cannabinoid derivatives

Abstract

This disclosure relates to cannabinoid derivatives having the structure of formula (I), [Case 1] TIFF2022540433000077.tif39170 The present invention relates to pharmaceutical compositions containing these, and to methods of using cannabinoid derivatives in the treatment or prevention of cannabinoid receptor-related diseases, including receptors selected from CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TRPV2, PPARγ, or μ-opioid receptors.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest in U.S. Provisional Patent Application No. 62 / 873,697, filed on 12 July 2019, which is incorporated herein by reference in its entirety.

[0002] This disclosure generally relates to cannabinoid derivatives, pharmaceutical compositions containing them, and methods for using cannabinoid derivatives. [Background technology]

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

[0004] CB1 and CB2 receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. CB1 and CB2 receptors are distinguished from each other by their amino acid sequences, tissue distribution, signaling mechanisms, and ability to bind to 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 to immune cells (e.g., macrophages and T cells), cells involved in bone formation and bone loss, and the gastrointestinal tract. These receptors are associated with many human diseases, including, among others, obesity, diabetes, fibrosis, liver disease, cardiovascular disease, cancer, pain, inflammation, MS spasms, and glaucoma.

[0005] Cannabinoids are compounds that are active on cannabinoid receptors in humans and have been associated with many of the pharmacological benefits for the diseases mentioned above. Plant-derived cannabinoids, also known as phytocannabinoids, are abundant 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 eligible medical conditions such as 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 GPCRs that have also 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 a variety of biological and neurological processes, including, among others, anxiety, appetite, cognition, and mood. Other receptors identified as being affected by cannabinoids or cannabinoid-like compounds include GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), and μ-opioid receptors. In fact, binding to these receptors is responsible for the off-target effects of cannabinoids.

[0007] One of the most common methods of using cannabinoids for medicinal purposes in many countries is through smoking cannabis. While it has proven beneficial for certain indications, smoking medical cannabis has drawbacks. For example, the smoke from the plant contains carcinogens and other toxins in addition to the desired cannabinoids. Severe use of cannabis through smoking is also associated with lung reduction, lung damage, and accelerated emphysema. Another drawback of smoking medical cannabis is the difficulty in maintaining control over the appropriate dosage of medicinal cannabis due to variations in the active ingredients (for example, the amount of active ingredients may vary depending on the differences present in plant varieties, as well as changes in growing conditions that lead to variations within the variation). Finally, consumption through smoking results in relatively low bioavailability of the target compound compared to other delivery methods.

[0008] A less common method of using cannabis for medical purposes is to extract beneficial cannabinoids from it. While many extraction processes have been developed for the isolation and purification of natural cannabinoids, isolating individual cannabinoids with high purity, both for use as active ingredients in pharmaceutical and product manufacturing, and / or for use in research and development, has been challenging. [Overview of the project] [Problems that the invention aims to solve]

[0009] Therefore, there is a need for novel ligands for cannabinoid receptors that have potential therapeutic benefits. [Means for solving the problem]

[0010] One aspect of this disclosure is a compound of formula (I): [ka] A compound having, or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharmaceutically acceptable salt, solvate, or hydrate of said compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, wherein

Chemical formula

Chemical formula

[0011] In another embodiment, the present disclosure relates to a compound described herein (e.g., a compound of formula (I)), or its enantiomers, diastereomers, racemates, tautomers, or metabolites, or a pharmaceutically acceptable salt, solvate, or hydrate of a compound, enantiomer, diastereomer, racemate, tautomer, or metabolite. In one embodiment, the pharmaceutically acceptable composition comprises a pharmaceutically acceptable excipient, diluent, or carrier.

[0012] In another embodiment, the Disclosure relates to a method for treating or preventing a disease in a subject that requires treatment or prevention of a disease such as a disease associated with cannabinoid receptors (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptors). In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound described herein, or its enantiomer, diastereomer, racemate, tautomer, or metabolite, or a pharmaceutically acceptable salt, solvate, or hydrate of a compound, enantiomer, diastereomer, racemate, tautomer, or metabolite. In one embodiment, the method comprises administering to a subject a pharmaceutically acceptable 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 nervosa (e.g., human immunodeficiency virus (HIV)-associated cachexia), anxiety disorders (e.g., social anxiety disorder, specific phobias, exam 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-related tremor and ataxia syndrome (FXTAS), frontotemporal dementia (behavioral variant), gingivitis fever, glaucoma, glioblastoma, glomerulonephropathy, Huntington's disease, hypertrophic scarring, inflammatory bowel disease (IBD) / irritable bowel syndrome (IBS), inflammation, inflammatory muscle disease, ischemia, kidney Fibrosis, keloids, leukodystrophy, hepatic fibrosis, cirrhosis, pulmonary fibrosis, migraines, multiple sclerosis, myocardial infarction, nausea (e.g., chemotherapy-induced nausea and vomiting (CINV), motion sickness), neuropathic pain (e.g., postherpetic neuralgia, painful diabetic neuropathy), nocturnal disorders, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid saving, opioid use disorder, osteoarthritis, osteoporosis, pain (e.g., acute or chronic pain), Parkinson's disease, post-concussion Syndromes / traumatic brain injury, psychosis / schizophrenia, post-traumatic stress disorder (PTSD), bone density 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 syndrome, tumors, and trigeminal neuralgia are among the conditions that may be treated.

[0014] In another aspect, this disclosure relates to the use of the compounds described herein, or their enantiomers, diastereomers, racemates, tautomers, or metabolites, or pharmaceutically acceptable salts, solvates, or hydrates of the compounds, enantiomers, diastereomers, racemates, tautomers, or metabolites, for the treatment or prevention of diseases associated with cannabinoid receptors (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptors).

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

[0016] In another aspect, the disclosure relates to the use of the compounds described herein, or their enantiomers, diastereomers, racemates, tautomers, or metabolites, or pharmaceutically acceptable salts, solvates, or hydrates of the compounds, enantiomers, diastereomers, racemates, tautomers, or metabolites, for selectively modulating the activity of CB1 or CB2 receptors.

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

[0018] Other aspects and embodiments of this disclosure will become apparent from the detailed description provided herein. [Modes for carrying out the invention]

[0019] This 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, this disclosure further relates to compounds, pharmaceutical compositions, methods, and uses that have the potential to treat or prevent one or more diseases associated with cannabinoid receptors.

[0020] The compounds disclosed herein may, if necessary, be given formula (I) [ka] With regard to this, or with regard to the various sub-compounds within structural formula (I), it can be generally defined as follows: [ka] Part, R 1a and R 1b , R 2 , R 3 , R 5 , and R 4 The groups are optionally selected independently from the groups (Ia)-(If), (1a)-(1h), (2a)-(2j), (3a)-(3s), (4a)-(4p), (5a)-(5c), and (6a)-(6cc) as defined below herein (for example, the compounds here having structural formulas as defined in any combination of the embodiments below).

[0021] In certain embodiments of compounds described otherwise in this specification, [ka] The parts are based on the following bases (1a) to (1h): [ka] Selected from.

[0022] In certain embodiments of compounds described elsewhere in this specification, R 1a and R 1b These are independently based on the following bases (2a)~(2j): (2a) Hydrogen, C1-C4 alkyl, C2-C4 alkenyl, hydroxy, halo, -O(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -CO2(C1-C4 alkyl), -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl, or -(C0-C4 alkyl)-heterocycloalkyl, (2b) Hydrogen, C1-C4 alkyl, hydroxyl, or -CO2(C1-C4 alkyl), (2c) Hydrogen, hydroxyl, or C1-C4 alkyl, (2d)C1-C4 alkyl, (2e)methyl, (2f)R 1a However, it is methyl, and R 1b However, it is hydrogen, (2g)R 1a and R 1b However, both are hydrogen, (2h)R 1a However, it is hydrogen, R 1b However, -NR 1c R 1d And, (2i)R 1a and R 1b However, together with carbon atoms, they form a cycloalkyl ring (e.g., a saturated cycloalkyl ring) containing 3 to 6 carbon ring members. (2j)R 1a and R 1bHowever, one of the following is selected: forms cyclopentyl together with a carbon atom.

[0023] In certain embodiments of compounds described elsewhere in this specification, R 2 The following bases (3a)~(3s): (3a) Hydrogen, Halo, C1-C8 alkyl, C2-C8 alkenyl, -CO2H, -(C0-C4 alkyl)-C(O)O(C1-C6 alkyl), -OR 2a , -(C1-C4 alkyl)OR 2a , -SR 2a -(C1-C4 alkyl)SR 2a , -NR 2b R 2c -(C1-C4 alkyl)NR 2b R 2c -(C1-C4 alkyl)C(O)NR 2b R 2c -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl, -(C0-C4 alkyl)-heterocycloalkyl, or oxo (3b) Hydrogen, -F, -Cl, C1-C8 alkyl, C2-C8 alkenyl, -CO2H, hydroxy, -(C0-C4 alkyl)-C(O)O(C1-C6 alkyl), -(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl, -(C0-C4 alkyl)-heterocycloalkyl, or oxo, (3c) Hydrogen, -F, -Cl, C1-C6 alkyl, C2-C6 alkenyl, hydroxy, -CO2H, -(C0-C2 alkyl)-C(O)O(C1-C6 alkyl) (e.g., -CO2(C1-C4 alkyl)), or oxo, (3d) Hydrogen, (3e)C1-C4 alkyl or C2-C4 alkenyl, (3f) C1-C4 alkyl groups optionally substituted with hydroxyl, (3g) C1-C4 alkyl groups, e.g., methyl, ethyl, or propyl (isopropyl or n-propyl, etc.), (3h)C2-C4 alkenyls, e.g., isopropenyl, (3i)-CO2H, -C(O)O(C1-C4 alkyl), or oxo, (3j)-CO2H, (3k) Oxo (3l)-CH2OH, (3m)-(C0-C4 alkyl)-aryl, -(C0-C4 alkyl)-heteroaryl, -(C0-C4 alkyl)-cycloalkyl or -(C0-C4 alkyl)-heterocycloalkyl, (3n)-OR 2a , -(C1-C4 alkyl)OR 2a , -SR 2a -(C1-C4 alkyl)SR 2a , -NR 2b R 2c -(C1-C4 alkyl)NR 2b R 2c , or -(C1-C4 alkyl)C(O)NR 2b R 2c , (3o)-OR 2a , -(C1-C4 alkyl)OR 2a , -NR 2b R 2c -(C1-C4 alkyl)NR 2b R 2c , or -(C1-C4 alkyl)C(O)NR 2b R 2c , (3p)-OR 2a , (3q)-NR 2b R 2c , As defined in (3r)(3n)~(3q), R 2a , R 2b and R 2c However, independently, they are hydrogen, C1-C4 alkyl, or -C(O)CH3. As defined in (3s)(3n)~(3q), R 2a , R 2b and R 2c However, it is independently selected from one of hydrogen or a C1-C4 alkyl group.

