, pharmaceutical compositions containing them, and methods of using the cannabinoid derivatives. [Background technology]

[0003] All individuals possess an endocannabinoid system, which consists of chemical receptors in the brain, immune system, and central nervous system, including, for example, cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. The endocannabinoid system regulates many important physiological processes, and several components of the endocannabinoid system, such as receptors, transporters, endocannabinoids, and enzymes involved in endocannabinoid synthesis and degradation, are being actively investigated as targets for treating a wide variety of indications.

[0004] CB1 and CB2 receptors are classes of cell membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. They are distinguished from each other by their amino acid sequences, tissue distribution, signaling mechanisms, and ability to bind subtype-specific ligands. CB1 receptors are primarily expressed in the central nervous system (CNS), lungs, liver, adipose tissue, and kidneys, while CB2 receptors are primarily localized in immune cells (e.g., macrophages and T cells), cells involved in bone formation and bone loss, and the gastrointestinal system. These receptors have been associated with many human diseases, including obesity, diabetes, fibrosis, liver disease, cardiovascular disease, cancer, pain, inflammation, MS, and glaucoma, among others.

[0005] Cannabinoids are compounds active at cannabinoid receptors in humans and have been implicated in numerous pharmacological benefits for the aforementioned diseases. Plant-derived cannabinoids, also known as phytocannabinoids, are present in large quantities in cannabis. The medical use of cannabis and related phytocannabinoids is gaining widespread acceptance in many countries, including the United States, as an alternative form of medicine. Many states have legalized their use for qualifying medical conditions, including chronic pain, epilepsy, sleep disorders, anxiety, cancer, glaucoma, nausea, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Crohn's disease, post-traumatic stress disorder (PTSD), arthritis, and fibromyalgia.

[0006] In addition to CB1 and CB2 receptors, other receptors are also involved in regulating the activity of cannabinoids in humans and / or animals. For example, serotonin receptors, such as 5HT1A and 5HT2A, are also GPCRs that have been identified as cannabinoid targets. Serotonin receptors regulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones. Similar to CB1 and CB2 receptors, serotonin receptors affect various biological and neurological processes, such as anxiety, appetite, cognition, and mood, among others. Other receptors identified to be affected by cannabinoids or cannabinoid-like compounds include GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), and μ-opioid receptors. In fact, the binding of these receptors is responsible for the off-target effects of cannabinoids.

[0007] One of the most common methods of medicinal use of cannabinoids in many countries is through smoking cannabis. While proven beneficial for certain indications, smoking medical cannabis has drawbacks. For example, smoke from plant matter contains carcinogens and other toxins in addition to the desired cannabinoids. Heavy use of cannabis through smoking has also been associated with pulmonary decline, lung damage, and accelerated emphysema. Another drawback of smoking medical cannabis is the difficulty of maintaining control over the proper administration of medicinal cannabis due to variations in active ingredients (e.g., the amount of active ingredient may vary depending on differences present in plant varieties as well as changes in growing conditions, resulting in intra-varietal variability). Finally, consumption through smoking results in relatively low bioavailability of target compounds compared to other delivery methods.

[0008] A less common method of utilizing cannabis for medical use is to extract beneficial cannabinoids from cannabis. While many extraction processes have been developed for the isolation and purification of natural cannabinoids, it has been difficult to isolate individual cannabinoids at high purity levels, both for the active ingredients used in pharmaceutical and product manufacturing and / or for research and development. Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there is a need for novel ligands of cannabinoid receptors with potential therapeutic benefit. [Means for solving the problem]

[0010] One aspect of the present disclosure is a compound of formula (I): [ka] 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: [ka] The part is, [ka] and R 1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; R 2 is oxo when attached to hydrogen, C1-C8 alkyl, hydroxy, -CO2H, -CO2(C1-C8 alkyl), or an appropriately saturated ring; R 3 But hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, -(OCH2CH2) 0-6 O(C1-C8 alkyl), -(C0-C4 alkyl)-NR 3a R 3b , -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl, and R 3a and R 3b are each independently hydrogen or C1-C6 alkyl; R 4 is hydrogen, -COH, or -CO(C-C alkyl); R 5a and R 5b But 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 -NR 5c R 5d and R 5c and R 5d are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -(C0-C4 alkyl)C(O) 1-2 (C1-C6 alkyl) or or R 5a and R 5b together with the carbon atoms to which they are attached form a cycloalkyl or heterocycloalkyl ring; Q 5 is O, S or NR 5e and R 5e is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(CH2CH2O) 1-8 (C1-C4 alkyl), -C(O)R 5f , -CO2R 5f , -(C1-C4 alkyl)-aryl, -(C1-C4 alkyl)-heteroaryl, -(C1-C4 alkyl)-cycloalkyl, or -(C1-C4 alkyl)-heterocycloalkyl, and each R 5f is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or -(CH2CH2O) 1-6 (C1-C4 alkyl), R 6 is hydrogen, hydroxy or [ka] wherein: R 6a and R 6b However, 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 -NR 6c R 6d and R 6c and R 6d are independently hydrogen, C-C alkyl, or —C(O)(C-C alkyl), or R 6c and R 6d together with the carbon atoms to which they are attached form a heterocycloalkyl ring; Or R 6a and R 6b together with the carbon atoms to which they are attached form a cycloalkyl or heterocycloalkyl ring; Q 6 But -Y 6 R 6e or -NR 6f R 6g and Y 6 is O or S, R 6e , R 6f and R 6g are independently hydrogen, C1-C8 alkyl, -(CH2CH2O) 1-8 (C1-C4 alkyl), -C(O)R 6h , -CO2R 6h , C2-C8 alkenyl, C2-C8 alkynyl, -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl, or R 6f and R 6g form a heterocycle together with the nitrogen to which they are attached, and each R 6h is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(CH2CH2O) 1-6(C1-C4 alkyl), During the ceremony, 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 to 10 ring carbons, is saturated or partially unsaturated, and optionally contains 1 or 2 fused cycloalkyl rings, each fused ring having 3 to 8 ring members and 0 to 6 R 7 is replaced by Each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently nitrogen, oxygen, or sulfur, is saturated or partially unsaturated, and optionally contains 1 or 2 fused cycloalkyl rings, each having 3 to 8 ring members and 0 to 6 R 7 is replaced by Each aryl is phenyl or naphthyl and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having from 4 to 8 ring members and from 0 to 5 R 8 is replaced by each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, each independently nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms, each independently nitrogen, oxygen, or sulfur, and optionally containing 1 or 2 fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members and 0-5 R 8 is replaced by During the ceremony, Each R 7 are independently oxo, C1-C4 alkyl (e.g., -CH3, -CH(CH3)2, -CF3, -CHF2), -Cl, -F, -Br, -CN, -SF5, -N3, nitro, -SR A , -S(O) 1-2 R A , -OR A , -NR BR 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 、-CO2R 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 、-OCO2R A 、-OC(O)NR B R A 、-NR B CO2R A 、-NR B C(O)NR B R A 、-SCO2R 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)NRB 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 are independently optionally substituted C1-C4 alkyl (e.g., —CH3, —CH(CH3)2, —CF3, —CHF2), —Cl, —F, —Br, —CN, —SF5, —N3, 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 , -CO2R 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 , -OCO2R A , -OC(O)NR B R A , -NR B CO2R A , -NRB C(O)NR B R A , -SCO2R 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 A is independently H or C1-C3 alkyl, and each R B are 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 R A and R B together with the nitrogen atom to which they are attached, combine to form an unsubstituted heterocycloalkyl ring of 3 to 6 ring members.

[0011] In another aspect, the disclosure relates to a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)), 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. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient, diluent, or carrier.

[0012] In another aspect, the disclosure relates to a method of treating or preventing a disease, such as a disease associated with a cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptor), in a subject in need thereof. In one embodiment, the method comprises administering to the subject a therapeutically effective amount of a compound described herein, 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. In one embodiment, the method comprises administering to the subject a pharmaceutical composition described herein.

[0013] In certain embodiments, diseases that may be treated or prevented with the compounds or compositions described herein include attention deficit / hyperactivity disorder (ADHD) / attention deficit disorder (ADD), alcohol use disorder, allergic asthma, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, anorexia (e.g., human immunodeficiency virus (HIV)-associated cachexia), anxiety disorders (e.g., social anxiety disorder, specific phobia, test anxiety, generalized anxiety disorder), arthritis, atherosclerosis, autism, and bipolar disorder. , burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic transplant nephropathy, cocaine use disorder, complex regional pain syndrome, chronic transplant nephropathy, depression, fibromyalgia, fragile X syndrome / fragile X-associated tremor and ataxia syndrome (FXTAS), frontotemporal dementia (behavioral variant), gingivitis fever, glaucoma, glioblastoma, glomerular nephropathy, Huntington's disease, hypertrophic scar, inflammatory bowel disease (IBD) / irritable bowel syndrome (IBS), inflammation, inflammatory myopathy, ischemia, kidney Fibrosis, keloids, leukodystrophy, liver fibrosis, liver cirrhosis, pulmonary fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea (e.g., chemotherapy-induced nausea and vomiting (CINV), motion sickness), neuropathic pain (e.g., post-herpetic neuralgia, painful diabetic neuropathy), nocturnal disorders, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, pain (e.g., acute or chronic pain), Parkinson's disease, post-concussion syndrome / traumatic brain injury, psychosis / schizophrenia, post-traumatic stress disorder (PTSD), bone mass regulation, rapid eye movement (REM) sleep behavior disorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skin conditions (e.g., acne, psoriatic arthritis), sleep disorders (e.g., insomnia, restless legs syndrome (RLS)), spinocerebellar ataxia, systemic fibrosis, systemic sclerosis, heat injury, tobacco use disorder / nicotine dependence, Tourette's syndrome, tumors, and trigeminal neuralgia.

[0014] In another aspect, the disclosure relates to the use of a compound described herein, 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, for the treatment or prevention of a disease associated with a cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptor).

[0015] In another aspect, the present disclosure relates to the use of a pharmaceutical composition described herein for the treatment or prevention of a disease associated with a cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptor).

[0016] In another aspect, the disclosure relates to the use of a compound described herein, 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, for selectively modulating the activity of a CB1 or CB2 receptor.

[0017] In another aspect, the present disclosure relates to the use of the pharmaceutical compositions described herein to selectively modulate the activity of CB1 or CB2 receptors.

[0018] Other aspects and embodiments of the present disclosure will be apparent in view of the detailed description provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure provides compounds that can function as ligands for one or more cannabinoid receptors and / or their prodrugs. As used herein, "cannabinoid receptor" refers to a broad class of receptors that bind to, interact with, and / or are functionally affected by cannabinoids or cannabinoid-like compounds. Cannabinoid receptors may include, but are not limited to, CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptors. In one embodiment, the present disclosure further relates to compounds, pharmaceutical compositions, methods, and uses that may treat or prevent one or more diseases associated with cannabinoid receptors.

[0020] The compound has formula (I) [ka] or for various subgenera within structural formula (I), [ka] Part, R 1 , R 2 , R 3 , R 4 , R 5a and R 5b , Q 5 , R 6 , R 6a and R 6b , and Q 6 are optionally independently selected from the groups (Ia)-(Ig), (1a)-(1f), (2a)-(2e), (3a)-(3k), (4a)-(4p), (5a)-(5e), ​​(6a)-(6x), (7a)-(7e), (8a)-(8f), (9a)-(9i), and (10a)-(10oo), as defined herein below (e.g., where the compound is of a structural formula as defined in any combination of the following embodiments).

[0021] In certain embodiments of the compounds otherwise described herein, [ka] The moiety may be any of the following groups (1a) to (1f): [ka] is selected from.

[0022] In certain embodiments of the compounds otherwise described herein, R 1 represents the following groups (2a) to (2e): (2a) hydrogen, C1-C4 alkyl or C2-C4 alkenyl; (2b) hydrogen, (2c) C2-C4 alkenyl, (2d) isopropenyl, (2e) C1-C4 alkyl substituted with hydroxy.

[0023] In certain embodiments of the compounds otherwise described herein, R 2 is the following group (3a) to (3k): (3a) hydrogen, C1-C4 alkyl, hydroxy, -CO2H, -CO2(C1-C4 alkyl), or oxo; (3b) hydrogen, C1-C6 alkyl, hydroxy, -CO2H, or oxo; (3c) hydrogen or C1-C6 alkyl; (3d) hydrogen, (3e) C1-C4 alkyl (e.g., methyl), (3f) methyl, ethyl, or propyl (e.g., isopropyl or n-propyl); (3g) hydroxy, oxo or CO2H, (3h) hydroxy, (3i) oxo, (3j)-CH2OH, (3k)-CO2H.

[0024] In certain embodiments of the compounds otherwise described herein, R 3 is the following group (4a) to (4p): (4a) Hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, -(OCH2CH2) 0-6 OCH3, -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl, (4b) Hydrogen, C1-C 12 alkyl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl; (4c) hydrogen, C1-C8 alkyl, -(C1-C4 alkyl)-heteroaryl or -(C1-C4 alkyl)-heterocycloalkyl; (4d) hydrogen, C4-C9 alkyl, -(C1-C2 alkyl)-heteroaryl or -(C1-C2 alkyl)-heterocycloalkyl; (4e) Hydrogen or C1-C 10 Alkyl, (4f) hydrogen, (4g) C2-C9 alkyl, for example, unsubstituted n-C2-C9 alkyl, (4h) C4-C6 alkyl, for example, unsubstituted n-C4-C6 alkyl, (4i) n-pentyl, (4j) 1,1-dimethylheptyl, (4k)n-propyl (4l) -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl; (4m)-(C0-C4 alkyl)-heterocycloalkyl, wherein the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms that are nitrogen, oxygen, or sulfur; and 0 to 4 R 7 -(C0-C4 alkyl)-heterocycloalkyl substituted with (4n)-(C0-C4 alkyl)-heterocycloalkyl, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms that are nitrogen, oxygen, or sulfur; and 0 to 4 R 7 -(C0-C4 alkyl)-heterocycloalkyl substituted by, wherein heterocycloalkyl is piperidinyl, pyrrolidinyl, azetidinyl or aziridinyl; (4o)-(C0-C4 alkyl)-heterocycloalkyl, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms that are nitrogen, oxygen, or sulfur, and 0 to 4 R 7 and heterocycloalkyl is azetidinyl, and is independently oxo, C-C alkyl, Cl, F, Br, —C(O)R A , or -CO2R A 1 to 2 R 7 is replaced by R A is H or C1-C3 alkyl; (4p)-(C0-C4 alkyl)-heterocycloalkyl, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms that are nitrogen, oxygen, or sulfur, and 0 to 4 R 7 is replaced by R 7 is selected from one of: —(C0-C4 alkyl)-heterocycloalkyl, where —C(O)CH3.

[0025] In certain embodiments of the compounds otherwise described herein, R 4 represents the following groups (5a) to (5e): (5a) hydrogen, -CO2H or -CO2(C1-C4 alkyl); (5b) hydrogen, -CO2H, -CO2CH3 or -CO2CH2CH3, (5c) hydrogen, (5d)-CO2H, (5e) -CO2(C1-C6 alkyl).

[0026] In certain embodiments of the compounds otherwise described herein, the compounds have the following structural formulas (Ia)-(Ig): [ka] It has one of the following.