[0024] In certain embodiments of compounds described elsewhere in this specification, R 3 The following are the bases (4a)~(4p): (4a) Hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkinyl, -(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, e.g., 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, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms which are nitrogen, oxygen or sulfur, and 0 to 4 R 7-(C0-C4 alkyl)-heterocycloalkyl, which is substituted with (4n)-(C0-C4 alkyl)-heterocycloalkyl, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms which are nitrogen, oxygen or sulfur, and 0 to 4 R 7 Substituted with, the heterocycloalkyl is piperidinyl, pyrrolidinyl, azetidinyl or azilidinyl, -(C0-C4 alkyl)-heterocycloalkyl, (4o)-(C0-C4 alkyl)-heterocycloalkyl, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms which are nitrogen, oxygen or sulfur, and 0 to 4 R 7 Substituted with, the heterocycloalkyl is azetidinyl, independently of oxo, C1-C4 alkyl, Cl, F, Br, -C(O)R A , or -CO2R A 1-2 R 7 Replaced with R A However, it is H or C1-C3 alkyl, -(C0-C4 alkyl)-heterocycloalkyl, (4p)-(C0-C4 alkyl)-heterocycloalkyl, where the heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms which are nitrogen, oxygen or sulfur, and 0 to 4 R 7 Replaced with R 7 However, it is selected from one of the following: -C(O)CH3, -(C0-C4 alkyl)-heterocycloalkyl.

[0025] In certain embodiments of compounds described elsewhere in this specification, R 5 These are independently based on the following bases (5a)~(5c): (5a) Hydrogen, C1-C6 alkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -C(O)O(C1-C4 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), or -C(O)N(C1-C4 alkyl)2 (5b) Hydrogen, C1-C6 alkenyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl), (5c) Selected from one of the hydrogen atoms.

[0026] In certain embodiments of the compounds described otherwise in this specification, the compounds have the following structural formulas (Ia) to (If): [ka] Take one of them.

[0027] In certain embodiments of compounds described elsewhere in this specification, R 4 The following are the bases (6a)~(6cc): (6a)-(C0-C1alkyl)-aryl, -(C0-C1alkyl)-heteroaryl, -(C0-C1alkyl)-cycloalkyl, or -(C0-C1alkyl)-heterocycloalkyl, (6b) -aryl, -heteroaryl, -cycloalkyl or -heterocycloalkyl, As defined in (6c)(6a)~(6b), the cycloalkyl or heterocycloalkyl group has 0 to 3 R 7 Substituted with aryl or heteroaryl, with 0-3 R 8 Replaced by, (6d)(6a)~(6b) as defined, where the cycloalkyl or heterocycloalkyl has 0 to 2 R 7 Substituted with, aryl or heteroaryl, 0 to 2 R 8 Replaced by, As defined in (6e)(6a)~(6b), the cycloalkyl or heterocycloalkyl is unsubstituted, and the aryl or heteroaryl is unsubstituted. (6f)(6a)~(6b) is defined as follows, and the cycloalkyl or heterocycloalkyl group has 1 to 2 R 7 Substituted with aryl or heteroaryl, with 1-2 R 8 Replaced by, (6g) 0-3 R 8 -(C0-C1 alkyl)-aryl substituted with, or 0-3 R 7 -(C0-C1 alkyl)-cycloalkyl substituted with (6h) 0-3 R 8 Substituted with -aryl or 0-3 R 7 Substituted with -cycloalkyl, (6i) 0 to 3 R 8 Substituted with -(C0-C1 alkyl)-aryl (e.g., phenyl or phenylmethyl), (6j) has 0 to 3 R 8 It is a phenyl substituted with, (6k) 0 to 3 R 7 Substituted with -(C0-C1 alkyl)-cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclopentylmethyl or cyclohexylmethyl), (6l) 0-3 R 7 Substituted with -cycloalkyl (e.g., cyclopentyl or cyclohexyl), (6m) 0-3 R 8 -(C0-C1 alkyl)-heteroaryl substituted with, or 0-3 R 7 -(C0-C1 alkyl)-heterocycloalkyl substituted with (6n) 0 to 3 R 8 - Heteroaryl or 0-3 R substituted 7 - Heterocycloalkyl substituted with (6o) 0-3 R 7 Monocyclic or bicyclic (C0-C1 alkyl) heterocycloalkyls substituted with (e.g., azilidinyl, azetidinyl, oxyranil, oxetanyl, 4,5-dihydroxazolyl, pyranyl, indolinyl, azilidinylmethyl, azetidinylmethyl, oxyranylmethyl, oxetanylmethyl, 4,5-dihydroxazolylmethyl, pyranylmethyl, or indolinylmethyl), (6p) 0 to 3 R 7Monocyclic or bicyclic heterocycloalkyls substituted with (e.g., azilidinyl, azetidinyl, oxyranil, oxetanil, 4,5-dihydroxazolyl, pyranil, or indolinyl), (6q) 0 to 3 R 8 Monocyclic or bicyclic -(C0-C1 alkyl)-heteroaryls substituted with (e.g., indolyl, benzo[d]imidazolyl, imidazo[4,5-b]pyrazine, fanell, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolylmethyl, benzo[d]imidazolylmethyl, imidazo[4,5-b]pyrazinemethyl, fanellmethyl, isoxazolylmethyl, oxadiazolylmethyl, pyrrolylmethyl, triazolylmethyl, tetrazolylmethyl, thiophenylmethyl, thiazolylmethyl, pyridinylmethyl, pyrimidinylmethyl, or pyrazinylmethyl), (6r) 0 to 3 R 8 Monocyclic or bicyclic heteroaryls substituted with (e.g., indolyl, benzo[d]imidazolyl, imidazo[4,5-b]pyrazine, fanel, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, thiophenyl, thiazolyl, pyridyl, pyrimidinyl, or pyrazinyl), As defined in (6s)(6a)~(6r), R 7 However, independently, oxo, C1-C4 alkyl, -Cl, -F, -Br, -CN, -SF5, -N3, nitro, -SR A , -S(O) 1-2 R A , -OR A -C1-C4 alkyl-OR A , -NR B R A -C1-C4 alkyl-NR B R A , -C(O)R A -C(O)NR B R A , -NR B C(O)R A -C(S)NR B R A, -NR B C(S)R A , -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 Ure A , -OS(O) 1-2 R A , -S(O) 1-2 NR B R A , -NR B S(O) 1-2 R A , unsubstituted phenyl, or 5-6 member unsubstituted heteroaryl, As defined in (6t)(6a)~(6r), R 7 However, independently, oxo, C1-C4 alkyl, -Cl, -F, -Br, -CN, -OR A -C1-C4 alkyl-OR A , -NR B R A -C1-C4 alkyl-NR B R A , -C(O)R A -C(O)NR B R A , -NR B C(O)R A , -CO2R A ,-OC(O)R A , -S(O) 1-2 Ure A , -OS(O) 1-2 R A , -S(O) 1-2 NR B R A , -NR B S(O) 1-2 R A , unsubstituted phenyl, or 5-6 member unsubstituted heteroaryl, As defined in (6u)(6a)~(6r), R 7However, independently, oxo, C1-C4 alkyl, -Cl, -F, -Br, -CN, -OR A -C1-C3 alkyl-OR A , -NR B R A -C1-C3 alkyl-NR B R A , -C(O)R A , unsubstituted phenyl, or 5-6 member unsubstituted heteroaryl, As defined in (6v)(6a)~(6r), R 7 However, independently, oxo, C1-C4 alkyl, -Cl, -F, -Br, -OR A -C1-C3 alkyl-OR A , -NR B R A -C1-C3 alkyl-NR B R A , unsubstituted phenyl, or unsubstituted pyridyl, As defined in (6w)(6a)~(6r), R 7 However, they are independently methyl, -F, hydroxy, or methoxy. As defined in (6x)(6a)~(6w), R 8 However, independently, C1-C4 alkyl, -Cl, -F, -Br, -CN, -SF5, -N3, nitro, -SR A , -S(O) 1-2 R A , -OR A -C1-C4 alkyl-OR A , -NR B R A -C1-C4 alkyl-NR B R A , -C(O)R A -C(O)NR B R A , -NR B C(O)R A -C(S)NR B R A , -NR B C(S)R A , -CO2R A ,-OC(O)R A -C(O)SR A ,-SC(O)RA , -C(S)OR A ,-OC(S)R A -C(S)SR A ,-SC(S)R A , -S(O) 1-2 Ure A , -OS(O) 1-2 R A , -S(O) 1-2 NR B R A , -NR B S(O) 1-2 R A , unsubstituted phenyl, or 5-6 member unsubstituted heteroaryl, As defined in (6y)(6a)~(6w), R 8 However, independently, C1-C4 alkyl, -Cl, -F, -Br, -CN, -OR A -C1-C4 alkyl-OR A , -NR B R A -C1-C4 alkyl-NR B R A , -C(O)R A -C(O)NR B R A , -NR B C(O)R A , -CO2R A ,-OC(O)R A , -S(O) 1-2 Ure A , -OS(O) 1-2 R A , -S(O) 1-2 NR B R A , -NR B S(O) 1-2 R A , unsubstituted phenyl, or 5-6 member unsubstituted heteroaryl, As defined in (6z)(6a)~(6w), R 8 However, independently, C1-C4 alkyl, -Cl, -F, -Br, -CN, -OR A -C1-C3 alkyl-OR A , -NR B R A -C1-C3 alkyl-NR B RA , -C(O)R A , unsubstituted phenyl, or 5-6 member unsubstituted heteroaryl, As defined in (6aa)(6a)~(6w), R 8 However, independently, C1-C4 alkyl, -Cl, -F, -Br, -OR A -C1-C3 alkyl-OR A , -NR B R A -C1-C3 alkyl-NR B R A , unsubstituted phenyl, or unsubstituted pyridyl, As defined in (6bb)(6a)~(6w), R 8 However, they are independently methyl, -F, hydroxy, or methoxy. (6cc) 3-methyl-1,2,4-oxadiazole-5-yl, 5-methyl-1,2,4-oxadiazole-3-yl, 1H-tetrazole-5-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-yl), 5-methyl-4H-1,2,4-triazol-3-yl, 1H-pyrrole-3-yl, 1H-pyrrole-2-yl, pyridine-2-yl, pyrimidine-4-yl, pyrazine-2-yl, pyrimidine-2-yl, pyridin-3-yl, pyrimidine-5-yl, pyridin-4-yl, fran-2-yl Select one from the following: thiophen-2-yl, thiophen-3-yl, thiazole-5-yl, thiazole-4-yl, indoline-2-yl, 1H-benzo[d]imidazole-2-yl, 9H-purine-8-yl, oxetane-2-yl, oxetane-3-yl, oxiran-2-yl, azailidine-2-yl, azailidine-1-yl, 1H-indole-2-yl, 4-(pyridine-3-yl)phenyl, isoxazole-5-yl, 4,5-dihydroxazole-2-yl, or 4H-pyran-4-yl.

[0028] Various specific embodiment numbers 1 to 720 of the Compounds of this Disclosure include the compound of formula (I) (or its enantiomers, diastereomers, racemates, tautomers, or metabolites, or pharmaceutically acceptable salts, solvates, or hydrates of the compound, enantiomers, diastereomers, racemates, tautomers, or metabolites) as each is defined in the following columns, where each entry is a cardinal number as defined above.

number

number

number

[0029] In certain additional embodiments, including those described with reference to formulas (I) and (Ia) to (If), and any of the above embodiments 1 to 720, the optionally substituted alkyl, alkenyl, and alkynyl compounds listed in any one of the above embodiments are each unsubstituted. In alternative additional embodiments, including those described with reference to formulas (I) and (Ia) to (If), and any of the above embodiments 1 to 720, the optionally substituted alkyl, alkenyl, and alkynyl compounds listed in any one of the above embodiments are each independently substituted or unsubstituted. In further alternative additional embodiments, including those described with reference to formulas (I) and (Ia) to (If), and any of the above embodiments 1 to 720, the optionally substituted alkyl, alkenyl, and alkynyl compounds listed in any one of the above embodiments are each substituted.

[0030] In certain additional embodiments, including the embodiments described with reference to formula (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as the embodiments described in the preceding paragraph, each cycloalkyl enumerated in any one of the embodiments described above is a 3 to 7-membered monocyclic cycloalkyl. For example, in certain specific embodiments, including the embodiments described with reference to formula (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as the embodiments described in the preceding paragraph, each cycloalkyl enumerated in any one of the embodiments described above is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

[0031] In certain additional embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as any embodiments described in the two preceding paragraphs above, each heterocycloalkyl enumerated in any one of the embodiments described above is a 4 to 7-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms selected from O, S, and N. For example, in certain specific embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as any embodiments described in the two preceding paragraphs above, each heterocycloalkyl enumerated in any one of the embodiments described above is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydro-2H-thiopyranyl. In certain embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If), any of the embodiments described above (1 to 720), and any embodiments described in the two preceding paragraphs above, each heterocycloalkyl listed in any one of the embodiments described above is pyrrolidine, piperidine, piperazine, tetrahydrofuran, (1H)dihydropyran, or morpholine (e.g., each unsubstituted).

[0032] In certain additional embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If), any of the embodiments described above (1 to 720), and any embodiments described in the three preceding paragraphs above, each aryl is phenyl.

[0033] In certain additional embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as any embodiments described in the four preceding paragraphs above, each heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from O, S, and N. For example, in certain specific embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as any embodiments described in the four preceding paragraphs above, each heteroaryl has 0 to 3 R 8 Substituted by, for example, unsubstituted, one R 8 Replaced by, or two R 8 It is a monocyclic heteroaryl substituted with . In certain, specific embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as any embodiments described in the four preceding paragraphs above, each heteroaryl is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl.

[0034] In certain additional embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If), and any of the embodiments 1 to 720 described above, as well as any embodiments described in the preceding paragraph above, each R 7 These 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 Ure 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, the embodiments described with reference to formulas (I) and (Ia) to (If) and any of the embodiments 1 to 720 described above, as well as any embodiments described in the preceding paragraph above, each R 7 These 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 That is the case.

[0035] In certain additional embodiments, including the embodiments described with reference to formulas (I) and (Ia) to (If), and any of the embodiments 1 to 720 described above, as well as any embodiments described in the preceding paragraph above, each R 8 These 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 Ure 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 the embodiments described with reference to formulas (I) and (Ia) to (If), and any of the embodiments 1 to 720 described above, as well as any embodiments described in the preceding paragraph above, each R 8 These 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 That is the case.

[0036] In some embodiments, this disclosure specifically states that 6,6,9-trimethyl-2-(3-methyl-1,2,4-oxadiazole-5-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(5-methyl-1,2,4-oxadiazole-3-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-tetrazole-5-yl)-6H-benzo[c]chromen-1-ol, 5-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)-1,3,4-oxadiazole-2(3H)-one, 6,6,9-trimethyl-2-(5-methyl-4H-1,2,4-triazol-3-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrole-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrole-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-4-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrazine-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-5-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-4-yl)-6H-benzo[c]chromen-1-ol, 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(thiazol-5-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(thiazol-4-yl)-6H-benzo[c]chromen-1-ol, 2-(Indolin-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(1H-Benzimidazol-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(9H-purin-8-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(oxetan-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(oxetan-3-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(oxiran-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(Aziridin-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(Aziridin-1-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(1H-Indol-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(4-(pyridin-3-yl)phenyl)-6H-benzo[c]chromen-1-ol, 2-(Isoxazol-5-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(4,5-Dihydrooxazol-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(4H-pyran-4-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(1-methyl-1H-pyrazol-5-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(Benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(1H-pyrazol-4-yl)-6H-benzo[c]chromen-1-ol, 2-(Benzo[b]thiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(4-methylthiophen-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(1H-tetrazol-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 1-Hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)-1,3,4-oxadiazol-2(3H)-one, 6,6,9-Trimethyl-2-(5-methyl-4H-1,2,4-triazol-3-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(1H-pyrrol-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrole-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrazine-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazole-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazole-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(indoline-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(1H-benzo[d]imidazole-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(9H-purine-8-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxetan-2-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxetan-3-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxiran-2-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(aziridine-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(aziridine-1-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(1H-indole-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(4-(pyridine-3-yl)phenyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(isoxazol-5-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(4,5-dihydroxazol-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(4H-pyran-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(1-methyl-1H-pyrazole-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrazole-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(benzothiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol, and This relates to compounds selected from 6,6,9-trimethyl-2-(4-methyl-2-thienyl)-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol.

[0037] In some embodiments, this disclosure specifically refers to, 6,6,9-trimethyl-3-pentyl-2-(pyridine-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-5-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-4-yl)-6H-benzo[c]chromen-1-ol, 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazole-5-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(1-methyl-1H-pyrazole-5-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrazole-4-yl)-6H-benzo[c]chromen-1-ol, 2-(benzo[b]thiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(4-methylthiophen-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridine-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol), 6,6,9-trimethyl-3-pentyl-2-(pyridine-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(thiophen-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, Trimethyl-3-pentyl-2-thiazol-5-yl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol, 6,6,9-Trimethyl-2-(1-methyl-1H-pyrazol-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(Benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(1H-pyrazol-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(Benzothiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol, and 6,6,9-Trimethyl-2-(4-methyl-2-thienyl)-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol. It further relates to a compound selected from the above.

[0038] In some embodiments, the present disclosure particularly relates to 6,6,9-Trimethyl-3-pentyl-2-(pyridin-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-Trimethyl-3-pentyl-2-(pyrimidin-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol), 6,6,9-Trimethyl-3-pentyl-2-(pyridin-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(Furan-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, Trimethyl-3-pentyl-2-thiazole-5-yl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(1-methyl-1H-pyrazole-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrazole-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(benzothiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol, and Further relating to compounds selected from 6,6,9-trimethyl-2-(4-methyl-2-thienyl)-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol.

[0039] In certain embodiments of the compounds described herein, the compound is in the form of a compound described herein, or a pharmaceutically acceptable salt thereof, an enantiomer, diastereomer, racemate, tautomer, or metabolite. Those skilled in the art will understand that a variety of pharmaceutically acceptable salts may be provided, for example, as described below in further detail.