[0027] In certain embodiments of the compounds otherwise described herein, R 5a and R 5b are independently the following groups (6a) to (6x): (6a) Hydrogen, C1-C6 alkyl, C2-C6 alkenyl, hydroxy, halo, -(C0-C4 alkyl)O(C1-C6 alkyl), -(CH2CH2O) 1-8 (C1-C4 alkyl), -(C0-C4 alkyl)C(O)(C1-C6 alkyl), -CO2H, -CO2(C1-C6 alkyl), -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl, -(C0-C4 alkyl)-heterocycloalkyl, or -NR 5c R 5d or R 5a and R 5b together with the carbon atoms form a cycloalkyl or heterocycloalkyl ring; (6b) hydrogen, C-C alkyl, C-C alkenyl, —(C-C alkyl)O(C-C alkyl), —(C-C alkyl)C(O)(C-C alkyl), —COH, —CO(C-C alkyl), —(C-C alkyl)-aryl, —(C-C alkyl)-heteroaryl, —(C-C alkyl)-cycloalkyl, —(C-C alkyl)-heterocycloalkyl, or R 5a and R 5btogether with the carbon atoms form a cycloalkyl or heterocycloalkyl ring; (6c) C1-C6 alkyl, C2-C6 alkenyl, —(C0-C4 alkyl)O(C1-C6 alkyl), —(C0-C4 alkyl)C(O)(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or R 5a and R 5b together with the carbon atoms form a cycloalkyl or heterocycloalkyl ring; (6d) hydrogen, C1-C6 alkyl, C2-C6 alkenyl, —(C0-C4 alkyl)O(C1-C6 alkyl), —(C0-C4 alkyl)C(O)(C1-C6 alkyl), —CO2H, or —CO2(C1-C6 alkyl); (6e) C1-C6 alkyl, C2-C6 alkenyl, —(C0-C4 alkyl)O(C1-C6 alkyl), —(C0-C4 alkyl)C(O)(C1-C6 alkyl), —CO2H, or —CO2(C1-C6 alkyl); (6f) hydrogen, C1-C6 alkyl, or C2-C6 alkenyl; (6g) hydrogen or C1-C4 alkyl, (6h) C1-C4 alkyl (e.g., methyl), (6i) hydrogen or methyl, (6j) hydrogen, C1-C4 alkyl, —CH2O(C1-C6 alkyl), —CH2C(O)(C1-C6 alkyl), —CO2H, or —CO2(C1-C6 alkyl); (6k)R 5a But, -NHR 5c R 5d and R 5c is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or —(C0-C4 alkyl)C(O)(C1-C6 alkyl), and R 5b is hydrogen, (6l)R 5ais -(C-C alkyl)-aryl, -(C-C alkyl)-heteroaryl, -(C-C alkyl)-cycloalkyl or -(C-C alkyl)-heterocycloalkyl, and R 5b is as defined herein; (6m)R 5a is unsubstituted or substituted phenyl, and R 5b is as defined herein; (6n)R 5a is unsubstituted phenyl, and R 5b is as defined herein; (6o)R 5a is a substituted phenyl, such as 4-fluorophenyl or 4-trifluoromethylphenyl, and R 5b is as defined herein; (6p) As defined in (6a) to (6o), R 5b is hydrogen, C1-C4 alkyl, -CH2OCH3, -CH2C(O)CH3, -CO2H, or -CO2(C1-C2 alkyl); (6q) As defined in (6a) to (6o), R 5b is methyl, (6r) As defined in (6a) to (6o), R 5b is hydrogen, (6s)R 5b is methyl, and R 5a is methyl, —CHO(C-C alkyl), —CHC(O)(C-C alkyl), —COH, or —CO(C-C alkyl); (6t)R 5a and R 5b together with the carbon atoms to form a C3-C6 cycloalkyl (e.g., cyclopentyl) or heterocycloalkyl ring consisting of 3 to 6 carbon members (6u)R 5a is C1-C4 alkyl (e.g., methyl or chloropropyl), —CH2OCH3, —CH2C(O)CH3, —CO2H, or —CO2(C1-C2 alkyl), and R 5bis hydrogen or methyl, (6v)R 5a is -CH2OCH3, -CO2H, or -CO2CH2CH3, and R 5b is methyl, (6w)R 5a is -CH2C(O)CH3, and R 5b is hydrogen or methyl, (6x) hydrogen, methyl, phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, carboxy, ethoxycarbonyl, acetyl, 2-methylprop-1-en-1-yl, propyl, 3-chloropropyl, methoxymethyl, or R 5a and R 5b together with the carbon to which they are attached form a cyclopentyl.

[0028] In certain embodiments of the compounds otherwise described herein, Q 5 is the following group (7a) to (7e): (7a) oxygen or sulfur, (7b) oxygen, (7c) Sulfur, (7d)NR 5e (7e)(7d) as defined in R 5e is hydrogen, C1-C8 alkyl, -C(O)R 5f , or -CO2R 5f and each R 5f is hydrogen or C1-C6 alkyl.

[0029] In certain embodiments of the compounds otherwise described herein, R 6 is the following group (8a) to (8f): (8a) hydrogen or hydroxy, (8b) hydrogen, (8c) hydroxy or [ka] (8d) hydroxy, (8e) [ka] (8f) (methoxy)methoxy, (2-methoxyethoxy)methoxy, (2-methoxy)propan-2-yloxy, (2,5,8,11,14-pentaoxa)hexadecan-15-yloxy, ((ethoxycarbonyl)oxy)methoxy, ((ethoxycarbonyl)oxy)ethyl-1-yloxy, ((2-methoxyethoxycarbonyl)oxy)ethyl-1-yloxy, ((tert-butylcarbonyl)oxy)methoxy, ((2-ethylbutylcarbonyl)oxy)methoxy, (( (acetyl)oxy)methoxy, ((methoxycarbonyl)(methyl)amino)methoxy, ((((2-methoxyethyl)oxy)carbonyl)(methyl)amino)methoxy, ((((2,5,8,11-tetraoxatridecan-13-yl)oxy)carbonyl)(methyl)amino)methoxy, ((methoxycarbonyl)(phenyl)amino)methoxy, ((methoxycarbonyl)(4-nitrophenyl)amino)methoxy or (1-methoxy)cyclopentoxy.

[0030] In certain embodiments of the compounds otherwise described herein, R 6a and R 6b is the following group (9a) to (9i): (9a) each independently represents hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, hydroxy, halo, -O(C-C alkyl), -C(O)(C-C alkyl), -CO(C-C alkyl), -(C-C alkyl)-aryl, -(C-C alkyl)-heteroaryl, -(C-C alkyl)-cycloalkyl, or -(C-C alkyl)-heterocycloalkyl; (9b) each independently is hydrogen, C1-C4 alkyl, hydroxy, or —CO2(C1-C4 alkyl); (9c) each independently is hydrogen or C1-C4 alkyl; (9d) Both are hydrogen, (9e)R 6a is methyl, and R 6b is hydrogen, (9f)R 6a and R 6b But both are methyl, (9g) each independently hydrogen or —NR 6d R 6c and R 6d and R 6c may each independently be hydrogen, C-C alkyl, or —C(O)(C-C alkyl), or R 6d and R 6c together with the carbon atom form a heterocycloalkyl ring of 3 to 5 carbon ring members, (9h)R 6a and R 6b together with the carbon atoms form a cycloalkyl ring (e.g., a saturated cycloalkyl ring) containing 3 to 6 carbon ring members; (9i)R 6a and R 6b together with the carbon atom form cyclopentyl.

[0031] In certain embodiments of the compounds otherwise described herein, Q 6 is the following group (10a) to (10oo): (10a)-Y 6 R 6e and Y 6 is O or S, (10b) as defined in (10a), and R 6e is hydrogen, C1-C8 alkyl, -(CH2CH2O) 1-8 (C1-C4 alkyl), -C(O)R 6h , -CO2R 6h , C2-C8 alkenyl, C2-C8 alkynyl, -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl, and each R 6his hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(CH2CH2O) 1-6 (C1-C4 alkyl), (10c)(10a) as defined in R 6e is hydrogen, C1-C4 alkyl, -(CH2CH2O) 1-4 CH3, -C(O)R 6h or -CO2R 6h and R 6h is hydrogen, C1-C8 alkyl or -(CH2CH2O) 1-6 (C1-C4 alkyl), (10d)(10a) as defined in R 6e is hydrogen, (10e)(10a) as defined in R 6e is deuterium, (10f)(10a) as defined in R 6e is C1-C4 alkyl, for example, methyl; (10g)(10a) as defined in R 6e But -(CH2CH2O) 1-4 CH3, (10h)(10a) as defined in R 6e is -CH2CH2OCH3, (10i)(10a) as defined in R 6e is -(CH2CH2O)4CH3, (10j)(10a) as defined in R 6e But -C(O)R 6h and R 6h is hydrogen, -C1-C8 alkyl, or -(CH2CH2O) 1-6 (C1-C4 alkyl), (10k)(10a) as defined in R 6e However, -CO2R 6h and R 6h is hydrogen, -C1-C8 alkyl, or -(CH2CH2O) 1-6 (C1-C4 alkyl), (10l)(10a) as defined in R 6e is -CO2H (e.g., R 6h is hydrogen), (10m)(10a) as defined in R 6e is -CO2(C1-C5 alkyl) (e.g., R 6h is C1-C5 alkyl, for example methyl, ethyl, butyl such as t-butyl, or pentyl such as pentan-3-yl; (10n)(10a) as defined in R 6e But -CO2-(CH2CH2O) 1-4 CH3 (e.g., R 6h But -(CH2CH2O) 1-4 CH3) (10o)(10a) as defined in R 6e is -CO2(C2-C8 alkenyl) or -CO2(C2-C8 alkynyl) (e.g., R 6h But R 6h and C2-C8 is alkenyl or C2-C8 alkynyl; (10p)(10b)~(11o), and Y 6 is O, (10q)(10b)~(11o) are as defined in Y 6 But S, (10r)-NR 6f R 6g , (10s)(10r) as defined in R 6f and R 6g are independently hydrogen, C1-C8 alkyl, -(CH2CH2O) 1-8 (C1-C4 alkyl), -C(O)R 6h , -CO2R 6h , C2-C8 alkenyl, C2-C8 alkynyl, -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl, or R 6f and R 6gform a heterocycle together with the nitrogen to which they are attached, and each R 6h is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(CH2CH2O) 1-6 (C-C alkyl), -(C-C alkyl)-aryl, -(C-C alkyl)-heteroaryl, -(C-C alkyl)-cycloalkyl or -(C-C alkyl)-heterocycloalkyl; (10t)(10r) as defined in R 6f is hydrogen, C1-C8 alkyl, -C(O)R 6h , -CO2R 6h , or -(CH2CH2O) 1-4 CH3 and R 6h is hydrogen, C1-C8 alkyl or -(CH2CH2O) 1-6 (C1-C4 alkyl), (10u)(10r) as defined in R 6f is hydrogen, (10v)(10r) as defined in R 6f is deuterium, (10w)(10r) as defined in R 6f is C1-C4 alkyl, for example, methyl; (10x)(10r) as defined in R 6f But -(CH2CH2O) 1-4 CH3, (10y)(10r) and R 6f is -CH2CH2OCH3, (10z)(10r) as defined in R 6f is -(CH2CH2O)4CH3, (10aa)(10r) as defined in R 6f But -C(O)R 6h and R 6h is hydrogen, -C1-C8 alkyl, or -(CH2CH2O) 1-6 (C1-C4 alkyl), and R 6gis hydrogen, C1-C4 alkyl, —C(O)C1-C4 alkyl, or —CO2(C1-C4 alkyl); (10bb)(10r) as defined in R 6f However, -CO2R 6h and R 6h is hydrogen, -C1-C8 alkyl, or -(CH2CH2O) 1-6 (C1-C4 alkyl), and R 6g is hydrogen, C1-C4 alkyl, —C(O)C1-C4 alkyl, or —CO2(C1-C4 alkyl); (10cc)(10r) and R 6f is -CO2H (e.g., R 6h is hydrogen), (10dd)(10r) as defined in R 6f is -CO2(C1-C5 alkyl) (e.g., R 6h is C1-C5 alkyl, for example methyl, ethyl, butyl such as t-butyl, or pentyl such as pentan-3-yl; (10ee)(10r) as defined in R 6f But -CO2-(CH2CH2O) 1-4 CH3 (e.g., R 6h But -(CH2CH2O) 1-4 CH3) (10ff)(10r) as defined in R 6f is -CO2(C2-C8 alkenyl) or -CO2(C2-C8 alkynyl) (e.g., R 6h But R 6h and C2-C8 is alkenyl or C2-C8 alkynyl; (10gg)(10r)~(10ff), and R 6g is hydrogen, (10hh)(10r)~(10ff), R 6g is -C1-C4 alkyl (e.g., methyl), (10ii) As defined in (10r) to (10ff), R6g is -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl; (10jj)(10r)~(10ff), and R 6g However, 0 to 2 R 8 or monocyclic heteroaryl, for example, unsubstituted phenyl or p-nitrophenyl, substituted with As defined in (10kk)(10r)~(10ff), R 6g is —C(O)C1-C4 alkyl; (10ll)(10r)~(10ff), R 6g is -C(O)CH3, (10mm)(10r)~(10ff), R 6g is -CO2(C1-C4 alkyl), As defined in (10nn)(10r)~(10ff), R 6g is -CO2CH3, (10oo)(10r) as defined in R 6f and R 6g which together with the nitrogen to which they are attached form a heterocyclic ring.

[0032] Various specific embodiments, numbers 1 to 544, of the compounds of the present disclosure include compounds of Formula (I) (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), each as defined in each column below, where each entry is a radical number as defined above.

number

number

[0033] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the foregoing embodiments is unsubstituted. In alternative additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the foregoing embodiments is independently substituted or unsubstituted. In further alternative additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the foregoing embodiments is substituted.

[0034] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as those described in the immediately preceding paragraph above, each cycloalkyl recited in any one of the foregoing embodiments is a 3- to 7-membered monocyclic cycloalkyl. For example, in certain, particular embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as those described in the immediately preceding paragraph above, each cycloalkyl recited in any one of the foregoing embodiments is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

[0035] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any embodiment described in the two paragraphs immediately above, each heterocycloalkyl recited in any one of the preceding embodiments is a 4- to 7-membered monocyclic heterocycloalkyl having 1-2 heteroatoms selected from O, S, and N. For example, in certain, particular embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any embodiment described in the two paragraphs immediately above, each heterocycloalkyl recited in any one of the preceding embodiments is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydro-2H-thiopyranyl. In certain, particular embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any of those described in the immediately preceding two paragraphs above, each heterocycloalkyl recited in any one of the foregoing embodiments is pyrrolidine, piperidine, piperazine, tetrahydrofuran, (1H)dihydropyran, or morpholine (e.g., each unsubstituted).

[0036] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any of the embodiments described in the immediately preceding three paragraphs above, each aryl is phenyl.

[0037] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any of the embodiments described in the four paragraphs immediately above, each heteroaryl is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from O, S, and N. For example, in certain, particular embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any of the embodiments described in the four paragraphs immediately above, each heteroaryl is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from O, S, and N. 8 substituted with, e.g., unsubstituted, one R 8 or two R 8 In certain, particular embodiments, including those described with reference to Formulas (I) and (Ia) through (Ig) and any of embodiments 1 through 544 above, as well as any of those described in the four paragraphs immediately above, each heteroaryl is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl.

[0038] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any embodiment described in the immediately preceding paragraph above, each R 7 are independently oxo, C1-C4 alkyl, Cl, F, Br, -CN, -SF5, -N3, 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 , -CO2R 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 In certain additional embodiments, including, for example, those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any embodiment described in the immediately preceding paragraph above, each R 7 are independently oxo, C1-C4 alkyl, Cl, F, Br, -CN, -SF5, -N3, nitro, -SR A , -S(O) 1-2 R A , -OR A , -NR B R A , or -C(O)R A is.