[0040] In certain embodiments of the compounds described herein, the compound is in the form of the compound described herein, or a solvate (e.g., hydrate) of its enantiomer, diastereomer, racemate, tautomer, or metabolite. Those skilled in the art will understand that a variety of solvates and / or hydrates may be formed.

[0041] Those skilled in the art will understand that the phrase "its enantiomers, diastereomers, racemates, tautomers, or metabolites, or pharmaceutically acceptable salts, solvates, or hydrates of the compound, enantiomers, diastereomers, racemates, tautomers, or metabolites" includes compounds in the form of salts, solvates, hydrates (including its enantiomers, diastereomers, racemates, or tautomers), or metabolites of basic compounds. However, in the specific embodiments described above, the compound is not in the form of a salt, solvate, or hydrate.

[0042] Application of treatment In some embodiments, the compounds of the 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 embodiment, the Disclosure relates to the use of at least one of the compounds of the Disclosure for binding to and / or interacting with a cannabinoid receptor.

[0043] In some embodiments, the compounds of the Disclosure may have affinity for one or both of the CB1 receptor and the CB2 receptor. In certain embodiments, the compounds of the Disclosure may have affinity for the CB1 receptor but not for the CB2 receptor. In certain embodiments, the compounds of the Disclosure may have affinity for the CB2 receptor but not for the CB1 receptor.

[0044] In some embodiments, the compounds of the disclosed herein may exhibit selectivity for one receptor rather than another. As used herein, “selectivity” means that a compound binds to, interacts with, or preferentially modulates to one receptor rather than another. In one embodiment, a compound is selective for one receptor rather than 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 for another receptor. In one embodiment, the affinity of the compounds disclosed herein to a receptor may be determined, for example, by a radioligand competitive binding assay as described in the examples herein.

[0045] In some embodiments, the compounds of this disclosure may have an affinity for the CB1 receptor, exhibiting selectivity for the CB1 receptor more than for the CB2 receptor.

[0046] In some embodiments, the compounds of this disclosure may have an affinity for CB2 receptors that is more selective to CB2 receptors than to CB1 receptors.

[0047] In some embodiments, the compounds of the Disclosure may function as agonists, partial agonists, indirect agonists, antagonists, reverse agonists, neutral agonists, or allosteric modulators for at least one cannabinoid receptor (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptors). In some embodiments, the compounds of the Disclosure may function as agonists, partial agonists, indirect agonists, antagonists, reverse agonists, neutral agonists, or allosteric modulators for CB1 and / or CB2 receptors. In some embodiments, the compounds of the Disclosure may function as agonists for CB1 and / or CB2 receptors. In some embodiments, the compounds of the Disclosure may function as antagonists for CB1 and / or CB2 receptors. In some embodiments, the compounds of this disclosure may function as indirect agonists to the 5HT1A receptor.

[0048] In some embodiments, the compounds of the present disclosure may act as prodrugs to compounds (e.g., metabolites) that function as agonists, partial agonists, indirect agonists, antagonists, reverse agonists, or neutral agonists to at least one of the cannabinoid receptors (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptors).

[0049] This disclosure further relates to the use of the compounds disclosed herein as therapeutic agents or as prodrugs for therapeutic agents.

[0050] In one embodiment, this disclosure relates to the use of compounds disclosed herein for the treatment or prevention of diseases associated with cannabinoid receptors (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptors). In one embodiment, “cannabinoid-related disease” means a disease, disorder, or condition that is treatable or preventable by acting on cannabinoid receptors (e.g., CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPAR (e.g., PPARγ), or μ-opioid receptors). In one embodiment, the compounds of the present disclosure may treat or prevent a condition by acting as an agonist, partial agonist, antagonist, reverse agonist, neutral agonist, or allosteric regulator of a cannabinoid receptor, or by acting as a prodrug of a compound (e.g., a metabolite) that acts as an agonist, partial agonist, antagonist, reverse agonist, neutral agonist, or allosteric regulator of a cannabinoid receptor. In a selective embodiment, the cannabinoid receptor is CB1 or CB2.

[0051] In one embodiment, the disclosure relates to the use of compounds disclosed herein for selectively modulating the activity of one receptor rather than another. 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 a selective embodiment, the disclosure relates to the use of compounds disclosed herein for selectively modulating the activity of a CB1 or CB2 receptor.

[0052] As used herein, “selectively modulating” is intended to mean the ability of the compounds of this disclosure to cause any change in the receptor activity. In one embodiment, “selectively modulating” means stimulating or inhibiting the receptor activity, directly or indirectly.

[0053] This disclosure also relates to methods for treating or preventing diseases such as diseases associated with cannabinoid receptors (e.g., CB1 and / or CB2). These methods include administering to a subject in need of such treatment or prevention one or more of the compounds of this disclosure described herein (e.g., compounds of formula (I)) or a pharmaceutical composition of this disclosure described herein in a therapeutically effective amount.

[0054] In certain embodiments, the diseases of this disclosure include ADHD / ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's disease, anorexia nervosa (e.g., HIV-related cachexia), anxiety disorders (e.g., social anxiety disorder, specific phobias, exam 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, glomerulonephropathy, Huntington's disease, hypertrophic scarring, IBD / IBS, inflammation, inflammatory muscle disease, ischemia, renal fibrosis, keloids, leukodystrophy, hepatic fibrosis, cirrhosis, Pulmonary fibrosis, migraines, multiple sclerosis, myocardial infarction, nausea (e.g., CINV, motion sickness), neuropathic pain (e.g., postherpetic neuralgia, painful diabetic neuropathy), nocturnal disorders, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid saving, 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 density 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, tumors, or trigeminal neuralgia.

[0055] The compounds and compositions of the Disclosure described herein may also be administered in combination with one or more secondary therapeutic agents. Therefore, in certain embodiments, the method also includes administering a therapeutically effective amount of one or more compounds or pharmaceutically active compositions described herein and one or more secondary therapeutic agents to a subject requiring such treatment or prophylaxis. Examples of suitable secondary therapeutic agents include temozolomide, camptothecin, doxorubicin, daunorubicin, vincristine, paclitaxel, neocarlutinostatin, calitiamycin, cisplatin, carboplatin, oxaliplatin, satoraplatin, picoplatin, lulutotecan, annamycin, docetaxel, tamoxifen, epirubicin, methotrexate, vinblastine, vincristine, topotecan, prednisone, and prednizo Ron, chloroquine, hydroxychloroquine, autophagy inhibitors, abt-737, leucovorin, psilocybin, psilocin, siloacetin, netupitant, palonosetron, aprepitant, 3,4-methylenedioxymethamphetamine, nicotine, ketamine, lithium salts (e.g., lithium citrate), valproic acid, bevacizumab, bortezomib, fluorouracil, gemcitabine, irinotecan, oxaliplatin, adalimumab, A 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), g Examples 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, lomazenil, benzodiazepines, benzamide, dexamethasone, gemcitabine, and palmitoylethanolamide.When administered in combination, the compounds and compositions of this disclosure as described herein, as well as secondary therapeutic agents, may be formulated as separate compositions administered simultaneously or sequentially, or the therapeutic agents may be administered as a single composition. In certain embodiments, the secondary therapeutic agent may be administered at half of its established maximum inhibitory concentration (IC). 50 It may be administered in amounts below the inhibitory concentration (IC). For example, a second-line treatment drug may be administered at an inhibitory concentration (IC). 50 It may be administered in amounts less than 1% of the total, for example, less than 10%, or less than 25%, or less than 50%, or less than 75%, or even less than 90%.

[0056] Prodrug In some embodiments, the compounds described herein may be prodrugs themselves or may be further modified to provide prodrugs.

[0057] The prodrugs according to this disclosure may be manufactured by replacing appropriate functional groups present in the compounds disclosed herein, such as in the embodiments described with reference to formulas (I) and (Ia) to (If), and in any of the above embodiments 1 to 720, with certain parts known to those skilled in the art as "pro-moies," as described in Design of Prodrugs by H. Bundgaard (Elsevier, 1985) and YMChoi-Sledeski and CGWermuth, Designing Prodrugs and Bioprecursors in Practice of Medicinal Chemistry, (Fourth Edition), Chapter 28, 657-696 (Elsevier, 2015).

[0058] In exemplary embodiments, the prodrugs according to the Disclosure are (a) ester or amide derivatives of carboxylic acids in the compounds disclosed herein, (b) ester, carbonate, carbamate, acetal, aminal, phosphate, or ether derivatives of hydroxyl groups in the compounds disclosed herein, (c) amide, imine, carbamate, or amine derivatives of amino groups in the compounds disclosed herein, (d) oxime or imine derivatives of carbonyl groups in the compounds disclosed herein, or (e) methyl, primary alcohol, or aldehyde groups that can be metabolically oxidized to carboxylic acids in the compounds disclosed herein.

[0059] For example, certain compounds of the present disclosure, such as those described in the embodiments with reference to formula (I) and (Ia) to (If) and any of the embodiments 1 to 720 above, may act as prodrugs themselves. In one embodiment, for example, compounds of the present disclosure, such as those described in the embodiments with reference to formula (I) and (Ia) to (If) and any of the embodiments 1 to 720 above, may act as prodrugs of cannabinoids, such as natural cannabinoids (e.g., CBD or CBDA).

[0060] References to compounds disclosed herein are deemed to include the compounds themselves and their prodrugs. This 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.

[0061] In some embodiments, the prodrug compounds of this disclosure may exhibit improved pharmacokinetics (PK), improved biodistribution, and / or improved formulation capabilities (e.g., stability in formulation). For example, in one embodiment, these characteristics may be improved compared to natural cannabinoids (e.g., CBD or CBDA).

[0062] In some embodiments, the prodrug compounds of this disclosure may exhibit unique or improved biological activity. For example, in one embodiment, these characteristics may be unique to or improved upon those of natural cannabinoids (e.g., CBD or CBDA).

[0063] Pharmaceutical compositions and dosage forms The compounds described herein can be usefully provided in the form of pharmaceutical compositions. Such compositions may contain, together with pharmaceutically acceptable excipients, diluents, or carriers, the compounds described in any one of the aforementioned embodiments or models described herein.

[0064] As described above, the compounds can be formulated in the form of the pharmaceutical composition itself, 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, but salts with lower solubility than the corresponding free acids and bases may also be formed.

[0065] Pharmaceutical compositions may be in the form of, for example, tablets, capsules, or parenteral formulations, but those skilled in the art will understand that compounds can be provided in a wide variety of pharmaceutical compositions.

[0066] The compounds of this disclosure may be administered orally, topically, parenterally, by inhalation or spray, or rectally, in a dosage unit formulation containing, for example, one or more pharmaceutically acceptable carriers, diluents, or excipients. As used herein, the term parenterally includes transdermal, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques. Pharmaceuticals containing the compounds of this disclosure may be provided, for example, in any of the formulations and dosage forms described herein.

[0067] Pharmaceutical compositions can be prepared using the compounds of this disclosure. For example, in one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent or excipient, and one of the compounds described above, with reference to a structural formula.

[0068] In the pharmaceutical compositions disclosed herein, one or more of the compounds of this disclosure may exist in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, optionally, other active ingredients. Pharmaceutical compositions containing the compounds of this disclosure may be in a form suitable for oral use, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, rigid or flexible capsules, or as syrups or elixirs.

[0069] Compositions intended for oral use may be prepared according to any suitable method for manufacturing 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 an active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants, e.g., corn starch or alginic acid; binders, e.g., starch, gelatin, or acacia; and smoothing agents, e.g., magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques. In some cases, such coatings may be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained activity over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0070] 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.

[0071] Formulations for oral use can also be presented as lozenges.

[0072] Formulations for oral use may also be presented as beverages or foods. For example, in one embodiment, the compounds of the present disclosure may be presented in a water-soluble formulation, such as that disclosed in PCT / CA2019 / 051698, comprising an emulsifier and a glycerin-based carrier surfactant. In other embodiments, the compounds of the present disclosure may be presented in a composition, such as that disclosed in PCT / CA2019 / 051704, comprising inulin and pectin.

[0073] The aqueous suspension contains the active substance in a mixture with excipients suitable for the preparation of the aqueous suspension. Such excipients may be suspending agents, such as dispersants or wetting agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol, such as heptadecaethyleneoxycetanol, or polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitol monooleate. The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoic acid, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0074] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings may be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0075] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients in mixtures of dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and colorants, may also be present.

[0076] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring rubbers, e.g., acacia rubber or tragacanth rubber; naturally occurring phosphatides, e.g., soybean, lecithin; and esters or partial esters derived from fatty acids and hexitol; anhydrides, e.g., sorbitan monooleate; and condensation products of the above partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0077] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, water constitutes less than 50% of the composition. In some embodiments, compositions containing less than 50% water have at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content is present in trace amounts in the composition.

[0078] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, alcohol constitutes less than 50% of the composition. In some embodiments, compositions containing 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.

[0079] Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations may also contain mitigating agents, preservatives, flavoring agents, and coloring agents. Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. These suspensions can be formulated according to known techniques using the preferred dispersants or wetting agents and suspending agents described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, generally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixative oils can be used as solvents or suspension media. For this purpose, any smooth fixative oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are useful in the preparation of injectable preparations.

[0080] The compounds of this disclosure can also be administered, for example, in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the compounds with suitable non-irritating excipients that are solid at normal temperatures but liquid at rectal temperature, and thus melt in the rectum to release the drug. Examples of such materials include cocoa butter and polyethylene glycol.

[0081] The compounds of this disclosure can also be administered parenterally in sterile culture media. Depending on the vehicle and concentration used, the drugs may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives, and buffers may be dissolved in the vehicle.

[0082] The composition can be formulated in unit dosage forms of the active ingredient. The term "unit dosage form" refers to physically distinct units as suitable doses for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in conjunction with suitable pharmaceutical excipients.

[0083] Compounds may be effective across a wide dose range and are generally administered in therapeutically effective doses. However, it should be understood that the actual amount of compound administered is usually determined by the physician, depending on the relevant circumstances, including the condition being treated or prevented, the chosen route of administration, the compound actually administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0084] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds described herein. When these preliminary formulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, and the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preliminary formulation is then subdivided into the above-described unit dosage forms, for example, containing 0.1 to about 500 mg of the active ingredient of the compounds described herein.

[0085] Tablets or pills can be coated or otherwise formulated to provide dosage forms that offer the advantage of sustained action. For example, a tablet or pill may consist of an inner and outer administration component, with the outer component in the form of an envelope over the inner component. The two components are separated by an enteric coating, which can resist disintegration in the stomach and allow the inner component to pass through the duodenum intact or delay its release. A variety of materials, including many high molecular weight acids and mixtures of high molecular weight acids with materials such as shellac, cetyl alcohol, and cellulose acetate, can be used for such enteric coatings or coatings.

[0086] The amount of compound or composition administered to a patient varies depending on the substance being administered, the purpose of administration (such as prevention or therapy), the patient's condition, and the method of administration. In therapeutic use, a composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially halt the symptoms of the disease and its complications. The effective dose will depend on the judgment of the attending physician, taking into account the disease condition being treated or prevented, as well as factors such as the severity of the disease, the patient's age, weight, and general health.

[0087] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or by sterile filtration. Aqueous solutions may be packaged for immediate use, or they may be lyophilized and the lyophilized preparation may be used in combination with a sterile aqueous carrier before administration. The pH of the compound preparation is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that certain use of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0088] The therapeutic dose of a compound may vary depending on, for example, the specific use in which the treatment is performed, the method of administering the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compound described herein in a pharmaceutical composition may vary depending on many factors, including the 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 dose ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dose is likely to depend on variables such as the type and degree of disease or disability progression, the overall health status of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients, and its route of administration. The effective dose can be estimated from dose-response curves derived from in vitro or animal model test systems.

[0089] The compounds described herein may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent such as antiviral agents, vaccines, antibodies, immunoenhancing agents, immunosuppressants, and anti-inflammatory agents.

[0090] Those skilled in the art can formulate the compounds described herein into pharmaceutical preparations, for example, based on the physicochemical properties of the compounds, the amount of compound required for a therapeutically effective dose, and the desired route of administration.

[0091] definition The terms used herein may be preceded and / or followed by a single dash "-" or a double dash "=" to indicate the bonding order between a 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 spiro substituents. 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 furthermore, substituents are intended to be read "left to right" with respect to the referenced chemical structure unless otherwise indicated by a dash. For example, arylalkyl, arylalkyl-, and -alkylaryl represent the same functional group.

[0092] For brevity, the chemical moieties are defined and referred to throughout primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terminology is also used to convey the corresponding multivalent moieties under appropriate structural circumstances that are obvious to those skilled in the art. For example, the "alkyl" moiety may refer to a monovalent radical (e.g., CH3-CH2-), but in some situations a divalent linkage moiety may be "alkyl," in which case those skilled in the art will understand alkyl to be a divalent radical (e.g., -CH2-CH2-) equivalent to the term "alkylene." (Similarly, in situations where a divalent moiety is required and it is stated that it is "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene). It is understood that all atoms have their usual valence numbers 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 this disclosure may be hypervalent, e.g., N-oxide or tetrasubstituted ammonium salts. In some cases, the part may be, for example, -B-(A) a It may also be defined as such, where a is either 0 or 1. In this case, if a is 0, the part is -B, and if a is 1, the part is -BA.

[0093] As used herein, the term “alkyl” includes saturated hydrocarbons having 1 to 10 carbon atoms (i.e., including 1 and 10), 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 3 carbon atoms, or a specified number of carbon atoms, such as 1, 2, 3, 4, 5, or 6. Alkyl groups can be linear or branched and, depending on the context, monovalent or divalent radicals (i.e., alkylene groups). For example, the “-(C1-C6 alkyl)-O-” part means the bonding of oxygen via an alkylene bridge having 1 to 6 carbon atoms, and C1-C3 alkyl represents the methyl, ethyl, and propyl parts. Examples of “alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, and hexyl.

[0094] The term "alkoxy" refers to an alkyl group, such as alkyl-O-, which has the previously given definition of "alkyl," where the number of carbon atoms is bonded to the parent molecule via an oxygen crosslink. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0095] The term "alkenyl," as used herein, refers to an unsaturated hydrocarbon having a specified number of carbon atoms, such as 2 to 10 carbon atoms (i.e., including 2 and 10), 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, or 6 carbon atoms, unless otherwise specified, and containing at least one carbon-carbon double bond. The alkenyl group may be linear or branched and, depending on the context, may be a monovalent or divalent radical (i.e., an alkenylene group). For example, the "-(C2-C6 alkenyl)-O-" part means an oxygen bond via an alkenylene bridge having 2 to 6 carbon atoms. Typical examples of alkenyls 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.

[0096] As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon having a specified number of carbon atoms, such as 2 to 10 carbon atoms (i.e., including 2 and 10), 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, or 6 carbon atoms, unless otherwise specified, and containing at least one carbon-carbon triple bond. The alkynyl group may be linear or branched and, depending on the context, may be a monovalent or divalent radical (i.e., an alkynylene group). For example, the "-(C2-C6 alkynyl)-O-" part means an oxygen bond via an alkenylene bridge having 2 to 6 carbon atoms. Typical examples of alkynyls include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0097] The term "aryl" refers to an aromatic ring system having a monocycle (e.g., phenyl) that is optionally condensed to another aromatic hydrocarbon ring, a non-aromatic hydrocarbon ring, or a 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 condensed to a non-aromatic heterocycle, such as 1H-2,3-dihydrobenzofuranyl and tetrahydroisoquinolinyl. Wherever an aryl group in this specification is designated as unsubstituted or "optionally substituted," it may be substituted with a variety of groups at one or more substituted positions, as shown, unless otherwise specified.