[0039] In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any embodiment described in the immediately preceding paragraph above, each R 8 are independently C1-C4 alkyl, Cl, F, Br, -CN, -SF5, -N3, 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)NRB R A , -NR B C(S)R A , -CO2R 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 In certain additional embodiments, including those described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, as well as any embodiment described in the immediately preceding paragraph above, each R 8 are independently C1-C4 alkyl, Cl, F, Br, -CN, -SF5, -N3, nitro, -SR A , -S(O) 1-2 R A , -OR A , -NR B R A , or -C(O)R A is.

[0040] In some embodiments, the present disclosure provides, inter alia: 7-hydroxy-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(m-tolyl)-5-pentyl-1,3-benzodioxin-4-one, 7-hydroxy-5-pentyl-2-phenyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-4-oxo-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-4-oxo-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-2-(2-methylprop-1-en-1-yl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-5-pentyl-8-(m-tolyl)-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-acetonyl-7-hydroxy-8-(m-tolyl)-5-pentyl-2-phenyl-1,3-benzodioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-5-pentyl-2,2-diphenyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, methyl 4-(7-hydroxy-4-oxo-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-2-yl)benzoate, 7-hydroxy-5-propyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-2-phenyl-5-propyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2,2-diphenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, methyl 4-(7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-4-oxo-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-2-yl)benzoate, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-spiro[1,3-benzodioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2,2-diphenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, methyl 4-(7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-4-oxo-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-2-yl)benzoate, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2,2-diphenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, and The present invention relates to a compound selected from the group consisting of methyl 4-(7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-4-oxo-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-2-yl)benzoate.

[0041] In some embodiments, the present disclosure provides, inter alia: 7-hydroxy-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(m-tolyl)-5-pentyl-1,3-benzodioxin-4-one, 7-hydroxy-5-pentyl-2-phenyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-5-pentyl-8-(m-tolyl)-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-acetonyl-7-hydroxy-8-(m-tolyl)-5-pentyl-2-phenyl-1,3-benzodioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-5-propyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-2-phenyl-5-propyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-spiro[1,3-benzodioxin-2,1'-cyclopentan]-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, and The present invention further relates to a compound selected from 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one.

[0042] In some embodiments, the present disclosure provides, inter alia: 7-hydroxy-2,2-dimethyl-8-(m-tolyl)-5-pentyl-1,3-benzodioxin-4-one, 2-acetonyl-7-hydroxy-8-(m-tolyl)-5-pentyl-2-phenyl-1,3-benzodioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-spiro[1,3-benzodioxin-2,1'-cyclopentan]-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, and The present invention further relates to a compound selected from 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one.

[0043] Compounds of the present disclosure are described herein with reference to Formula (I), including embodiments 1-544 and the compounds listed in the above three paragraphs, with the exception that the present disclosure does not include the compound: 7-hydroxy-2,2-dimethyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one.

[0044] In certain embodiments of the compounds otherwise described herein, the compound is in the form of a pharmaceutically acceptable salt of a compound described herein, or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof. Those skilled in the art will appreciate that a variety of pharmaceutically acceptable salts can be provided, for example, as described in further detail below.

[0045] In certain embodiments of the compounds otherwise described herein, the compound is in the form of a solvate (e.g., a hydrate) of the compound described herein, or of an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof. Those skilled in the art will recognize that various solvates and / or hydrates can be formed.

[0046] Those skilled in the art will understand that the phrase "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" includes a compound in the form of a salt, solvate, or hydrate of the base compound (including its enantiomer, diastereomer, racemate, or tautomer), or a metabolite of the base compound. However, in certain embodiments described above, the compound is not in the form of a salt, solvate, or hydrate.

[0047] Treatment application In some embodiments, the compounds of the present disclosure have affinity for at least one cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptor). Thus, in another aspect, the present disclosure relates to the use of at least one of the compounds of the present disclosure for binding to and / or interacting with a cannabinoid receptor.

[0048] In some embodiments, the compounds of the present disclosure may have affinity for one or both of the CB1 receptor and the CB2 receptor.In certain embodiments, the compounds of the present disclosure may have affinity for the CB1 receptor but may not have affinity for the CB2 receptor.In certain embodiments, the compounds of the present disclosure may have affinity for the CB2 receptor but may not have affinity for the CB1 receptor.

[0049] In some embodiments, the compounds of the present disclosure may exhibit selectivity for one receptor over another. As used herein, "selectivity" means that a compound binds to, interacts with, or preferentially regulates one receptor over another. In one embodiment, a compound is selective for one receptor over another if its affinity for one receptor is at least 1.25 times, at least 1.5 times, at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, or at least 100 times greater than that of another receptor. In one embodiment, the affinity of a compound disclosed herein for a receptor can be determined, for example, by a radioligand competitive binding assay, such as that described in the Examples herein.

[0050] In some embodiments, compounds of the present disclosure may have affinity for the CB1 receptor with selectivity for the CB1 receptor over the CB2 receptor.

[0051] In some embodiments, compounds of the present disclosure may have affinity for the CB2 receptor, with selectivity for the CB2 receptor over the CB1 receptor.

[0052] In some embodiments, compounds of the present disclosure may function as agonists, partial agonists, indirect agonists, antagonists, inverse agonists, neutral agonists, or allosteric modulators of at least one cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptor). In some embodiments, compounds of the present disclosure may function as agonists, partial agonists, indirect agonists, antagonists, inverse agonists, neutral agonists, or allosteric modulators of CB1 and / or CB2 receptors. In some embodiments, compounds of the present disclosure may function as agonists of CB1 and / or CB2 receptors. In some embodiments, compounds of the present disclosure may function as antagonists of CB1 and / or CB2 receptors. In some embodiments, compounds of the present disclosure may function as indirect agonists for the 5HT1A receptor.

[0053] In some embodiments, compounds of the present disclosure may act as prodrugs to compounds (e.g., metabolites) that function as agonists, partial agonists, indirect agonists, antagonists, inverse agonists, or neutral agonists for at least one cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptor).

[0054] The present disclosure further relates to the use of the compounds disclosed herein as therapeutically active substances or as prodrugs to therapeutically active substances.

[0055] In one embodiment, the present disclosure relates to the use of the compounds disclosed herein for the treatment or prevention of a disease associated with a cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, a PPAR (e.g., PPARγ), or a μ-opioid receptor). In one embodiment, "cannabinoid-associated disease" is meant to refer to a disease, disorder, or condition that is treatable or preventable by acting on a cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, a PPAR (e.g., PPARγ), or a μ-opioid receptor). In one embodiment, the compounds of the present disclosure can treat or prevent conditions by acting as agonists, partial agonists, antagonists, inverse agonists, neutral agonists, or allosteric modulators of cannabinoid receptors, or by acting as prodrugs of compounds (e.g., metabolites) that act as agonists, partial agonists, antagonists, inverse agonists, neutral agonists, or allosteric modulators of cannabinoid receptors. In an alternative embodiment, the cannabinoid receptor is CB1 or CB2.

[0056] In one embodiment, the present disclosure relates to the use of the compounds disclosed herein for selectively modulating the activity of one receptor over another receptor. In one embodiment, at least one of the receptors is a cannabinoid receptor. In one embodiment, both receptors are cannabinoid receptors. In one embodiment, the receptors are CB1 and CB2. In an alternative embodiment, the present disclosure relates to the use of the compounds disclosed herein for selectively modulating the activity of CB1 or CB2 receptors.

[0057] As used herein, "selectively modulate" is intended to refer to the ability of the compounds of the present disclosure to cause any change in the activity of a receptor. In one embodiment, "selectively modulate" means to directly or indirectly stimulate or inhibit the activity of a receptor.

[0058] The present disclosure also relates to methods for treating or preventing diseases, such as diseases associated with cannabinoid receptors (e.g., CB1 and / or CB2), which methods comprise administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula (I)) described herein or a pharmaceutical composition of the present disclosure described herein.

[0059] In certain embodiments, diseases of the present disclosure include ADHD / ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's disease, anorexia (e.g., HIV-associated cachexia), anxiety disorders (e.g., social anxiety disorder, specific phobia, test anxiety, generalized anxiety disorder), arthritis, atherosclerosis, autism, bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic transplant nephropathy, cocaine use disorder, complex regional pain syndrome, congestive heart failure, depression, fibromyalgia, fragile X syndrome / FXTAS, frontotemporal dementia (behavioral variant), gingivitis fever, glaucoma, glioblastoma, glomerular nephropathy, Huntington's disease, hypertrophic scarring, IBD / IBS, inflammation, inflammatory myopathy, ischemia, renal fibrosis, keloids, leukodystrophy, liver fibrosis, liver cirrhosis, These conditions include, but are not limited to, pulmonary fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea (e.g., CINV, motion sickness), neuropathic pain (e.g., post-herpetic neuralgia, painful diabetic neuropathy), nocturnal disorder, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, pain (e.g., acute or chronic pain), Parkinson's disease, post-concussion syndrome / traumatic brain injury, psychosis / schizophrenia, PTSD, bone mass regulation, REM sleep behavior disorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skin conditions (e.g., acne, psoriatic arthritis), sleep disorders (e.g., insomnia, RLS), spinocerebellar ataxia, systemic fibrosis, systemic sclerosis, heat injury, tobacco use disorder / nicotine dependence, Tourette's syndrome, tumor, or trigeminal neuralgia.

[0060] The compounds and compositions of the present disclosure described herein can also be administered in combination with one or more second-line therapeutic agents. Thus, in certain embodiments, the method also includes administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more compounds of the present disclosure described herein or a pharmaceutical composition of the present disclosure described herein and one or more second-line therapeutic agents. Examples of suitable second-line therapeutic agents include temozolomide, camptothecin, doxorubicin, daunorubicin, vincristine, paclitaxel, neocarzinostatin, calicheamicin, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, lurtotecan, annamycin, docetaxel, tamoxifen, epirubicin, methotrexate, vinblastine, vincristine, topotecan, prednisone, and rituximab. lon, chloroquine, hydroxychloroquine, autophagy inhibitors, abt-737, leucovorin, psilocybin, psilocin, ciloacetin, netupitant, palonosetron, aprepitant, 3,4-methylenedioxymethamphetamine, nicotine, ketamine, lithium salts (e.g., lithium citrate), valproic acid, bevacizumab, bortezomib, fluorouracil, gemcitabine, irinotecan, oxaliplatin, adalimumab, acetaminophen Zathioprine, infliximab, citalopram, mirtazapine, sertraline, esketamine, fluoxetine, paroxetine, venlafaxine, fenfluramine, vigabatrin, bupropion, atomoxetine, memantine, clobazam, stiripentol, cyclosporine, tacrolimus, methylprednisolone, megestrol acetate, biguanides (e.g., metformin), sulfonylureas (e.g., glipizide, tolbutamide), gaclosporin, fluoxetine ... These include, but are not limited to, bapentin, baclofen, clonazepam, dantrolene, diazepam, tizanidine, buprenorphine, naltrexone, opioids (e.g., codeine, oxycodone, morphine), amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, clonidine, romazenil, benzodiazepines, benzamides, dexamethasone, gemcitabine, and palmitoylethanolamide.When administered as a combination, the disclosed compounds and compositions described herein and the second therapeutic agent can be formulated as separate compositions that are administered simultaneously or sequentially, or the therapeutic agents can be administered as a single composition. In certain embodiments, the second therapeutic agent is administered at a concentration above its established half-maximal inhibitory concentration (IC). 50 For example, the second therapeutic agent may be administered in an amount below the inhibitory concentration (IC 50 ), for example, less than 1%, for example, less than 10%, or less than 25%, or less than 50%, or less than 75%, or even less than 90% of the total amount of the active ingredient.

[0061] Prodrug In some embodiments, the compounds described herein may themselves be prodrugs or may be further modified to provide prodrugs.

[0062] Prodrugs according to the present disclosure can be prepared by replacing appropriate functional groups present in the compounds disclosed herein, such as, for example, the embodiments described with reference to Formulas (I) and (Ia)-(Ig) and any of the above embodiments 1-544, with certain moieties known to those skilled in the art as "pro-moieties," as described in *Design of Prodrugs* by H. Bundgaard (Elsevier, 1985) and *YM Choi-Sledeski and *C.G. Wermuth, *Designing Prodrugs and Bioprecursors in Practice of Medicinal Chemistry*, (Fourth Edition), Chapter 28, 657-696 (Elsevier, 2015).

[0063] In exemplary embodiments, a prodrug according to the present disclosure is (a) an ester or amide derivative of a carboxylic acid in the compounds disclosed herein; (b) an ester, carbonate, carbamate, acetal, aminal, phosphate, or ether derivative of a hydroxyl group in the compounds disclosed herein; (c) an amide, imine, carbamate, or amine derivative of an amino group in the compounds disclosed herein; (d) an oxime or imine derivative of a carbonyl group in the compounds disclosed herein; or (e) a methyl, primary alcohol, or aldehyde group that can be metabolically oxidized to a carboxylic acid in the compounds disclosed herein.

[0064] Certain compounds of the present disclosure, such as, for example, the embodiments described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, may themselves act as prodrugs. In one embodiment, compounds of the present disclosure, such as, for example, the embodiments described with reference to Formulas (I) and (Ia)-(Ig) and any of embodiments 1-544 above, may act as prodrugs of a cannabinoid, such as, for example, a naturally occurring cannabinoid (e.g., CBD or CBDA).

[0065] Reference to the compounds disclosed herein is considered to include the compounds themselves and their prodrugs. The present disclosure includes such prodrug compounds, as well as any pharmaceutically acceptable salts of such prodrug compounds, and / or any solvates, hydrates, enantiomers, diastereomers, racemates, tautomers, or metabolites of such prodrug compounds and their salts.

[0066] In some embodiments, the prodrug compounds of the present disclosure may exhibit improved pharmacokinetics (PK), improved biodistribution, and / or improved formulation capabilities (e.g., stability in formulations). For example, in one embodiment, these characteristics may be improved over natural cannabinoids (e.g., CBD or CBDA).

[0067] In some embodiments, the prodrug compounds of the present disclosure may exhibit unique or improved biological activity. For example, in one embodiment, these characteristics may be unique or improved over those of naturally occurring cannabinoids (e.g., CBD or CBDA).

[0068] Pharmaceutical Compositions and Dosage Forms The compounds described herein can be usefully provided in the form of pharmaceutical compositions. Such compositions comprise the compounds described in any one of the above aspects or embodiments described herein together with a pharmaceutically acceptable excipient, diluent or carrier.

[0069] The compounds can be formulated as pharmaceutical compositions themselves, as described above, or in the form of hydrates, solvates, or pharmaceutically acceptable salts. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases can also be formed.

[0070] The pharmaceutical composition may be in the form of, for example, a tablet, capsule, or parenteral formulation, although one of ordinary skill in the art will appreciate that the compounds may be provided in a wide variety of pharmaceutical compositions.

[0071] The compound of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray, or rectally, for example, in a dosage unit formulation containing one or more pharmaceutically acceptable carriers, diluents or excipients.As used herein, the term parenteral includes percutaneous, subcutaneous, intravascular (for example, intravenous), intramuscular, or intrathecal injection or infusion techniques, etc.The pharmaceutical preparation comprising the compound of the present disclosure can be provided, for example, in any of the formulations and dosage forms described herein.