[0098] The terms “halogen” or “halo” refer to fluorine, chlorine, bromine, and iodine. In certain embodiments of each and all embodiments described herein as otherwise, the terms “halogen” or “halo” refer to fluorine or chlorine. In certain embodiments of each and all embodiments described herein as otherwise, the terms “halogen” or “halo” refer to fluorine. The term “fluoroalkyl” refers to an alkyl group substituted with at least one fluorine (i.e., as described herein as otherwise). “Fluoroalkyl” includes alkyl groups substituted with multiple fluorine atoms, such as perfluoroalkyl groups. Examples of fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl-2-yl, and 2,2,3,3,3-pentafluoropropyl-1-yl.

[0099] 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, a heteroaryl group has one, two, three, or four heteroatoms. A heteroaryl can be condensed with one or more non-aromatic rings, such as a cycloalkyl or heterocycloalkyl ring, which are described herein. In one embodiment of the compounds of the present invention, the heteroaryl group is bonded to the rest of the structure via atoms in the heteroaryl group aromatic ring. In another embodiment, the heteroaryl group is bonded to the rest of the structure via non-aromatic ring atoms.Examples of heteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridadinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolidinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, and oxadiazo. Lil, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthilidinyl, isochromanil, chromanil, isoindolinyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, prinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidoazothiazolyl, benzisoxazinyl, benzoxazinyl, benzopyranil, benzothiopyranil, chloro Monyl, Chromanonyl, Pyridinyl-N-oxide, Isoindlinonyl, Benzodioxanil, 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 Examples include isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolidinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranil S-oxide, and benzothiopyranil S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, and imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl.In a particular embodiment, 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. Where a heteroaryl group is designated as unsubstituted or "optionally substituted" as herein, it may be substituted with a variety of groups at one or more substituted positions, as shown, unless otherwise specified.

[0100] The term "heterocycloalkyl" refers to a non-aromatic ring or ring system containing at least one heteroatom preferably selected from nitrogen, oxygen, and sulfur, wherein the heteroatom is located within the non-aromatic ring. Heterocycloalkyls may have 1, 2, 3, or 4 heteroatoms. Heterocycloalkyls may be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). Heterocycloalkyls include monocyclic groups with 3 to 8 ring-constituent atoms, as well as bicyclic and polycyclic ring systems including bridging and fusion systems, where each ring contains 3 to 8 ring-constituent atoms. Heterocycloalkyl rings are optionally condensed with other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings. In certain embodiments, heterocycloalkyls have 3 to 7 members in the monocyclic ring. In other embodiments, heterocycloalkyls have 5 or 6 members in the monocyclic ring. In some embodiments, heterocycloalkyls have 3, 4, 5, 6, or 7 members in the monocyclic ring. Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (in each case also being "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, azepanil, azetidinyl, pyrrolidinyl, tetrahydropyranil, piperidinyl, tetrahydrofuranil, Examples include, but are not limited to, tetrahydrothienyl, 3,4-dihydroisoquinoline-2(1H)-yl, isoindolidionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyradinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide.Particularly desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinoline-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, isoindolidionyl, and piperazinonyl. When heterocycloalkyl groups in this specification are unsubstituted or "optionally substituted," they may be substituted with a variety of groups at one or more substituted positions, as shown, unless otherwise specified.

[0101] The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ring system that may be saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl). Cycloalkyl rings may optionally condense with other cycloalkyl rings or otherwise bond to other cycloalkyl rings (e.g., crosslinking systems). Certain examples of cycloalkyl groups in this disclosure have 3 to 7 members in a monoring, for example, 5 or 6 members in a monoring. In some embodiments, cycloalkyl groups have 3, 4, 5, 6 or 7 members in a monoring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl, and bicyclo[2.2.1]heptane. Cycloalkyl groups in this specification may be unsubstituted or, where specified as “optionally substituted,” may be substituted with a variety of groups at one or more substituted positions as shown.

[0102] The term "ring system" includes monocyclic rings as well as fused and / or bridged polycyclic rings.

[0103] The term "amino" can refer to a primary amino group, a secondary amino group, or a tertiary amino group, depending on the context.

[0104] The term "carbonyl" refers to the -C(O)- group.

[0105] The terms "hydroxy" and "hydroxyl" refer to the -OH group.

[0106] The term "oxo" refers to a double-bonded oxygen atom and may be designated as =O, or it may be used to indicate an oxo-substituted carbon, for example, when describing a carbonyl "C(O)".

[0107] The term "oxy" refers to the -O- group.

[0108] The term "sulfonyl" refers to the -SO2- group.

[0109] When used to modify a particular group or radical, the term "substituted" means, unless otherwise specified, that one or more hydrogen atoms of that particular group or radical are substituted independently of each other by the same or different substituents as defined below.

[0110] As used herein, the term “metabolite” means a compound resulting from the metabolism of a compound of the Disclosure, including the embodiments described with reference to formulas (I) and (Ia) to (If), and any of the embodiments described above (1 to 720). In one embodiment, the metabolite is an active metabolite, meaning a physiologically active compound. In one embodiment, the metabolite is an active compound obtained from the metabolism of a prodrug described herein.

[0111] The term "pharmaceutically acceptable" generally refers to a compound, substance, or composition that is safe, non-toxic, and bioacceptable.

[0112] As used herein, the term “pharmaceutically acceptable salt” refers to both pharmaceutically acceptable acids and base addition salts. Such pharmaceutically acceptable salts include, but are not limited to, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanic acids such as acetic acid, and HOOC-(CH2) with n = 0-4. n This includes salts such as -COOH. Non-toxic pharmaceutically acceptable base addition salts include, but are not limited to, salts of bases such as sodium, potassium, calcium, and ammonium. Those skilled in the art will recognize a wide variety of non-toxic, pharmaceutically acceptable addition salts.

[0113] Those skilled in the art of medicinal chemistry will also understand that the disclosed structures are intended to include isotopic enriched forms of the compounds of the present invention. As used herein, “isotope” includes atoms having 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 has three isotopic forms: protium, deuterium, and tritium. As will be obvious to those skilled in the art when considering the compounds of the present invention, certain compounds can enrich a particular isotope of an atom at a given position. For example, a compound having a fluorine atom can enrich radioactive fluorine isotopes. 18 It can be synthesized in a form enriched with F. Similarly, the compound may be enriched with the heavier isotopes of hydrogen, deuterium and tritium, and similarly, 13 These compounds can be enriched with radioactive isotopes of carbon, such as 13C. Such isotopic variant compounds undergo different metabolic pathways and may be useful in studying, for example, the ubiquitination pathway and its role in disease. Of course, in certain embodiments, the compounds have substantially the same isotopic properties as naturally occurring materials.

[0114] The compounds of this disclosure may contain chiral centers that may be either (R) or (S) in structure, or mixtures thereof. Accordingly, the present invention also includes, where applicable, stereoisomers of the compounds described herein, either individually or in any proportion. Stereoiomers 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 enantiomer starting materials or by separating isomers of the compounds of the present invention.

[0115] Isomers may further include tautomers and geometric isomers. Examples of geometric isomers include, but are not limited to, cis or trans isomers across double bonds. Other isomers are intended within the compounds of this disclosure. Isomers may be used either in their pure form or in mixtures with other isomers of the compounds disclosed herein.

[0116] Those skilled in the chemical art will also understand that, unless otherwise indicated, the disclosed structures are intended to include all possible stereoisomers of the claimed molecule, including mixtures of certain or all stereoisomers. However, compounds depicted with a particular stereochemistry at one or more stereocenters indicate the compound in that particular embodiment having the indicated stereochemistry. Compounds and stereocenters depicted with ambiguous stereochemistry imply the transmission of any stereoisomer or mixture thereof, e.g., a racemic mixture of the compound or a purified subset of stereoisomers. In some embodiments, the compounds of this disclosure may have a natural THC-type stereochemistry, as shown below: [ka]

[0117] As used herein, the terms “individual,” “patient,” or “subject” refer to any animal, including mammals, preferably humans, where used interchangeably.

[0118] As used herein, the terms “therapeutic dose” or “effective dose” refer to the amount of an active compound or pharmaceutical agent that elicits a desired biological or pharmaceutical response in a cell, tissue, system, animal, individual, or human being, as determined by a researcher, veterinarian, physician, or other clinician.

[0119] In a particular embodiment, the effective amount is (i) Inhibiting the progression of the disease, (ii) Preventive use, for example, in individuals who are susceptible to a disease, condition or disorder, or otherwise at risk of such disease, condition or disorder, but who have not yet experienced or shown the pathology or overall symptoms of the disease, (iii) inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or total symptoms of a disease, condition or disorder. (iv) Improving the disease, condition or disorder in an individual experiencing or exhibiting the pathology or overall symptoms of the disease, condition or disorder, such as reducing the severity of the disease, or (v) to induce the biological effect being referenced, and which may be a suitable amount for that purpose.

[0120] As used herein, the terms “treatment” and “to treat” mean (i) improving the disease, condition or disorder (or its symptoms) referred to, for example, reducing the severity of the disease or its symptoms, in an individual experiencing or exhibiting the pathological or total symptoms of the disease, condition or disorder (i.e., restoring or improving the pathology and / or total symptoms), or (ii) inducing the biological effect referred to, for example, inducing apoptosis or inhibiting glutathione synthesis.