[0072] Pharmaceutical compositions can be prepared using the compounds of the present disclosure.For example, in one embodiment, pharmaceutical compositions comprise pharmaceutically acceptable carriers, diluents or excipients and the compound described above with reference to any one of the structural formulas.

[0073] In the pharmaceutical compositions disclosed herein, one or more compounds of the present disclosure can be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and if desired, other active ingredients.The pharmaceutical compositions containing the compounds of the present disclosure can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0074] Compositions intended for oral use can be prepared according to any suitable method for preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated by known techniques. In some cases, such coatings can be prepared by appropriate techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained activity over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.

[0075] Formulations for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0076] Formulations for oral use may also be presented as lozenges.

[0077] Formulations for oral use can also be presented as beverages or foods. For example, in one embodiment, the compounds of the present disclosure can be presented in a water-soluble formulation, such as that disclosed in PCT / CA2019 / 051698, which includes an emulsifier and a glycerin-based carrier surfactant. In other embodiments, the compounds of the present disclosure can be presented in a composition, such as that disclosed in PCT / CA2019 / 051704, which includes inulin and pectin.

[0078] Aqueous suspensions contain the active substance in a mixture with excipients suitable for the manufacture of aqueous suspensions.Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersants or wetting agents such as naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0079] Oily suspension can be prepared by suspending active ingredients in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin.Oily suspension can contain thickening agent, such as beeswax, hard paraffin or cetyl alcohol.Sweetener and flavoring agent can be added to make the oral preparations palatable.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0080] Dispersible powders and granules suitable for preparing aqueous suspension by adding water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0081] Pharmaceutical compositions can also be in the form of oil-in-water emulsion.Oil phase can be vegetable oil or mineral oil or their mixture.Suitable emulsifiers can be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and the condensation products of the above partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.Emulsion can also contain sweeteners and flavoring agents.

[0082] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, water comprises less than 50% of the composition. In some embodiments, a composition comprising less than 50% water has at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content is present in trace amounts in the composition.

[0083] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, alcohol comprises less than 50% of the composition. In some embodiments, compositions comprising less than 50% alcohol have at least 1%, 2%, 3%, 4%, or 5% alcohol. In other embodiments, the alcohol content is present in trace amounts in the composition.

[0084] Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations can also contain emollients, preservatives, flavorings, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils can be used as solvents or suspending media. For this purpose, any smooth, fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are useful in the preparation of injectables.

[0085] The compound of the present disclosure can also be administered in the form of suppositories, for example, for rectal administration of drugs.These compositions can be prepared by mixing compound with suitable non-irritating excipients that are solid at normal temperature but liquid at rectal temperature, and therefore melt in rectum and release drug.Such materials include cocoa butter and polyethylene glycol.

[0086] The compound of the present disclosure can also be administered parenterally in sterile medium.Drug can be suspended or dissolved in vehicle depending on the vehicle and concentration used.Advantageously, adjuvants such as local anesthetic, preservative and buffering agent can be dissolved in vehicle.

[0087] The composition can be formulated in a unit dosage form of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a dosage unit for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0088] The compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition to be treated or prevented, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0089] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds described herein. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, and the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the compounds described herein.

[0090] Tablets or pills can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, a tablet or pill can be composed of an inner dosage component and an outer dosage component, with the outer dosage component being in the form of an envelope over the inner dosage component. The two components are separated by an enteric layer, which can serve to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be released later. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0091] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated or prevented, as well as factors such as the severity of the disease, the age, weight, and general health of the patient, and will depend on the judgment of the attending physician.

[0092] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for ready use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0093] The therapeutic dosage of a compound may vary depending, for example, on the particular application for which the treatment is being administered, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds described herein can be provided in a physiological buffer containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. Dosages are likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0094] The compounds described herein can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immunostimulant, an immunosuppressant, an anti-inflammatory agent, etc.

[0095] One skilled in the art will formulate the compounds described herein into pharmaceutical formulations based, for example, on the physicochemical properties of the compound, the amount of compound needed for a therapeutically effective amount, and the desired route of administration.

[0096] definition Terms used herein may be preceded and / or followed by a single dash "-" or a double dash "=" to indicate the bond order between the named substituent and its parent moiety, with a single dash indicating a single bond and a double dash indicating a double bond or a pair of single bonds in the case of a spiro substituent. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety, and further, substituents are intended to be read "left to right" with respect to the referenced chemical structure unless the dash indicates otherwise. For example, arylalkyl, arylalkyl-, and -alkylaryl indicate the same functional group.

[0097] For brevity, chemical moieties are defined and referred to throughout primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under appropriate structural circumstances apparent to one of ordinary skill in the art. For example, an "alkyl" moiety can refer to a monovalent radical (e.g., CH3-CH2-), while in some situations, a divalent linking moiety can be "alkyl," in which case one of ordinary skill in the art would understand the alkyl to be the divalent radical equivalent to the term "alkylene" (e.g., -CH2-CH2-). (Similarly, in situations where a divalent moiety is required and is described as "aryl," one of ordinary skill in the art would understand the term "aryl" to refer to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal valence for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of S). Nitrogen in the compounds of the present disclosure can be hypervalent, e.g., an N-oxide or tetrasubstituted ammonium salt. In some cases, the moiety may be, for example, -B-(A) a where a is 0 or 1. In such case, when a is 0, the moiety is -B, and when a is 1, the moiety is -BA.

[0098] As used herein, the term "alkyl" includes saturated hydrocarbons having a specified number of carbon atoms from 1 to 10 (i.e., inclusive), 1 to 8, 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6. Alkyl groups can be straight or branched chain and, depending on the context, can be monovalent or divalent radicals (i.e., alkylene groups). For example, the moiety "-(C1-C6 alkyl)-O-" refers to attachment of an oxygen through an alkylene bridge having 1 to 6 carbons, and C1-C3 alkyl represents methyl, ethyl, and propyl moieties. Examples of "alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec-, and tert-butyl, pentyl, and hexyl.

[0099] The term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge, such as alkyl-O-, where the term "alkyl" has the definition previously given. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0100] The term "alkenyl," as used herein, unless otherwise specified, refers to an unsaturated hydrocarbon containing 2 to 10 carbons (i.e., inclusive), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons, and containing at least one carbon-carbon double bond. Alkenyl groups can be straight-chained or branched and, depending on the context, can be monovalent or divalent radicals (i.e., alkenylene groups). For example, the moiety "-(C2-C6 alkenyl)-O-" refers to attachment of oxygen through an alkenylene bridge having 2 to 6 carbons. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

[0101] The term "alkynyl," as used herein, unless otherwise specified, refers to an unsaturated hydrocarbon having a specified number of carbon atoms, such as 2 to 10 carbons (i.e., inclusive), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons, and containing at least one carbon-carbon triple bond. Alkynyl groups can be straight-chained or branched and, depending on the context, can be monovalent or divalent radicals (i.e., alkynylene groups). For example, the moiety "-(C2-C6 alkynyl)-O-" refers to attachment of oxygen through an alkenylene bridge having 2 to 6 carbons. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0102] The term "aryl" refers to an aromatic ring system having a single ring (e.g., phenyl) optionally fused to another aromatic hydrocarbon ring or a non-aromatic hydrocarbon ring or heterocycle. "Aryl" includes ring systems having multiple fused rings, at least one of which is carbocyclic and aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. "Aryl" also includes ring systems having a first carbocyclic aromatic ring fused to a non-aromatic heterocycle, e.g., 1H-2,3-dihydrobenzofuranyl and tetrahydroisoquinolinyl. The aryl groups herein are unsubstituted or, if designated as "optionally substituted," can be substituted in one or more substitutable positions with various groups as indicated, unless otherwise specified.

[0103] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine. In certain embodiments of each and every embodiment otherwise described herein, the term "halogen" or "halo" refers to fluorine or chlorine. In certain embodiments of each and every embodiment otherwise described herein, the term "halogen" or "halo" refers to fluorine. The term "fluoroalkyl" refers to an alkyl group (i.e., as otherwise described herein) substituted with at least one fluorine. "Fluoroalkyl" includes alkyl groups substituted with multiple fluorines, such as perfluoroalkyl groups. Examples of fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroprop-2-yl, and 2,2,3,3,3-pentafluoroprop-1-yl.

[0104] The term "heteroaryl" refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen, and sulfur in the aromatic ring. Most commonly, heteroaryl groups have 1, 2, 3, or 4 heteroatoms. Heteroaryls can be fused to one or more non-aromatic rings, such as cycloalkyl or heterocycloalkyl rings, where cycloalkyl and heterocycloalkyl rings are described herein. In one embodiment of the compounds of the present invention, the heteroaryl group is bonded to the remainder of the structure via an atom in the aromatic ring of the heteroaryl group. In another embodiment, the heteroaryl group is bonded to the remainder of the structure via a non-aromatic ring atom.Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, and the like. aryl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, isoindolinyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidoazothiazolyl, benzisoxazinyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, chloro Mononyl, chromanonyl, pyridinyl N-oxide, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl.In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl. Heteroaryl groups herein are unsubstituted or, if specified as "optionally substituted," can be substituted at one or more substitutable positions with various groups as indicated, unless otherwise specified.

[0105] The term "heterocycloalkyl" refers to a non-aromatic ring or ring system containing at least one heteroatom, preferably selected from nitrogen, oxygen, and sulfur, in a non-aromatic ring. Heterocycloalkyls can have 1, 2, 3, or 4 heteroatoms. Heterocycloalkyls can be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). Heterocycloalkyls include monocyclic groups of 3 to 8 ring atoms, as well as bicyclic and polycyclic ring systems, including bridged and fused systems, in which each ring contains 3 to 8 ring atoms. Heterocycloalkyl rings are optionally fused to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings. In certain embodiments, heterocycloalkyl groups have 3 to 7 members in a single ring. In other embodiments, heterocycloalkyl groups have 5 or 6 members in a single ring. In some embodiments, heterocycloalkyl groups have 3, 4, 5, 6, or 7 members in a single ring. Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (in each case also "quinuclidinyl" or a quinuclidine derivative), azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, These include, but are not limited to, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindolidionyi, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide.Particularly preferred heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e., oxo-substituted tetrahydrofuranyl), γ-butriolactamyl (i.e., oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolidionyi, and piperazinonyl. Heterocycloalkyl groups herein are unsubstituted or, if designated "optionally substituted," can be substituted at one or more substitutable positions with various groups, as indicated, unless otherwise specified.

[0106] The term "cycloalkyl" refers to a non-aromatic carbocyclic ring or ring system that can be saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl). Cycloalkyl rings can be optionally fused to or otherwise attached to other cycloalkyl rings (e.g., bridged systems). Certain examples of cycloalkyl groups of the present disclosure have 3 to 7 members in a single ring, e.g., 5 or 6 members in a single ring. In some embodiments, cycloalkyl groups have 3, 4, 5, 6, or 7 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl, and bicyclo[2.2.1]heptane. Cycloalkyl groups herein can be unsubstituted or, if designated "optionally substituted," can be substituted at one or more substitutable positions with various groups as indicated.

[0107] The term "ring system" includes monocyclic rings and fused and / or bridged polycyclic rings.

[0108] The term "amino" refers to a primary, secondary, or tertiary amino group, depending on the context.

[0109] The term "carbonyl" refers to the group -C(O)-.

[0110] The terms "hydroxy" and "hydroxyl" refer to an --OH group.

[0111] The term "oxo" refers to a double-bonded oxygen, sometimes designated as =O, or may be used to indicate an oxo-substituted carbon, for example, in describing a carbonyl "C(O)".

[0112] The term "oxy" refers to the group --O--.

[0113] The term "sulfonyl" means a -SO2- group.

[0114] The term "substituted," when used to modify a particular group or radical, means, unless otherwise specified, that one or more hydrogen atoms of the particular group or radical are replaced, independently of each other, with the same or different substituents, as defined below.

[0115] As used herein, the term "metabolite" refers to a compound resulting from metabolism of a compound of the present disclosure, including any of the embodiments described with reference to Formulae (I)-(III) and (Ia)-(Ig) and any of embodiments 1-544 above. In one embodiment, the metabolite is an active metabolite, meaning it is a biologically active compound. In one embodiment, the metabolite is an active compound obtained from metabolism of a prodrug described herein.

[0116] The term "pharmaceutically acceptable" is meant to refer to a compound, substance, or composition that is generally safe, non-toxic, and biologically tolerable.

[0117] As used herein, the phrase "pharmaceutically acceptable salts" refers to both pharmaceutically acceptable acid and base addition salts. Such pharmaceutically acceptable salts include those derived from alkanoic acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, and acetic acids; HOOC-(CH2) where n is 0-4; n -COOH, etc. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. One of ordinary skill in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0118] Those skilled in the art of medicinal chemistry will also understand that the disclosed structures are intended to include isotopically enriched forms of the compounds of the present invention. As used herein, "isotopes" include atoms with the same atomic number but different mass numbers. As known to those skilled in the art, certain atoms, such as hydrogen, occur in different isotopic forms. For example, hydrogen includes three isotopic forms: protium, deuterium, and tritium. In consideration of the compounds of the present invention, as will be apparent to those skilled in the art, certain compounds can be enriched at a given position with a specific isotope of the atom at that position. For example, a compound having a fluorine atom can be enriched with a radioactive fluorine isotope. 18 The compounds may be synthesized in a form enriched in F. Similarly, the compounds may be enriched with the heavier isotopes of hydrogen, deuterium and tritium, as well as 13 The compounds may be enriched with radioactive isotopes of carbon, such as C. Such isotopically variant compounds undergo different metabolic pathways and may be useful, for example, in studying the ubiquitination pathway and its role in disease. Of course, in certain embodiments, the compounds have substantially the same isotopic signature as the naturally occurring material.

[0119] The compounds of the present disclosure may contain chiral centers, which may be in either the (R) or (S) configuration, or may include mixtures thereof. Thus, the present invention also includes, where applicable, stereoisomers of the compounds described herein, individually or mixed in any proportion. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures (racemates), and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials or by separating isomers of the compounds of the present invention.

[0120] Isomers can also include tautomers and geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across double bonds. Other isomers are contemplated within the compounds of the present disclosure. Isomers can be used either in pure form or in mixtures with other isomers of the compounds disclosed herein.

[0121] Those skilled in the chemical arts will also understand that unless otherwise indicated, the disclosed structures are intended to encompass all possible stereoisomers of the claimed molecules, including mixtures of a particular or all stereoisomers. However, compounds drawn with a particular stereochemistry at one or more stereocenters represent compounds in that particular embodiment with the indicated stereochemistry. Compounds and stereocenters drawn with ambiguous stereochemistry are meant to convey any stereoisomer or mixture thereof, for example, a racemic mixture of a compound or a purified subset of stereoisomers. In some embodiments, compounds of the present disclosure may have the natural CBD-type stereochemistry, as shown below: [ka]

[0122] As used herein, the terms "individual," "patient," or "subject," when used interchangeably, refer to any animal, including a mammal, preferably a human.

[0123] As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response sought in a cell, tissue, system, animal, individual or human by a researcher, veterinarian, physician or other clinician.

[0124] In certain embodiments, the effective amount is: (i) inhibiting disease progression; and (ii) prophylactic use, e.g., preventing or limiting the onset of a disease, condition, or disorder in individuals who may be susceptible to or otherwise at risk for the disease, condition, or disorder, but who have not yet experienced or exhibited the pathology or symptomology of the disease; and (iii) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder; (iv) improving the referenced disease state, e.g., ameliorating the disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., ameliorating or improving the pathology and / or symptomology), such as reducing the severity of the disease; or (v) It may be an amount suitable for inducing the referenced biological effect.

[0125] As used herein, the terms "treatment" and "treating" mean (i) improving the referenced disease state, condition, or disorder (or a symptom thereof), e.g., reducing the severity of the disease, or a symptom thereof, in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., ameliorating or improving the pathology and / or symptomology), or (ii) inducing the referenced biological effect (e.g., inducing apoptosis or inhibiting glutathione synthesis).

[0126] As used herein, the term "preventing" or "prevent" means to completely or partially eliminate or delay the onset in a subject of a referenced disease state, condition, or disorder (or a symptom thereof).

[0127] Method of preparation Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001, or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0128] The compounds described herein can be purified by any means known in the art, including chromatographic means such as HPLC, preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal phase and reverse phase and ionic resin. Most typically, the disclosed compounds are purified through silica gel and / or alumina chromatography. For example, see Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.S.Nyder and J.J.Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed. E.Stahl, Springer-Verlag, New York, 1969. In a further embodiment, the compounds can be purified by preparative HPLC.

[0129] During any of the processes for the preparation of the compounds of interest, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is from JFW McOmie, “Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973, in TWGreene and PGMWuts, “Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press,London and New York 1981,in "Methoden der organischen Chemie,"Houben-Weyl,4.sup.th edition,Vol.15 / l,Georg Thieme Verlag,Stuttgart 1974,in H.-D.Jakubke and H.Jescheit,"Aminosauren,Peptide,Proteine,"Verlag Chemie,Weinheim,Deerfield Beach,and Basel 1982,and / or in Jochen This can be achieved by conventional protecting groups as described in standard texts such as Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate," Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0130] As used herein, a "leaving group" (e.g., suitable as LG) refers to the portion of a reactant (e.g., an alkyl halide of the present disclosure) that is displaced from a first reactant in a chemical reaction. A comprehensive and non-limiting list of suitable leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, NY (2013). Examples of suitable leaving groups include, but are not limited to, halogens (such as Cl or Br), acetoxy, and sulfonyloxy groups (such as methylsulfonyloxy, trifluoromethylsulfonyloxy ("triflate"), p-toluenesulfonyloxy ("tosylate"), etc.).

[0131] The compounds disclosed herein can be made using procedures familiar to those skilled in the art, for example, as described in Scheme 1, Scheme 2, Scheme 3, or Scheme 4 below (see, for example, He, X., et al., Org. Biomol. Chem., 16:5533-5538, 2018; Lin, F., et al., RSC Adv., 4:19856-19860, 2014; and Waugh, T.M., et al., ChemMedChem, 15:114-124; 2020). Those skilled in the art can adapt the reaction sequences of the schemes and examples provided herein to the desired target molecule. Of course, in certain circumstances, those skilled in the art will use different reagents to affect one or more of the individual steps or to use certain protected versions of substituents. Furthermore, those skilled in the art will recognize that the compounds of the present disclosure can be fully synthesized using different routes. For example, one of ordinary skill in the art may adapt the procedures described herein and / or other procedures well known to those of ordinary skill in the art to make the compounds described herein. [ka] In the formula, R 1 , R 2 , R 3, R 5a , and R 5b is as defined in formula (I). [ka] In the formula, R 1 , R 2 , R 3 , R 5a , and R 6 is as defined in formula (I). [ka] In the formula, R 1 , R 2 , R 3 , R 6 , and R 8 is as defined in formula (I). [ka] In the formula, R 5a is as defined in formula (I). [ka] In the formula, R 1 , R 2 , R 3 , R 5a , R 5b , and R 6 is as defined in formula (I). [ka] In the formula, R 5a and R 5b is as defined in formula (I). [ka] In the formula, R 1 , R 2 , R 3 , R 5a , R 5b , and R 6 is as defined in formula (I). [ka] In the formula, R 5a and R 5b is as defined in formula (I). [Example]

[0132] The preparation of the compounds of this disclosure is further illustrated by the following examples, which should not be construed in any way as limiting the disclosure in scope or spirit to the particular procedures and compounds described therein. These examples are provided to illustrate the invention.

[0133] Example 1: Preparation of 2,4-dihydroxy-3-(3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid [ka] A mixture of 2-(3-methylcyclohex-2-en-1-yl)-5-pentyl-benzene-1,3-diol (100 mg, 0.36 mmol) and magnesium methyl carbonate (MMC) solution (2.0 M in dimethylformamide (DMF), 1.82 mL) in a sealed vial was stirred at 110 °C for 2 h under nitrogen. The mixture was cooled, acidified with HCl 1N, and extracted with ethyl acetate (EtOAc). The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 2,4-dihydroxy-3-(3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid (64 mg, 0.2 mmol, 55% yield) as a red oil. 1H NMR(400MHz,CDCl3):δ12.0(1H,s),6.95(1H,br),6.28(1H,s),5.65(1H,br),4.07-4.02(1H,br),2.95-2 .82(2H,m),2.19-1.83(4H,m),1.81(3H,s),1.76-1.47(4H,m),1.39-1.30(4H,m),0.91(3H,t,J=7.0Hz). ESI-MS[MH] - :317.34.

[0134] Example 2: 7-Hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one (12c) [ka] To a solution of 2,4-dihydroxy-3-(3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid (22 mg, 0.069 mmol) and 4-phenylbut-3-yn-2-one (10 μL, 0.069 mmol) in dichloromethane (DCM, 0.5 mL) was added morpholine (1 μL, 0.014 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours and concentrated. The crude mixture was purified by column chromatography on silica gel (ethyl acetate-hexane) to afford 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one (47% yield) as a yellow oil. 1H NMR(400MHz,CDCl3):δ7.47-7.26(5H,m),6.76,6.60(1H,s),6.32,6.29(1H, s),5.57,5.53(1H,s),4.07-4.04(1H,m),3.26-3.17(2H,m),3.08-2.99(1H,m ),2.75-2.62(1H,m),2.30,2.26(3H,s),2.20-1.88(4H,m),1.84-1.73(4H,m) ,1.62-1.51(1H,m),1.45-1.31(2H,m),1.27-1.04(4H,m),0.84-0.79(3H,m). ESI-MS [M+Na]+: 485.35.

[0135] Example 3: 7-Hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (14c) [ka] To a solution of 2,4-dihydroxy-3-(3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid (30 mg, 0.094 mmol) and 3-butyn-2-one (7 μL, 0.094 mmol) in DCM (0.5 mL) was added morpholine (2 μL, 0.014 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours and concentrated. The crude mixture was purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (33% yield) as a yellow oil. 1H NMR (400 MHz, CDCl): δ 6.89 and 6.88 (1H, s), 6.47 (1H, s), 5.90-5.84 (1H, m), 5.60 and 5.58 (1H, s), 3.77-3.74 (1H, m), 3.23-3.05 (3H, m), 2.88-2.77 (1H, m), 2.28 and 2.27 (3H, s), 2.17-2.01 (2H, m), 1.91-1.80 (5H, m), 1.67-1.48 (4H, m), 1.37-1.33 (4H, m), 0.91-0.87 (3H, m). ESI-MS [M+Na]+: 409.30.

[0136] Example 4: 7-Hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (1c) [ka] A mixture of 2,4-dihydroxy-3-(3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid (30 mg, 0.094 mmol), tribasic potassium phosphate (40 mg, 0.19 mmol), and DCM (273 μL, 4.27 mmol) in DMF (0.75 mL) was stirred at 100 °C for 2 h in a sealed vial. The mixture was diluted with brine and extracted with EtOAc. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (DCM-hexane, then ethyl acetate-hexane) to give 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (13% yield). 1H NMR (400MHz, CDCl3): δ6.86(1H,s),6.48(1H,s),5.6(1H,br),5.53(2H,dd,J=8.5,5.0Hz),3.88-3.82(1H,m),3 .05-2.92(2H,m),2.18-1.84(4H,m),1.81(3H,s),1.73-1.45(4H,m),1.40-1.32(4H,m),0.89(3H,t,J=7.0Hz). ESI-MS [M+H]: 331.38, [M+Na]: 353.41, [MH]: 329.33.

[0137] Example 5: 7-Hydroxy-2,2-dimethyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (2c) [ka] Step 1: To a solution of ethyl 2,4-dihydroxy-6-pentyl-benzoate (500 mg, 1.98 mmol) in acetone (15 mL) was added potassium carbonate (822 mg, 5.95 mmol) and benzyl bromide (706 μL, 5.95 mmol). The mixture was refluxed for 18 hours and cooled to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic extract was dried over NaSO and concentrated to give ethyl 2,4-dibenzyloxy-6-pentyl-benzoate (850 mg, 1.97 mmol).

[0138] Step 2: A mixture of ethyl 2,4-dibenzyloxy-6-pentyl-benzoate (850 mg, 1.97 mmol), potassium hydroxide (400 mg, 7.13 mmol) in dimethyl sulfoxide (DMSO, 10 mL) and water (1 mL) was stirred at 90 °C for 18 h. The mixture was diluted with HCl 1N and extracted with DCM. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 2,4-dibenzyloxy-6-pentyl-benzoic acid (630 mg, 1.56 mmol, 78% yield over two steps).

[0139] Step 3: To a round-bottom flask containing Pd / C (312 mg, 2.93 mmol) was added EtOAc (5 mL). To this mixture was added a solution of 2,4-dibenzyloxy-6-pentyl-benzoic acid (625 mg, 1.55 mmol) in EtOAc (10 mL). The flask was backfilled with nitrogen and stirred under a hydrogen balloon for 18 h. The mixture was filtered through Celite, and the filtrate was concentrated to give 2,4-dihydroxy-6-pentyl-benzoic acid (305 mg, 1.36 mmol, 88%).

[0140] Step 4: To a solution of 2,4-dihydroxy-6-pentyl-benzoic acid (100 mg, 0.45 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.022 mmol), and acetone (49 μL, 0.67 mmol) in dimethoxyethane (DME, 0.5 mL) was added dropwise a solution of thionyl chloride (49 μL, 0.67 mmol) in DME (0.2 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, diluted with NaHCO and extracted with EtOAc. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-2,2-dimethyl-5-pentyl-1,3-benzodioxin-4-one (115 mg, 0.44 mmol, 98%).

[0141] Step 5: To a solution of 7-hydroxy-2,2-dimethyl-5-pentyl-1,3-benzodioxin-4-one (50 mg, 0.19 mmol) and p-toluenesulfonic acid monohydrate (4 mg, 0.019 mmol) in chloroform (3 mL) was added dropwise a solution of 1-methylcyclohex-2-en-1-ol (23 mg, 0.21 mmol) in chloroform (1.5 mL) over 2 min at 0 °C. After stirring at room temperature for 48 h, saturated aqueous NaHCO was added and the mixture was extracted with chloroform. The organic extract was concentrated and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-2,2-dimethyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-1,3-benzodioxin-4-one (13% yield). 1 H NMR (400MHz, CDCl3): δ6.76(1H,s),6.41(1H,s),5.59(1H,s),3.86-3.80(1H,m),3.01-2.96(2H,m),2.17-1.8 4(4H,m),1.80(3H,s),1.69(3H,s),1.66(3H,s),1.63-1.46(4H,m),1.39-1.29(4H,m),0.89(3H,t,J=7.0Hz). ESI-MS [M+Na]: 381.46, [MH]: 357.44.

[0142] Example 6: Preparation of 2,4-dihydroxy-3-(m-tolyl)-6-pentyl-benzoic acid [ka] A solution of 2-(m-tolyl)-5-pentyl-benzene-1,3-diol (150 mg, 0.55 mmol) in methyl magnesium carbonate solution (2 M in DMF, 2.77 mL) was stirred at 95° C. for 45 min. After cooling to room temperature, the mixture was acidified with HCl 1N and extracted with EtOAc. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 4-dihydroxy-3-(m-tolyl)-6-pentyl-benzoic acid (70 mg, 0.22 mmol, 40% yield). 1 H NMR (400MHz, CDCl3): δ11.9(1H,br),7.42(1H,t,J=7.5Hz),7.26-7.17(3H,m),6.48(1H,s),2. 95(2H,t,J=8.0Hz),2.41(3H,s),1.67-1.59(2H,m),1.39-1.33(4H,m),0.91(3H,t,J=7.0Hz). ESI-MS[M+H] + :315.1.

[0143] Example 7: 2-acetonyl-7-hydroxy-8-(m-tolyl)-5-pentyl-2-phenyl-1,3-benzodioxin-4-one (12a) [ka] To a solution of 2,4-dihydroxy-3-(m-tolyl)-6-pentyl-benzoic acid (15 mg, 0.048 mmol) and 4-phenylbut-3-yn-2-one (7 μL, 0.048 mmol) in DCM (0.5 mL) was added morpholine (1 μL, 0.01 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours and concentrated. The crude mixture was purified by column chromatography on silica gel (ethyl acetate-hexane) to give 2-acetonyl-7-hydroxy-8-(m-tolyl)-5-pentyl-2-phenyl-1,3-benzodioxin-4-one (17% yield). 1H NMR (400MHz, CDCl3): δ7.48(1H,t,J=7.5Hz),7.32(1H,d,J=7.5Hz),7.26-7.18(7H,m),6.50(1H,s),5.53(1H,s),3.14-3.05(1H,m) ,3.12(1H,d,J=14Hz),2.98(1H,d,J=14Hz),2.83-2.74(1H,m),2.47(3H,s),2.16(3H,s),1.51-1.13(6H,m),0.83(3H,t,J=7.0Hz). ESI-MS[M+Na]+:481.29.

[0144] Example 8: 7-Hydroxy-2,2-dimethyl-8-(m-tolyl)-5-pentyl-1,3-benzodioxin-4-one (2a) [ka] To a suspension of 2,4-dihydroxy-3-(m-tolyl)-6-pentyl-benzoic acid (16 mg, 0.050 mmol) in trifluoroacetic acid (TFA, 84 μL, 1.09 mmol), trifluoroacetic anhydride (TFAA; 42 mg, 0.19 mmol) and acetone (18 μL, 0.25 mmol) were added. After stirring at room temperature for 18 h, aqueous NaHCO was added and the mixture was extracted with EtOAc. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-2,2-dimethyl-8-(m-tolyl)-5-pentyl-1,3-benzodioxin-4-one (12% yield). 1 H NMR (400MHz, CDCl3): δ7.40(1H,t,J=7.5Hz),7.25(1H,d,J=7.5Hz),7.12-7.09(2H,m),6.61(1H,s),5.51(1 H,s),3.10-3.06(2H,m),2.41(3H,s),1.62(6H,s),1.55-1.36(6H,m),0.91(3H,t,J=7.0Hz),ESI-MS[M+Na] + :377.24, [M+H] + :355.23.

[0145] Example 9: 7-Hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-spiro[1,3-benzodioxin-2,1′-cyclopentan]-4-one (9c) [ka] To a solution of 2,4-dihydroxy-6-pentyl-benzoic acid (50 mg, 0.22 mmol), DMAP (1.4 mg, 0.01 mmol), and cyclopentanone (28 mg, 0.334 mmol) in dimethoxyethane (0.5 mL) was added dropwise a solution of thionyl chloride (24 μL, 0.33 mmol) in dimethoxyethane (0.2 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, diluted with aqueous NaHCO and extracted with EtOAc. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-5-pentyl-spiro[1,3-benzodioxin-2,1'-cyclopentan]-4-one (30 mg, 0.10 mmol, 46%).