[0121] As used herein, the terms “prevention” or “prevention” mean to completely or partially eliminate or delay the onset of the disease, condition, or disorder (or its symptoms) in the subject matter of the referenced disease, condition, or disorder.

[0122] Preparation method Numerous common references are available that provide generally known chemosynthetic 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).

[0123] 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, including conventional phase, reversed phase, and ionic resins, can be used. Most typically, the disclosed compounds are purified via silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. LRSnyder and JJ Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed. E. Stahl, Springer-Verlag, New York, 1969. In further embodiments, the compounds may be purified by preparative HPLC.

[0124] During any of the processes for preparing the target compound, it may be necessary and / or desirable to protect any sensitive or reactive groups of the relevant molecules. 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 described in standards 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.

[0125] As used herein, “leaving group” (preferably LG, for example) refers to a portion of a reactant (e.g., an alkylhalide of this disclosure) that is substituted from the first reactant in a chemical reaction. A comprehensive and non-limiting list of preferred leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, NY (2013). Examples of preferred leaving groups include, but are not limited to, halogens (such as Cl or Br), acetoxy, and sulfonyloxy groups (such as methylsulfonyloxy, trifluoromethylsulfonyloxy ("triflate"), and p-toluenesulfonyloxy ("tosylate")).

[0126] The compounds disclosed herein can be prepared using procedures well known to those skilled in the art, for example, as described in Schemes 1-5 and 6a-6c. Those skilled in the art can adapt the reaction sequences of the schemes and examples provided herein to a 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 the substituents. Furthermore, those skilled in the art will recognize that the compounds of this disclosure can be synthesized entirely using different routes. For example, those skilled in the art can prepare the compounds described herein by adapting the procedures described herein and / or other procedures well known to those skilled in the art. [ka] In the formula, R 1 , R 2 , R 3 , and R 4 The compound is defined in formula (I), where X is a halogen and -BY2 is an organoboron (e.g., -BH2, -B(OH)2, -B(OCH3)2, pinacoryl-B-, etc.). [ka] In the formula, R 8 This is defined in equation (I). [ka] In the formula, R 8 This is defined in equation (I). [ka] [ka] In the formula, R 8 This is defined in equation (I). [ka] [ka] [ka] [Examples]

[0127] 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 this disclosure in scope or spirit to the specific procedures and compounds described therein. These examples are provided to illustrate the invention.

[0128] Compound synthesis and formulation Example 1: Preparation of 2-bromo-6,6,9-trimethyl-2-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol [ka] To a solution of tetrahydrocannabinol (THC, 1.24 g, 3.94 mmol) in dichloromethane (DCM, 10 mL), N-bromosuccinimide (NBS, 631.65 mg, 3.55 mmol) in DCM (19.7 mL) and methanol (MeOH, 2 mL) was added dropwise over 10 minutes at 0°C. The resulting mixture was stirred at 0°C for 3 hours. The mixture was quenched with an aqueous solution of saturated sodium thiosulfate pentahydrate (Na2S2O3·5H2O) and extracted with DCM. The organic extract was dried over Na2SO4, filtered, and concentrated. The crude sample was purified by flash column chromatography using a hexane and DCM gradient to obtain (6aR,10aR)-2-bromo-6,6,9-trimethyl-2-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol as a dark brown oil (59% yield). 1 H NMR(400MHz,chloroform-d)δ6.38(s,2H),5.91(s,1H),3.29(d,J=10.9Hz,1H),2.73-2.55(m,2H),2.23-2.14(m,2H),1.97- 1.90(m,1H),1.75-1.67(m,5H),1.67-1.53(m,3H),1.45(s,5H),1.38(d,J=7.3Hz,5H),1.11(s,4H),0.98-0.87(m,4H). ESI-MS[M+H] + :394.80.

[0129] Example 2: 6,6,9-trimethyl-3-pentyl-2-(pyridine-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(12b) [ka] 3-Pyridylboronic acid (249.99 mg, 2.03 mmol), palladium(0)tetrakis(triphenylphosphine) (58.75 mg, 50.84 μmol), and potassium phosphate (431.70 mg, 2.03 mmol) were packed into microwave vials (2-5 mL) equipped with a stirring bar and purged with argon. (6aR,10aR)-2-bromo-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (200 mg, 508.44 μmol) was added as a solution in dioxane (3 mL), followed by the addition of water (1 mL). The container was sealed and then microwaved at 180 °C for 3 minutes. The mixture was diluted with ethyl acetate and washed with brine (once), water:brine (1:1, twice), and brine (once). The organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The crude sample was purified by flash column chromatography eluting with ethyl acetate and hexane. The product containing the fraction was concentrated under vacuum and then further purified by preparative HPLC (ACN / H2O / 0.1%FA). Lyophilization yielded the desired product (19 mg, 10%) as a white solid. 1 H NMR(d6-DMSO,400MHz)δ8.53-8.47(m,1H),8.34(brs,1H),8.11(brs,1H),7.61-7. 56(m,1H),7.44-7.38(m,1H),6.26-6.18(m,2H),3.26-3.18(m,1H),2.19-2.13(m, 2H),2.13-2.06(m,2H),1.93-1.85(1.94-1.85(m,1H),1.61(s,3H),1.57-1.48(m, 1H), 1.40-1.30 (m, 4H), 1.30-1.20 (m, 2H), 1.12-0.98 (m, 7H), 0.72 (t, J=8Hz, 3H).

[0130] Example 3: 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(17b) [ka] Potassium phosphate (161.89 mg, 762.66 μmol), palladium(0)tetrakis(triphenylphosphine) (44.06 mg, 38.13 μmol), and 3-thienylboronic acid (97.59 mg, 762.66 μmol) were packed into microwave vials (2-5 mL) equipped with a stirring bar and purged with argon. (6aR,10aR)-2-bromo-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (150 mg, 381.33 μmol) was added as a solution in dioxane (3 mL), followed by the addition of water (1 mL). The containers were capped and then microwaved at 180 °C for 3 minutes. The mixture was diluted with ethyl acetate and washed with brine (once), brine:water (1:1, twice), and brine (once). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude sample was purified by flash column chromatography on silica gel eluted with a DCM and hexane gradient. (6aR,10aR)-6,6,9-trimethyl-3-pentyl-2-(3-thienyl)-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (49 mg, 123.56 μmol, 32.40% yield) was isolated as a waxy solid.

[0131] 1 H NMR(d6-DMSO,400MHz)δ7.62(brs,1H),7.58-7.54(m,1H),7.30-7.38(m,1H),6.9 7-6.94(m,1H),6.28-6.23(m,1H),6.18(s,1H),3.22-3.14(m,1H),2.27-2.15(m,2 H),2.14-2.06(m,2H),1.93-1.84(m,1H),1.61(s,3H),1.55-1.47(m,1H),1.39-1. 31(m,4H),1.31-1.23(m,2H),1.17-1.05(m,4H),1.02(s,3H),0.76(t,J=6Hz,3H).

[0132] Example 4: 6,6,9-trimethyl-3-pentyl-2-(pyrimidine-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol)(13b) [ka] To a solution of (6aR,10aR)-2-bromo-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (100 mg, 0.254 mmol) in dioxane (2 mL) and ethanol (1 mL), palladium(0)tetrakis(triphenylphosphine) (Pd(PPh3)4, 15 mg, 0.013 mmol), pyrimidine-5-ylboronic acid (41 mg, 0.331 mmol), and cesium carbonate (Cs2CO3, 248 mg, 0.762 mmol) were added. The mixture was degassed with argon and stirred in a sealed microwave vial at 130°C under microwave conditions for 6 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, and concentrated. The crude mixture was isolated by reverse-phase column chromatography eluted with acetonitrile water to obtain 5'-methyl-4-pentyl-2'-(propa-1-en-2-yl)-3-(pyrimidine-5-yl)-1',2',3',4'-tetrahydro-[1,1'biphenyl]-2,6-diol as a white solid (5% yield). 1 H NMR (400MHz, CDCl3): δ(ppm)9.26(s,1H),8.73(s,2H),6.46(s,1H),6.19(s,1H),4.64(s,1H),3.24(bd,1H),2.32-2.14(m,5H),2.06 -1.94(m,1H),1.80-1.67(m,3H),1.54-1.44(m,3H),1.43-1.32(m,3H),1.31-1.24(m,1H),1.22-1.11(s,7H),0.81(t,J=7.0Hz,3H). ESI-MS[M+H] + = 392.9.

[0133] Example 5: 6,6,9-trimethyl-3-pentyl-2-(pyridine-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(14b) [ka] Following the procedure of Example 4, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-2-(pyridine-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (2.6% yield) was obtained using pyridine-4-ylboronic acid. 1 H NMR (400MHz, CDCl3): δ(ppm)8.77(s,2H),7.32(s,2H),6.42(s,1H),6.31(s,1H),3.26(d,J=10.9Hz,1H),2.32-2.14(m ,4H),2.03(s,1H),2.01-1.90(m,2H),1.84-1.53(m,6H),1.53-1.26(m,3H),1.23-1.09(m,7H),0.81(t,J=6.8Hz,3H). ESI-MS[M+H] + = 391.9.

[0134] Example 6: 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(15b) [ka] To a solution of (6aR,10aR)-2-bromo-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (170 mg, 0.432 mmol) in dioxane (2.16 mL) and water (0.17 mL), palladium(0)tetrakis(triphenylphosphine) (Pd(PPh3)4, 49.94 mg, 0.043 mmol), 2-furylboronic acid (193.43 mg, 1.73 mmol), and tribasic potassium phosphate (K3PO4, 366.95 mg, 1.73 mmol) were added. The mixture was degassed with argon and stirred in a sealed microwave vial at 180°C under microwave conditions for 5 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, and concentrated. The crude mixture was isolated by reverse-phase column chromatography eluted with acetonitrile water to obtain (6aR,10aR)-2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (4% yield). 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.70(s,1H),6.54(dd,J=3.0,1.9Hz,1H),6.3 6(d,J=3.2Hz,1H),6.25(s,1H),6.20(s,1H),3.20(d,J=10.4Hz,1H),2.33-2.22(m, 3H),2.11(s,2H),1.90(d,J=11.6Hz,1H),1.63(s,3H),1.52(t,J=11.2Hz,2H),1.3 7(s,3H),1.34-1.26(m,3H),1.20-1.11(m,5H),1.04(s,3H),0.80(t,J=7.0Hz,3H). ESI-MS[M+H] + :381.00.