[0146] To a solution of 7-hydroxy-5-pentyl-spiro[1,3-benzodioxin-2,1'-cyclopentan]-4-one (30 mg, 0.1 mmol) and p-toluenesulfonic acid monohydrate (9.8 mg, 0.05 mmol) in chloroform (2 mL) was added dropwise a solution of 1-methylcyclohex-2-en-1-ol (14 mg, 0.12 mmol) in chloroform (1 mL) over 2 min at 0 °C. After stirring at room temperature for 18 h, saturated aqueous NaHCO was added and the mixture was extracted with chloroform. The organic extract was concentrated and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-spiro[1,3-benzodioxin-2,1'-cyclopentan]-4-one (23% yield). 1H NMR (400MHz, CDCl3): δ6.74(1H,s),6.41(1H,s),5.58(1H,s),3.87-3.80(1H,s),2.98(2H,dd,J=9.0 ,6.5Hz),2.17-2.01(6H,m),1.90-1.47(10H,m),1.80(3H,s),1.37-1.33(4H,m),0.90-0.87(3H,m). ESI-MS[M+Na]+:407.46.

[0147] Example 10: 7-Hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (1d) [ka] A mixture of cannabidiolic acid (CBDA; 72 mg, 0.20 mmol), KPO (85 mg, 0.40 mmol), and DCM (0.50 mL) in DMF (1 mL) was stirred at 100 °C for 1.5 h in a sealed vial. The mixture was diluted with brine and extracted with EtOAc. The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane), followed by reverse-phase C (CHCN-HO) to give 7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (13% yield). 1 H NMR (400MHz, CDCl3): δ6.63(1H,s),6.48(1H,s),5.56(1H,s),5.48(1H,d,J=5.0Hz),5.31(1H,d,J=5.0Hz),4.54-4.52(1H,m),4 .27(1H,s),3.87-3.83(1H,m),3.03-2.92(2H,m),2.32-2.13(3H,m),1.82-1.48(10H,m),1.38-1.29(4H,m),0.90-0.87(3H,m). ESI-MS[M+H]+:371.24.

[0148] Example 11: 7-Hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one (12d) [ka] To a solution of CBDA (73 mg, 0.20 mmol) and 4-phenylbut-3-yn-2-one (30 μL, 0.20 mmol) in DCM (1.5 mL) was added morpholine (4 μL, 0.041 mmol) at room temperature. The mixture was stirred at room temperature for 24 h and concentrated. The crude mixture was purified by column chromatography on silica gel (ethyl acetate-hexanes) followed by reverse-phase C18 (CH3CN-HO) to give 7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one (27% yield). 1 H NMR (400MHz, DMSO-d6): δ10.53(1H,br),7.45-7.31(5H,m),6.30 and 6.25(1H,s),5.11(1H,s),4.56-4.44(2H,m), 3.96-3.95(1H,m),3.38-2.93(4H,m),2.51-1.98(5H,m),1.80-1.59(8H),1.30-0.98(7H),0.77(3H,t,J=7.0Hz). ESI-MS[M+H] + :503.30.

[0149] Example 12: 7-Hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (14d) [ka] To a solution of CBDA (100 mg, 0.28 mmol) and 3-butyn-2-one (22 μL, 0.28 mmol) in DCM (2 mL) was added morpholine (5 μL, 0.056 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours and concentrated. The crude mixture was purified by column chromatography on silica gel (ethyl acetate-hexane, followed by DCM) to give 7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (19% yield). 1 H NMR (400 MHz, CDCl3): δ 6.69 and 6.61 (1H, s), 6.49 and 6.48 (1H, s), 5.85 (t, J = 5.0 Hz) and 5.70 (1H, dd, J = 7.5, 3.0 Hz), 5.54 (1H, s), 4.58-4.54 (1H, m), 4.34 and 4.26 (1H, s), 3.79-3.76 (1H, m), 3.23-2.74 (5H, m), 2.34-2.08 (5H, m), 1.84-1.60 (10H, m), 1.36-1.33 (4H, m), 0.91-0.87 (3H, m). ESI-MS [M+H] + :427.20.

[0150] Example 13: 7-Hydroxy-2,2-dimethyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (2d) [ka] To a stirred solution of 7-hydroxy-2,2-dimethyl-5-pentyl-1,3-benzodioxin-4-one (70 mg, 0.26 mmol), MgSO (20 mg), and camphor-10-sulfonic acid (β) (12 mg, 0.53 mmol) in dry DCM (2 mL) at room temperature was added a solution of 1-methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol (44 mg, 0.29 mmol) in DCM (2 mL) dropwise over 1 h. The mixture was stirred at room temperature for 18 h, diluted with aqueous NaHCO, and extracted with DCM. The organic extract was dried over Na2SO4, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexanes) followed by reverse-phase C18 (CH3CN-HO) to give 7-hydroxy-2,2-dimethyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (7% yield). 1 H NMR (400MHz, CDCl3): δ6.45(1H,s),6.41(1H,s),5.49(1H,s),4.53(1H,s),4.40(1H,s),3.86-3.82(1H,m),2.99(2H,t,J=7.5Hz),2. 43-2.09(3H,m),1.84-1.72(5H,m),1.67(3H,s),1.66(3H,s),1.61(3H,s),1.60-1.51(2H,m),1.36-1.32(4H,m),0.90-0.86(3H,m). ESI-MS[M+H] + :399.20.

[0151] Example 14: 7-Hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (11d) [ka] To a solution of olivetolic acid (200 mg, 0.89 mmol), DMAP (5 mg, 0.044 mmol), and methoxyacetone (118 mg, 1.34 mmol) in DME (1 mL) was added dropwise a solution of thionyl chloride (98 μL, 1.34 mmol) in DME (0.5 mL) at 0 °C. The mixture was stirred at room temperature for 3 h, diluted with aqueous NaHCO3, and extracted with EtOAc. The organic extract was dried over Na2SO4, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane) to give 7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-1,3-benzodioxin-4-one (120 mg, 46% yield).

[0152] To a stirred solution of 7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-1,3-benzodioxin-4-one (70 mg, 0.24 mmol), camphor-10-sulfonic acid (β) (5.5 mg, 0.024 mmol) in dry DCM (2 mL) was added a solution of 1-methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol (54 mg, 0.36 mmol) in DCM (2 mL) over 1 h at room temperature. The mixture was stirred at room temperature for 3 h, diluted with NaHCO3, and extracted with DCM. The organic extract was dried over Na2SO4, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexanes) followed by reverse-phase C18 (CH3CN-HO) to give 7-hydroxy-2-(methoxymethyl)-2-methyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (2% yield). 1H NMR(400MHz,CDCl3):δ6.51(1H,br),6.45-6.44(1H,s),5.51(1H,br),4.58-4.56(1H,s),4.42(1H,br),3.89(1H,m),3.68-3.56(2H,m),3.45-3.44( 3H,s),3.11-2.92(2H,m),2.42-2.11(3H,m),1.84-1.77(5H,m),1.70(3H, s),1.65-1.64(3H,s),1.58(2H,m),1.38-1.33(4H,m),0.93-0.89(3H,m). ESI-MS[M+Na]+:451.40.

[0153] Example 15: 7-Hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (16d) [ka] A mixture of CBDA (100 mg, 278.96 μmol), KPO (118 mg, 0.56 mmol), and 1,1-dichloroethane (0.5 mL) in DMF (1.0 mL) was stirred at 130 °C for 18 h in a sealed vial. The mixture was diluted with EtOAc and washed with brine (three times). The organic extract was dried over NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate-hexane), followed by reverse-phase C (CHCN-HO) to give 7-hydroxy-2-methyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (21% yield). 1H NMR (400MHz, CDCl3): δ6.63-6.40(2H,m),5.56-5.34(2H,m),4.66-4.23(2H,m),3.88-3.82(1H,m),3.24-3 .75(2H,m),2.51-2.09(3H,m),1.81-1.73(5H,m),1.67-1.54(8H,m),1.36-1.30(4H,m),0.90-0.87(3H,m). ESI-MS[M+H] + :384.90.

[0154] Example 16: 2-Ethyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (17d) [ka] A mixture of CBDA (50 mg, 0.14 mmol), KPO (59 mg, 0.28 mmol), and 1,1-dichloropropane (0.30 mL) in DMF (0.60 mL) was stirred at 130 °C for 4 h in a sealed vial. The mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over NaSO, concentrated, and purified using reverse-phase C column chromatography (CHCN-HO) to give 2-ethyl-7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (23% yield). 1H NMR(400MHz,CDCl3):δ6.63(s),6.55(1H,s),6.46(s),6.45(s,1H),5.56(s),5.53(1H, s),5.37(t,J=5.0Hz),5.22(1H,dd,J=4.0Hz),4.55-4.52(1H,m),4.34(s),4.26(1H,s), 3.87-3.82(1H,m),3.24-2.75(2H,m),2.40-2.08(3H,m),2.02-1.88(2H,m),1.85-1.75 (5H,m),1.67-1.52(5H,m),1.36-1.31(4H,m),1.10(3H,t,J=7.5Hz),0.90-0.87(3H,m). ESI-MS[M+H]+:398.90.

[0155] Example 17: 7-Hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (7d) [ka] To a solution of olivetolic acid (200 mg, 0.89 mmol), DMAP (5 mg, 0.044 mmol), and 2,4-pentanedione (134 mg, 1.34 mmol) in dimethoxyethane (1 mL) was added dropwise a solution of thionyl chloride (98 μL, 1.34 mmol) in dimethoxyethane (0.5 mL) at 0 °C. The mixture was stirred at room temperature for 3 h, diluted with aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate-hexane) to give 2-acetonyl-7-hydroxy-2-methyl-5-pentyl-1,3-benzodioxin-4-one (110 mg, 40% yield).

[0156] To a stirred solution of 2-acetonyl-7-hydroxy-2-methyl-5-pentyl-1,3-benzodioxin-4-one (85 mg, 0.28 mmol), camphor-10-sulfonic acid (β) (6.5 mg, 0.028 mmol) in dry DCM (2 mL) was added a solution of (1S,4R)-4-isopropenyl-1-methyl-cyclohex-2-en-1-ol (63 mg, 0.42 mmol) in DCM (2 mL) at room temperature over 1 h. The mixture was stirred at room temperature for 3 h, diluted with aqueous NaHCO3, and extracted with DCM. The organic extract was dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate-hexanes) followed by reverse-phase C18 (CH3CN-HO) to give 7-hydroxy-2-methyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (1% yield). 1 H NMR(400MHz,CDCl3):δ6.55(1H,s),6.45(1H,s),5.47(1H,s),4.53(1H,s),4.38(1H,s),3.82-3.80(1 H,m),3.18-2.85(4H,m),2.38-2.09(6H,m),1.80-1.55(13H,m),1.37-1.31(4H,m),0.90-0.87(3H,m). ESI-MS[M+Na]+:463.41.

[0157] Example 18: 7-Hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one (3d) [ka] A mixture of CBDA (50 mg, 0.14 mmol), KPO (59 mg, 0.28 mmol), and α,α-dichlorotoluene (0.2 mL) in DMF (0.6 mL) was stirred at 120 °C for 18 h in a sealed vial. The mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate-hexanes), followed by reverse-phase C (CHCN-HO) to give 7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one (21%). 1 H NMR (400MHz, CDCl3): δ7.62-7.44(5H,m),6.68-6.52(2H,m),6.31(s),6.14(1H,s),5.57(s),5.54(1H,s),4.58(s),4.55(1H,s),4.3 6(s),4.26(1H,s),3.90-3.84(1H,m),3.28-2.81(2H,m),2.39-2.20(3H,m),1.80-1.65(9H,m),1.41-1.34(5H,m),0.92-0.88(3H,m). ESI-MS[M+H]+:446.90.

[0158] Example 19: Preparation of cannabidivarinic acid [ka] A suspension of cannabidivarin (620 mg, 2.16 mmol) in magnesium methyl carbonate (MMC) solution (10.82 mL, 2.0 M in DMF) was stirred at 110° C. for 1.5 hours. After cooling to room temperature, the mixture was acidified with HCl 1N and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and concentrated. The crude mixture was dissolved in Et2O and extracted with aqueous NaOH (2N). The aqueous extract was acidified with HCl 1N until a precipitate appeared, and the mixture was extracted with Et2O. The organic extract was dried over Na2SO4 and concentrated to give cannabidivarinic acid (298 mg, 42% yield). 1H NMR (400MHz, CDCl3): δ11.89(1H,s),6.63(1H,s),6.25(1H,s),5.56(1H,s),4.54(1H,s),4.39(1H,s),4.11-4.0 8(1H,m),2.94-2.76(2H,m),2.39-2.04(4H,m),1.80(3H,s),1.72(3H,s),1.61-1.59(4H,m),0.97-0.92(3H,m). ESI-MS[MH]-:328.90.

[0159] Example 20: 7-Hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one (23d) [ka] A mixture of cannabidivarin (100 mg, 0.30 mmol), KPO (128 mg, 0.61 mmol), and DCM (0.50 mL) in DMF (1.0 mL) was stirred at 100 °C for 1.5 h in a sealed vial. The mixture was diluted with brine and extracted with ethyl acetate. The organic extract was dried over NaSO, concentrated, and purified by reverse-phase column chromatography (C18) (CHCN-HO) to give 7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one (11% yield). 1 H NMR(400MHz,CDCl3):δ6.64(1H,s),6.48(1H,s),5.56(1H,s),5.48(1H,d,J=5.0Hz),5.31(1H,d,J=5.0Hz),4.53-4.52(1H,m),4.27(1H,s),3.8 7-3.83(1H,m),2.96(2H,t,J=7.5Hz),2.34-2.09(3H,m),1.82(3H,s),1 .82-1.73(2H,m),1.65(3H,s),1.65-1.54(2H,m),0.96(3H,t,J=7.0Hz). ESI-MS[M+H]+:342.90.

[0160] Example 21: 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one (24d) [ka] To a solution of cannabidivaric acid (100 mg, 0.30 mmol) and 4-phenylbut-3-yn-2-one (44 μL, 0.30 mmol) in DCM (2 mL) was added morpholine (5 μL, 0.060 mmol) at room temperature. The mixture was stirred at room temperature for 24 h and concentrated. The crude material was purified by flash chromatography on silica gel (ethyl acetate-hexanes) followed by reverse-phase C18 (CH3CN-HO) to give 7-hydroxy-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one (38% yield). 1 H NMR (400MHz, CDCl3): δ7.58-7.26(5H,m),6.67(s),6.37(1H,s),6.40(s),6.28(1H,s),5.52(s),5.45(1H,s),4.68(s),4.39(1H,s),4.60(1H ,s),4.06-4.04(1H,m),3.22-2.37(5H,m),2.28-1.99(5H,m),1.86-1. 83(5H,m),1.70(s),1.67(3H,s),1.49-1.35(2H,m),0.86-0.72(3H,m). ESI-MS[M+H]+:474.90.

[0161] Example 22: The following compounds may be prepared according to procedures known to those skilled in the art, for example, in view of Scheme 1 and / or Schemes 2a-2c and / or Schemes 3a-3b and / or Schemes 4a-4b and Examples 1-21.

number

[0162] The present disclosure also provides a method for preparing a phenolic alcohol comprising: [ka] In certain embodiments, the substituent is [ka] are (methoxy)methyl, (2-methoxyethoxy)methyl, (2-methoxy)propan-2-yl, (2,5,8,11,14-pentaoxa)hexadecan-15-yl, ((ethoxycarbonyl)oxy)methyl, ((ethoxycarbonyl)oxy)ethyl-1-yl, ((2-methoxyethoxycarbonyl)oxy)ethyl-1-yl, ((tert-butylcarbonyl)oxy)methyl, ((2-ethylbutylcarbonyl)oxy)methyl, ((acetonitrile) The substituents may be (7-methoxymethoxy)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, (((2-methoxyethyl)oxy)carbonyl)(methyl)amino)methyl, (((2,5,8,11-tetraoxatridecan-13-yl)oxy)carbonyl)(methyl)amino)methyl, ((methoxycarbonyl)(phenyl)amino)methyl, ((methoxycarbonyl)(4-nitrophenyl)amino)methyl, or (1-methoxy)cyclopentyl. For example, when substituted with a (methoxy)methyl substituent, such an analog of compound 1a is (7-methoxymethoxy)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, and analogs of all other compounds in such table are specifically contemplated.

[0163] Radioligand competitive binding assay - CB1 and CB2 Example 23: Compounds of the present disclosure were tested for CB1 receptor binding affinity and CB2 receptor binding affinity. As used herein, "binding affinity" refers to the experimentally determined IC50 as described herein. 50 It is represented by the value IC 50 The lower the value, the higher the binding affinity. A compound of the present disclosure is said to have "binding selectivity" if it has a higher binding affinity for one receptor than the other. For example, an IC of 1 μM for CB1 and 0.1 μM for CB2. 50 Compounds with the formula are 10-fold more selective for the CB2 receptor.

[0164] Preparation of CB1 membranes Membranes were prepared from CHO-K1 (Chinese hamster ovary) cells stably transfected with the human CB1 receptor (catalog no. ES-110-C, Perkin Elmer, Boston, MA). Cells were grown adherently and maintained in HAM's F12 medium containing 10% fetal bovine serum (FBS), penicillin, streptomycin, and geneticin (G418) at 37°C in a humidified atmosphere of 5% CO2 according to the manufacturer's instructions.

[0165] For membrane preparation, cells were washed with PBS and scraped off the plates in cold homogenization buffer (25 mM HEPES (pH 7.4), 2 mM EDTA) containing a protease inhibitor cocktail (Sigma catalog no. P8340). The cell suspension was homogenized using a Pro-PK-01200D Polytron homogenizer (Pro Scientific) and then centrifuged at 120,000 × g for 30 minutes. The supernatant was discarded, and the pellet was resuspended in homogenization buffer and stored at -80 °C until use.

[0166] CB1 Radioligand Binding Assay: CP55,940 is a synthetic cannabinoid that mimics the effects of naturally occurring THC. CP55,940 acts as a full agonist at both the cannabinoid CB1 and CB2 receptors. Radiolabeled ligands represent one of the most sensitive methods for probing receptor binding biology. In this experiment, 3H-radiolabelled CP55,940, i.e., [3H]CP55,940 (Perkin Elmer, Boston, MA), was used as the radioligand for the CB1 receptor.

[0167] The [3H]CP55,940 displacement assay was used to determine the binding affinity of the compounds to the CB1 receptor (Scheme 5, below).

[0168] [ka] Competitive binding experiments (single dose and dose response) were performed by incubating 0.8 nM [H]CP55,940 (specific activity 101 Ci / mmol, Perkin Elmer) and different concentrations of the compounds disclosed herein with membranes prepared as described above from CHO-K1 cells expressing human CB1 receptors (6 μg protein / well), 50 mM Tris-HCl (pH 7.4), 5 mM MgCl, 1 mM CaCl, and 2 mg / mL BSA.

[0169] For single dose experiments, compound stocks (usually 10 mM in DMSO) were diluted to working stocks in binding buffer to give final compound concentrations of 10 μM and 1 μM. For dose-response experiments, test compounds were serially diluted to determine the IC 50 The desired concentration range for determination was obtained. In each case, the compound was pre-incubated with the membrane for 20 minutes before the addition of the radioligand.

[0170] After incubation with the radioligand for 60 minutes at 37°C, the MultiScreen® plates were presoaked for 60 minutes in 50 mM Tris-HCl (pH 7.4) containing 0.33% polyethyleneimine (PEI). HTS + Incubations were terminated by rapid filtration of the assay mixture through a 96-well filter plate (Millipore, catalog no. MSFCNXB). Nonspecific binding (NSB) was determined in the presence of 10 μM unlabeled CP55,940. After drying the filter plates at 50°C for at least 60 minutes, filter-bound radioactivity was determined by scintillation spectroscopy using a 1450 MicroBeta plate counter (Perkin Elmer, Boston, MA). From dose-response experiments, the IC 50 The values ​​were determined (Table 1, CB1 IC 50 (See

[0171] Some compounds of the present disclosure have shown selectivity for the CB1 receptor over the CB2 receptor (see, for example, Table 1). In Table 1 below, the fold difference in selectivity between CB1 and CB2 is shown, with the fold difference presented in the column for the receptor that showed the higher binding affinity (i.e., CB1 or CB2). If the test compound has approximately the same affinity for both receptors, this is represented by a value of 1.00 in the column for both receptors.

[0172] Preparation of CB2 membranes Membranes were prepared from CHO-K1 (Chinese hamster ovary) cells stably transfected with the human CB2 receptor (catalog no. ES-111-C, Perkin Elmer, Boston, MA). Cells were grown adherently and maintained in HAM's F12 medium containing 10% fetal bovine serum (FBS), penicillin, streptomycin, and geneticin (G418) at 37°C in a humidified atmosphere of 5% CO2 according to the manufacturer's instructions.

[0173] For membrane preparation, cells were washed with PBS and scraped off the plates in cold homogenization buffer (25 mM HEPES (pH 7.4), 2 mM EDTA) containing a protease inhibitor cocktail (Sigma catalog no. P8340). The cell suspension was homogenized using a Pro-PK-01200D Polytron homogenizer (Pro Scientific) and then centrifuged at 120,000 × g for 30 minutes. The supernatant was discarded, and the pellet was resuspended in homogenization buffer and stored at -80 °C until use.

[0174] CB2 radioligand binding assay In this experiment, 3H radiolabeled CP55,940, i.e., [3H]CP55,940 (Perkin Elmer, Boston, MA), was used as the radioligand for the CB2 receptor to determine the binding affinity of the compounds to the CB2 receptor (Scheme 5, above).

[0175] Competitive binding experiments (single dose and dose response) were performed by incubating 0.6 nM [H]CP55,940 (specific activity 101 Ci / mmol, Perkin Elmer) and different concentrations of the compounds disclosed herein with membranes prepared as described above from CHO-K1 cells expressing human CB2 receptors (1 μg protein / well), 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 1 mM CaCl2, and 2 mg / mL BSA.

[0176] For single dose experiments, compound stocks (usually 10 mM in DMSO) were diluted to working stocks in binding buffer to give final compound concentrations of 10 μM and 1 μM. For dose-response experiments, test compounds were serially diluted to determine the IC 50 The desired concentration range for determination was obtained. In each case, the compound was pre-incubated with the membrane for 20 minutes before the addition of the radioligand.

[0177] After incubation with the radioligand for 60 minutes at 37°C, the MultiScreen® plates were presoaked for 60 minutes in 50 mM Tris-HCl (pH 7.4) containing 0.33% polyethyleneimine (PEI). HTS + Incubations were terminated by rapid filtration of the assay mixture through a 96-well filter plate (Millipore, catalog no. MSFCNXB). Nonspecific binding (NSB) was determined in the presence of 10 μM unlabeled CP55,940. After drying the filter plates at 50°C for at least 60 minutes, filter-bound radioactivity was determined by scintillation spectroscopy using a 1450 MicroBeta plate counter (Perkin Elmer, Boston, MA). From dose-response experiments, the IC 50 The values ​​were determined (Table 1, CB2 IC 50 (See

[0178] Some compounds of the present disclosure have shown selectivity for the CB2 receptor over the CB1 receptor (see, for example, Table 1). Again, in Table 1 below, the fold difference in selectivity between CB1 and CB2 is shown, with the fold difference presented in the column for the receptor that showed the higher binding affinity (i.e., CB1 or CB2). If the test compound has approximately the same affinity for both receptors, this is represented by a value of 1.00 in the columns for both receptors. [Table 1]

[0179] Radioligand competitive binding assay-5HT1A Example 24: 8-OH-DPAT is a chemical from the aminotetralin chemical class that is widely used to study the function of the 5HT1A receptor. 8-OH-DPAT was one of the first major 5HT1A receptor full agonists discovered. Radiolabeled ligands represent one of the most sensitive methods for probing receptor binding biology. In this experiment, 3H-radiolabelled 8-OH-DPAT, i.e., [3H]8-OH-DPAT (Perkin Elmer, Boston, MA), was used as the radioligand for the 5HT1A receptor.

[0180] Preparation of 5HT1A membranes Membranes were prepared from CHO-K1 (Chinese hamster ovary) cells stably transfected with the human 5HT1A receptor (catalog no. ES-310-C, Perkin Elmer, Boston, MA). Cells were grown adherently and maintained in advanced DMEM / F12 containing 2.5% dialyzed FBS, penicillin, streptomycin, and geneticin (G418) at 37°C in a humidified atmosphere of 5% CO2 according to the manufacturer's instructions.

[0181] For membrane preparation, cells were washed with PBS and scraped off the plates in cold homogenization buffer (25 mM HEPES (pH 7.4), 2 mM EDTA) containing a protease inhibitor cocktail (Sigma catalog no. P8340). The cell suspension was homogenized using a Pro-PK-01200D Polytron homogenizer (Pro Scientific) and then centrifuged at 120,000 × g for 30 minutes. The supernatant was discarded, and the pellet was resuspended in homogenization buffer and stored at -80 °C until use.

[0182] 5HT1A radioligand binding assay The [3H]8-OH-DPAT displacement assay was used to determine the binding affinity of the compounds to the 5HT1A receptor (Scheme 6, below).

[0183] [ka] Competitive binding experiments (single dose and dose response) were performed by incubating 0.8 nM [H]8-OH-DPAT (specific activity 200 Ci / mmol, Perkin Elmer) and different concentrations of the compounds disclosed herein with membranes prepared as described above from CHO-K1 cells expressing human 5HT receptors (20 μg protein / well), 50 mM Tris-HCl (pH 7.4), 10 mM MgSO, 0.5 mM EDTA, and 0.1% ascorbic acid.

[0184] For single dose experiments, compound stocks (usually 10 mM in DMSO) were diluted to working stocks in binding buffer to give final compound concentrations of 10 μM and 1 μM. For dose-response experiments, test compounds were serially diluted to determine the IC 50 The desired concentration range for determination was obtained. In each case, the compound was pre-incubated with the membrane for 20 minutes before the addition of the radioligand.

[0185] After incubation with the radioligand for 60 minutes at 27°C, the MultiScreen® plates were presoaked for 60 minutes in 50 mM Tris-HCl (pH 7.4) containing 0.33% polyethyleneimine (PEI). HTS + Incubations were terminated by rapid filtration of the assay mixture through a 96-well filter plate (Millipore, catalog no. MSFCNXB). Nonspecific binding (NSB) was determined in the presence of 10 μM unlabeled 8-OH-DPAT. After drying the filter plate at 50°C for at least 60 minutes, filter-bound radioactivity was determined by scintillation spectroscopy using a 1450 MicroBeta plate counter (Perkin Elmer, Boston, MA).

[0186] Compounds of the present disclosure exhibited IC50s at the human 5HT1A receptor in the range of about 2.1 to about 5.0 μM.

[0187] Simulated gastric fluid (SGF) assay Example 25: In a microcentrifuge tube, 626.5 μL of a solution containing 1.1x assay buffer (37.6 mM NaCl, pH 1.2-1.5) was diluted with 70 μL of 10x pepsin solution (Sigma-Aldrich Co. Catalog No. P7012, 80,000 U / mL in milliQ water). The resulting solution was incubated in an orbital mixer at 37 °C and 1,200 rpm for 5 min before adding 3.5 μL of test compound (2 mM, DMSO). Samples were incubated under the same conditions for as long as needed.

[0188] At the designated time points, 150 μL sample aliquots were transferred to microcentrifuge tubes containing 24 μL of acid quench solution (0.5 M NaHCO3). After vortexing the tubes for 5 seconds, 348 μL of protein precipitation solution containing an internal standard (25 μM glyburide, ACN) was added. The tubes were vortexed again for 20 seconds and stored on ice.

[0189] Finally, the tubes were centrifuged for 15 min at 5,000 × g and 4° C. The remaining percentage of test compound compared to time 0 was quantified in the supernatant by HPLC / LC-MS or LC-MS / MS.

[0190] Compounds of the present disclosure tested in the SGF assay exhibited half-lives ranging from about 4 minutes to 56 minutes, and the half-lives were found to be tunable (and adjustable) based on substituent modifications of the compounds.

[0191] Further Biological Examples Example 26: TRP activation: measurement of cation flux by intracellular calcium detection Transient receptor potential ion channels (TRPs) are nonselective, ligand-gated cation channels that integrate a variety of physical and chemical stimuli. Upon activation, these channels translocate Ca 2+ This leads to the gating of cations, including ATP, thus generating changes in intracellular calcium concentration. The single-wavelength fluorescent indicator Fluo-4 acetoxymethyl (AM) is used to measure intracellular calcium flux and concentration in cells expressing TRPs and stimulated with cannabinoids. The Fluo-4 Direct™ Calcium Assay Kit (Molecular Probes, Invitrogen, Carlsbad, CA, USA) allows for the direct addition of reagents to microplate wells containing cultured cells without the need for medium removal or washing steps, thus facilitating the process of target screening.

[0192] Human embryonic kidney (HEK-293) cells are used to express different TRPs, including TRPV1 and TRPV2, as adapted from Moriello et al. ("Assay of TRPV1 Receptor Signaling," Methods In Molecular Biology (2016) 1412:65-76, incorporated herein by reference). Cells are grown in Eagle's minimum essential medium supplemented with 10% fetal bovine serum (FBS), 1% penicillin and streptomycin (pen / strep), and maintained in an incubator at 37°C in 5% CO2. Cells are seeded into 96-well plates and polyethyleneimine (PEI) media, which are used to transiently transfect HEK-293 cells with expression vectors containing the open reading frames (ORFs) of the TRPs of interest. As a negative control, transfections using an empty expression vector are performed.

[0193] 24-48 hours after transfection, cells are treated with Fluo-4 Direct™ (Molecular Probes) for 30-60 minutes, followed by exposure to cannabinoids and benchmark compounds for different periods of time. After incubation, fluorescence is measured using a microplate reader (excitation at 494 nm and emission at 516 nm).

[0194] Data analysis is performed by generating a nonlinear regression curve and all data points corrected for background fluorescence and the negative control. Agonist responses are normalized to the effect of a reference agonist, and antagonist responses are normalized to the EC50 of the reference agonist. 80 was normalized to

[0195] Example 27: PPARγ Activation: Nuclear Hormone Receptor Activation Assay Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptors (NHRs). The Pathhunter® PPARγ Protein Interaction Assay (DiscoverX, Fremont, CA, USA) reports activation of NHRs based on enzyme complementation of β-galactosidase, rendering a chemiluminescent signal.

[0196] We use the CHO-K1 PPARγ cell line (DiscoverX), which stably expresses the target receptor. Cells are grown using reagents provided by the manufacturer (DiscoverX) and maintained in an incubator at 37°C in 5% CO2. Cells are harvested and seeded into black-skirted, clear-bottom 96-well plates, allowed to adhere overnight, and then recovered. Subsequently, cells are incubated with cannabinoids and / or benchmark compounds such as troglitazone and rosiglitazone for 30–90 minutes at 37°C in 5% CO2. Then, detection reagents (DiscoverX) provided by the manufacturer are added to the wells, and the plate is incubated in the dark for 1 hour, followed by chemiluminescence detection using a microplate reader. Data analysis is performed by generating nonlinear regression curves and all data points corrected for background luminescence and negative control. Agonist responses are normalized to the effect of a reference agonist, and antagonist responses are normalized to the EC50 of the reference agonist. 80 Basal activity of the cells is set to 0%.

[0197] Throughout this application, numerous references are made to patents and printed publications. Each of the cited patents and printed publications is herein individually incorporated by reference in its entirety.

[0198] Finally, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, and not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings herein. Accordingly, the invention is not limited to that precisely as shown and described.

Claims

1. Structural formula: 【Chemistry 1】 A compound having the formula: 【Chemistry 2】 The part is, 【Chemistry 3】 and R 1 is hydrogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl or C 2 -C 8 is alkynyl, R 2 is hydrogen, C 1 -C 8 Alkyl, hydroxy, -CO 2 H, -CO 2 (C 1 -C 8 alkyl), or, when attached to an appropriately saturated ring, oxo; 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, R 3a and R 3b are each independently hydrogen or C 1 -C 6 is alkyl, R 4 is hydrogen, -CO 2 H, or -CO 2 (C 1 -C 6 alkyl), R 5a and R 5b But 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 and 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 Or R 5a and R 5b together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; Q 5 is O, S or NR 5e and 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, and 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), R 6 is hydrogen, hydroxy or 【Chemistry 4】 where: R 6a and R 6b However, 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 and 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 the nitrogen atom to which they are attached form a heterocycloalkyl ring, or Or R 6a and R 6b together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; Q 6 But, -Y 6 R 6e Or -NR 6f R 6g and 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, R 5e and R 5f are independently deuterium, or R 6f and R 6g form a heterocycle together with the nitrogen to which they are attached, and 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), During the ceremony, Each alkyl, alkenyl and alkynyl is unsubstituted, fluorinated, chlorinated, substituted with one or two hydroxyl or C 1 -C 6 substituted with an alkoxy group or with one or two oxo groups; Each cycloalkyl has 3 to 10 ring carbons, is unsaturated or partially unsaturated, and optionally contains 1 or 2 fused cycloalkyl rings, each fused ring having 3 to 8 ring members and 0 to 6 R 7 is replaced by Each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each of which is independently nitrogen, oxygen, or sulfur, is unsaturated or partially unsaturated, and optionally contains 1 or 2 fused cycloalkyl rings, each of which has 3 to 8 ring members and 0 to 6 R 7 is replaced by Each aryl is phenyl or naphthyl and optionally contains 1 or 2 fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having from 4 to 8 ring members and 0 to 5 R 8 is replaced by Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, each independently, nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms, each independently, nitrogen, oxygen, or sulfur, and optionally contains 1 or 2 fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members and 0-5 R 8 is replaced by During the ceremony, Each R 7 independently, oxo, C 1 -C 4 Alkyl (e.g., —CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CHF 2 ), -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 N.R. 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 ) N.R. B R A or -NR B S (O) 1-2 N.R. B R A and Each R 8 is independently an optionally substituted C 1 -C 4 Alkyl (e.g., —CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CHF 2 ), -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 N.R. 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 ) N.R. B R A or -NR B S (O) 1-2 N.R. B R A and Each R A are independently H or C 1 -C 3 alkyl, and each R B However, 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, combine to form an unsubstituted heterocycloalkyl ring of 3 to 6 ring members, or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharma- ceutically acceptable salt, solvate, or hydrate of said compound, enantiomer, diastereomer, racemate, tautomer, or metabolite.

2. The part 【Chemistry 5】 but, 【Chemistry 6】 2. The compound of claim 1,

3. R 1 is hydrogen or a substituted or unsubstituted C 1 -C 4 Alkyl or C 2 -C 4 3. The compound of claim 1 or 2, which is alkenyl or isopropenyl.

4. R 2 is hydrogen, C 1 -C 4 Alkyl, C 1 -C 6 alkyl, hydroxy, -CH 2 OH, -CO 2 H, -CO 2 (C 1 -C 4 4. The compound according to claim 1, wherein the aryl group is aryl, aryloxy ...

5. R 3 is hydrogen, C 1 -C 12 Alkyl, C3-C9 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 1 -C 2 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, -(C 0 -C 4 5. The compound of claim 1, wherein R 3 is heterocycloalkyl-(C 1 -C 2 alkyl)-heterocycloalkyl, n-pentyl, 1,1-dimethylheptyl, n-propyl, piperidinyl, pyrrolidinyl, azetidinyl, or aziridinyl, or R 3 is azetidinyl and is substituted with one to two R 7 which are independently oxo, C 1 -C 4 alkyl, -Cl, -F, -Br, -C(O)R A , or -CO 2 R A , where R A is H or C 1 -C 3 alkyl.

6. R 3 is azetidinyl substituted with 1 to 2 R 7 , and R 7 is -C(O)CH 3 6. The compound of claim 5,

7. The compound has the formula: 【Chemistry 15】 【change】 2. The compound of claim 1,

8. R 5a and R 5b are independently hydrogen, C 1 -C 6 Alkyl, C1-C4 alkyl, C 2 -C 6 Alkenyl, -(C 0 -C 4 Alkyl)O(C 1 -C 6 alkyl), -(C 0 -C 4 alkyl)C(O)(C 1 -C 6 alkyl), -CO 2 H, -CO 2 (C 1 -C 6 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 R 5a and R 5b together with the carbon atoms form a cycloalkyl or heterocycloalkyl ring; R 5b is methyl and R 5a is methyl, —CH 2 O(C 1 -C 6 alkyl), —CH 2 C(O)(C 1 -C 6 alkyl), —CO 2 H, or —CO 2 (C 1 -C 6 alkyl); or The compound according to any one of claims 1 to 7, wherein R 5a is -NHR 5c R 5d , R 5c is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or -(C 0 -C 4 alkyl)C(O)(C 1 -C 6 alkyl), and R 5b is hydrogen.

9. R 5a But -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, or -(C 0 -C 4 The compound of any one of claims 1 to 7, wherein R 5a is (alkyl)-heterocycloalkyl, or R 5a is unsubstituted or substituted phenyl.

10. R 5b is hydrogen, C 1 -C 4 Alkyl, -CH 2 OCH 3 , -CH 2 C(O)CH 3 , -CO 2 H or -CO 2 (C 1 -C 2 The compound according to any one of claims 1 to 8, wherein R 5b is methyl, or R 5b is alkyl.

11. R 5b The compound according to any one of claims 1 to 10, wherein is hydrogen.

12. R 5a and R 5b C consisting of 3 to 6 carbon members together with the carbon atom 3 -C 6 forming a cycloalkyl or heterocycloalkyl ring; R 5a and R 5b taken together form cyclopentyl; or A compound according to any one of claims 1 to 8, wherein R 5a is C 1 -C 4 alkyl, -CH 2 OCH 3 , -CH 2 C(O)CH 3 , -CO 2 H or -CO 2 (C 1 -C 2 alkyl) and R 5b is hydrogen or methyl.

13. Q 5 is oxygen, sulfur, or NR 5e; or A compound according to any one of claims 1 to 12, wherein Q 5 is NR 5e and R 5e is hydrogen, C 1 -C 8 alkyl, -C(O)R 5f , or -CO 2 R 5f , each R 5f being hydrogen or C 1 -C 6 alkyl.

14. R 6 is hydrogen, hydroxyl, or 【Chemistry 23】 The compound according to any one of claims 1 to 13,

15. R 6a and R 6b each independently represents hydrogen, C 1 -C 4 Alkyl, hydroxy, or -CO 2 (C 1 -C 4 alkyl); R 6a and R 6b are each independently hydrogen or -NR 6c R 6d , and at least one of R 6a and R 6b is -NR 6c R 6d , and R 6c and R 6d can each independently be hydrogen, C 1 -C 4 alkyl, or -C(O)(CH 2 ) 0-4 CH 3 , or R 6c and R 6d together with the nitrogen atom form a heterocycloalkyl ring; R 6a and R 6b are both hydrogen; R 6a is methyl and R 6b is hydrogen; R 6a and R 6b are both methyl; or R 6a and R 6b together with the carbon atom form a cycloalkyl ring containing 3 to 6 carbon ring members; or 15. The compound of claim 14, wherein R6a and R6b together with the carbon atom form a cyclopentyl.

16. Q 6 But Y 6 R 6e or -NR 6f R 6g, and Y 6 is O or S, R 6e But hydrogen, deuterium, 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 6h , -CO 2 R 6h , -(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, and each R 6h is hydrogen, -C 1 -C 8 Alkyl, or -(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl); 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 heterocycle and each R 6h is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(CH2CH2O)1-6 (C1-C4 alkyl); 16. The compound according to claim 14 or 15.

17. R 6e is hydrogen, C 1 -C 4 Alkyl, -(CH 2 CH 2 O) 1-4 CH 3 , -C(O)R 6h , or -CO 2 R 6h and R 6h is hydrogen, C 1 -C 8 Alkyl, or -(CH 2 CH 2 O) 1-6 (C 1 -C 4 alkyl); R 6e is methyl, -CH 2 CH 2 OCH 3 , or -(CH 2 CH 2 O) 4 CH 3 ; R 6e is -C(O)R 6h where R 6h is hydrogen, C 1 -C 5 alkyl, or -(CH 2 CH 2 O) 1-4 CH 3 ; or 17. The compound of claim 16, wherein R 6e is --CO 2 R 6h , where R 6h is hydrogen, C 1 -C 5 alkyl, or --(CH 2 CH 2 O) 1-4 CH 3 .

18. R 6f But hydrogen, deuterium, C 1 -C 8 Alkyl, -C(O)R 6h , -CO 2 R 6h , or -(CH 2 CH 2 O) 1-4 CH 3 and R 6h is hydrogen, C 1 -C 8 Alkyl, -(CH 2 CH 2 O) 1-6 (C 1 -C 4 17. The compound of claim 16, wherein the aryl group is -(alkyl), methyl, -CH 2 CH 2 OCH 3 , or -(CH 2 CH 2 O) 4 CH 3.

19. R 6f -C(O)R 6h and R 6h is hydrogen, C 1 -C 5 Alkyl, or -(CH 2 CH 2 O) 1-4 CH 3 or R 6f is --CO 2 R 6h , where R 6h is hydrogen, C 1 -C 5 alkyl, or --(CH 2 CH 2 O) 1-4 CH 3 .

20. R 6g is hydrogen, -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, -(C 0 -C 4 20. The compound of claim 16, 18 or 19, wherein R 8 is a phenyl or monocyclic heteroaryl substituted with 0-2 R 8 .

21. each alkyl is unsubstituted; and / or each cycloalkyl is cyclopropane, cyclobutane, cyclopentane, or cyclohexane; and / or each heterocycloalkyl is pyrrolidine, piperidine, piperazine, tetrahydrofuran, (1H)dihydropyran, or morpholine; and / or each aryl is phenyl; and / or said phenyl is substituted with 0-3 R 8 ; and / or each heteroaryl is a monocyclic heteroaryl; and / or The compound of any one of claims 1 to 20, wherein the monocyclic heteroaryl is substituted with 0-3 R 8 .

22. Each R 7 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 N.R. B R A , or -NR B S (O) 1-2 R A and / or 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)RA , -C(S)NR BRA , -NR B C(S)RA , -CO 2 R A , -OC(O)RA , -C(O)SR A , -SC(O)RA , -C(S)OR A , -OC(S)RA , -C(S)SR A , -SC(S)RA , -S(O) 1-2 OR A , -OS(O) 22. The compound according to any one of claims 1 to 21, which is -S(O) 1-2 NR B R A or -NR B S(O) 1-2 R A .

23. 7-hydroxy-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(m-tolyl)-5-pentyl-1,3-benzodioxin-4-one, 7-hydroxy-5-pentyl-2-phenyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-4-oxo-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-4-oxo-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-2-(2-methylprop-1-en-1-yl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-5-pentyl-8-(m-tolyl)-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-acetonyl-7-hydroxy-8-(m-tolyl)-5-pentyl-2-phenyl-1,3-benzodioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-5-pentyl-2,2-diphenyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, methyl 4-(7-hydroxy-4-oxo-2-(2-oxopropyl)-5-pentyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-2-yl)benzoate, 7-hydroxy-5-propyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(2-oxopropyl)-2-phenyl-5-propyl-8-(m-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylic acid, ethyl 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-pentyl-2,2-diphenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, methyl 4-(7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-4-oxo-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-2-yl)benzoate, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(5-methyl-2-(prop-1-en-2-yl)phenyl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2,2-dimethyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-spiro[1,3-benzodioxin-2,1′-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-pentyl-2,2-diphenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, methyl 4-(7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-4-oxo-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-2-yl)benzoate, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methylcyclohex-2-en-1-yl)-2-(2-oxopropyl)-2-phenyl-5-propyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylic acid, Ethyl 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-4-oxo-5-pentyl-4H-benzo[d][1,3]dioxine-2-carboxylate, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-methylprop-1-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-spiro[benzo[d][1,3]dioxin-2,1'-cyclopentan]-4-one, 2-(3-chloropropyl)-7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(methoxymethyl)-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-phenyl-4H-benzo[d][1,3]dioxin-4-one, 2-(4-fluorophenyl)-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-butyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-methyl-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 2-ethyl-7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-2,2-diphenyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-2-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(4-nitrophenyl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, 7-hydroxy-2-(4-methoxyphenyl)-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one, and 2. The compound of claim 1 which is methyl 4-(7-hydroxy-8-(3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-4-oxo-2-(2-oxopropyl)-5-pentyl-4H-benzo[d][1,3]dioxin-2-yl)benzoate.

24. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharma- ceutically acceptable salt, solvate, or hydrate of said compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, and a pharma- ceutically acceptable excipient, diluent, or carrier.

25. A composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 for use in the treatment or prevention of a disease associated with cannabinoid receptors.

26. 26. The composition or pharmaceutical composition of claim 25, wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptors.

27. The disease may be acute pain, ADHD / ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's disease, anorexia (e.g., HIV-associated cachexia), anxiety disorder (e.g., social anxiety disorder, specific phobia, test anxiety, generalized anxiety disorder), arthritis, atherosclerosis, autism, bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic pain, chronic transplant nephropathy, cocaine use disorder, complex regional pain syndrome, congestive heart failure, depression, fibromyalgia, fragile X syndrome / FXTAS, frontotemporal dementia (behavioral variant), gingivitis fever, glaucoma, glioblastoma, glomerular nephropathy, Huntington's disease, hypertrophic scar, IBD / IBS, inflammation, inflammatory myopathy, ischemia, renal fibrosis, keloids, leukodystrophy, liver fibrosis, liver cirrhosis, pulmonary fibrosis, 27. The composition or pharmaceutical composition for use according to claim 25 or 26, wherein the condition is a chronic condition such as rheumatoid arthritis, migraine, multiple sclerosis, myocardial infarction, nausea (e.g. CINV, motion sickness), neuropathic pain (e.g. post-herpetic neuralgia, painful diabetic neuropathy), nocturnal disorder, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, Parkinson's disease, post-concussion syndrome / traumatic brain injury, psychosis / schizophrenia, PTSD, bone mass regulation, REM sleep behavior disorder, reperfusion injury, Rett's syndrome, rheumatoid arthritis, skin conditions (e.g. acne, psoriatic arthritis), sleep disorders (e.g. insomnia, RLS), spinocerebellar ataxia, systemic fibrosis, systemic sclerosis, heat injury, tobacco use disorder / nicotine dependence, Tourette's syndrome, tumor, or trigeminal neuralgia.

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