[0135] Example 7: Trimethyl-3-pentyl-2-thiazole-5-yl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol(18b) [ka] Following the procedure of Example 6, (6aR)-6,6,9-trimethyl-3-pentyl-2-thiazole-5-yl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (9.5% yield) was obtained using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole. 1 H NMR(400MHz,chloroform-d)δ9.04(s,1H),7.82(s,1H),6.41(s,1H),6.38-6.35 (m,1H),3.27(d,J=11.0Hz,1H),2.34-2.28(m,2H),2.19(d,J=7.4Hz,2H),2 .03(s,2H),1.94(d,J=5.1Hz,1H),1.75(s,1H),1.70(s,3H),1.47(s,4H),1 .46-1.39(m,3H),1.21(d,J=3.2Hz,4H),1.16(s,4H),0.84(t,J=6.9Hz,3H).

[0136] Example 8: 6,6,9-trimethyl-2-(1-methyl-1H-pyrazole-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(33b) [ka] A solution of (6aR)-2-bromo-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (80 mg, 0.3 mmol) in dioxane (1.5 mL) contains palladium(II) acetate (Pd(OAc)2, 4.57 mg, 0.020 mmol), (2-methylpyrazole-3-yl)boronic acid (102.44 mg, 813.51 mmol), and tert-butoxide sodium (NaO2). tBu (58.64 mg, 0.610 mmol) and 3-(t-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (rac BI-DIME, 13.44 mg, 0.040 mmol) were added. The mixture was degassed with argon and stirred in a sealed microwave vial at 180°C under microwave conditions for 6 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, and concentrated. The crude mixture was isolated by reverse-phase column chromatography eluting with hexane and ethyl acetate, and subsequently obtained (6aR,10aR)-6,6,9-trimethyl-2-(1-methyl-1H-pyrazole-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol as a white solid by HPLC eluting with acetonitrile and water (4.5% yield). 1 H NMR(400MHz,CDCl3):δ(ppm)7.71(s,1H),6.42(s,1H),6.38(s,1H),6.32( s,1H),3.71-3.65(bd,3H),3.27(d,J=10.9Hz,1H),2.36-2.27(m,1H),2.2 2-2.03(m,4H),2.00-1.92(m,2H),1.81-1.72(s,3H),1.50-1.45(m,3H),1 .46-1.37(m,3H),1.31-1.19(m,4H),1.18-1.12(m,4H),0.87-0.81(m,3H). ESI-MS[M+H] + =394.9.

[0137] Example 9: 2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(34b) [ka] Following the procedure of Example 6, (6aR,10aR)-2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (22% yield) was obtained using benzofuran-2-ylboronic acid. 1 H NMR(400MHz,CD3CN):δ(ppm)7.70(d,J=7.6Hz,1H),7.57(d,J=8.1Hz,1H),7.39-7.27(m,2H),6.90(s,1H),6.61(s,1H),6.34-6.39(m,2H),3.2 8-3.20(m,1H),2.54-2.36(m,2H),1.73-1.63(m,4H),1.52-1.35(m,6H) ,1.34-1.25(m,1H),1.26-1.13(m,4H),1.11(s,3H),0.80-0.75(m,3H). ESI-MS[M+H] + = 431.0.

[0138] Example 10: 6,6,9-trimethyl-3-pentyl-2-(1H-pyrazole-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(35b) [ka] Following the procedure of Example 6, (1H-pyrazole-4-yl)boronic acid was used to obtain (6aR,10aR)-6,6,9-trimethyl-3-pentyl-2-(1H-pyrazole-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (7.2% yield). 1 H NMR (400MHz, CDCl3): δ7.65(s,2H),6.41-6.37(m,2H),3.30-3.22(m,1H),2.34-2.27(m,3H),2.22-2.14(m,4H), 1.98-1.91(m,3H),1.78-1.70(m,1H),1.49-1.37(m,6H),1.26-1.17(m,4H),1.15(s,3H),0.83(t,J=6.9Hz,3H). ESI-MS[M+H] + = 381.0.

[0139] Example 11: 2-(benzothiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol(36b) [ka] Following the procedure of Example 6, (6aR,10aR)-2-(benzothiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (14% yield) was obtained using benzo[b]thiophene-2-ylboronic acid. 1 H NMR (400MHz, chloroform-d) δ7.91(d,J=7.5Hz,1H),7.85(d,J=7.9Hz,1H),7.45-7.40( m,2H),7.27(s,1H),6.41(s,2H),5.44(s,1H),3.29(d,J=9.9Hz,2H),2.51-2.40(m ,3H),2.19(d,J=6.9Hz,3H),1.95(d,J=11.7Hz,2H),1.76(s,2H),1.69(s,4H),1.5 6(s,15H),1.47(s,4H),1.21(d,J=3.5Hz,6H),1.18(s,3H),0.81(t,J=6.8Hz,4H). ESI-MS[M+H] + :447.10.

[0140] Example 12: 6,6,9-trimethyl-2-(4-methyl-2-thienyl)-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol(37b) [ka] Following the procedure of Example 6, (6aR,10aR)-6,6,9-trimethyl-2-(4-methyl-2-thienyl)-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (14% yield) was obtained using (4-methylthiophen-2-yl)boronic acid. 1 H NMR (400MHz, chloroform-d) δ7.08-7.06(m,1H),6.82(d,J=1.6Hz,1H),6.43-6.39(m ,1H),6.37(s,1H),5.43(s,1H),3.27(d,J=11.1Hz,1H),2.39(td,J=7.7,4.5Hz, 2H),2.34(d,J=1.2Hz,3H),2.18(s,2H),1.94(d,J=3.3Hz,1H),1.78-1.70(m,1H ),1.69(s,3H),1.46(s,7H),1.29-1.19(m,5H),1.16(s,3H),0.90-0.80(m,3H). ESI-MS[M+H] + :411.00.

[0141] Example 13: The following compounds can be prepared according to procedures known to those skilled in the art, taking into consideration schemes 1-5, schemes 6a-6c, and examples 1-12.

number

[0142] Radioactive ligand competitive binding assays - CB1 and CB2 Example 14: The compounds disclosed herein were tested for CB1 receptor binding affinity and CB2 receptor binding affinity. As used herein, “binding affinity” refers to the experimentally determined IC as described herein. 50 Represented by a value. IC 50 A lower value indicates higher binding affinity. A compound of this disclosure can be said to have "binding selectivity" if it has a higher binding affinity to one receptor than to the other. For example, 1 μM IC for CB1 and 0.1 μM IC for CB2 50 Compounds containing this compound exhibit 10-fold selectivity for the CB2 receptor.

[0143] Preparation of CB1 film Membranes were prepared from CHO-K1 (Chinese hamster ovary) cells stably transfected with human CB1 receptor (catalog number ES-110-C, Perkin Elmer, Boston, MA). The cells were grown adherently and maintained in HAM F12 medium containing 10% fetal bovine serum (FBS), penicillin, streptomycin, and geneticin (G418) at 37°C in a humid atmosphere of 5% CO2, according to the manufacturer's instructions.

[0144] For membrane preparation, cells were washed with PBS, and the plate was scraped in a low-temperature homogenization buffer containing a protease inhibitor cocktail (25 mM HEPES (pH 7.4), 2 mM EDTA) (Sigma catalog number 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, the pellet was resuspended in the homogenization buffer, and stored at -80°C until use.

[0145] CB1 radioactive ligand binding assay: CP55,940 is a synthetic cannabinoid that mimics the effects of naturally occurring THC. CP55,940 acts as a full agonist on both cannabinoid CB1 and CB2 receptors. Radiolabeled ligands represent one of the most sensitive methods for probing receptor binding biology. In this experiment, 3H radiolabeled CP55,940, i.e., [3H]CP55,940 (Perkin Elmer, Boston, MA), was used as a radioligand for the CB1 receptor.

[0146] The binding affinity of the compounds to the CB1 receptor was determined using the [3H]CP55,940 substitution assay (Scheme 7, below). [ka]

[0147] Competitive coupling experiments (single dose and dose-response) were conducted by incubating 0.8 nM [3H]CP55,940 (specific activity 101 Ci / mmol, Perkin Elmer) and different concentrations of the compounds disclosed herein in membranes prepared as described above from CHO-K1 cells expressing human CB1 receptor (6 μg protein / well), 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 1 mM CaCl2, and 2 mg / mL BSA.

[0148] For single-dose experiments, compound stock (typically 10 mM in DMSO) was diluted in a working stock in binding buffer to obtain final compound concentrations of 10 μM and 1 μM. For dose-response experiments, the test compound was sequentially diluted to obtain IC50. 50 The desired concentration range for determination was obtained. In each case, the compound was pre-incubated in a membrane for 20 minutes, after which the radioactive ligand was added.

[0149] MultiScreen® is pre-soaked for 60 minutes in 50 mM Tris-HCl (pH 7.4) containing 0.33% polyethyleneimine (PEI) after incubation with a radioactive ligand at 37°C for 60 minutes. HTS + Incubation was terminated by rapidly filtering the assay mixture through a 96-well filter plate (Millipore, catalog number MSFCNXB). Nonspecific binding (NSB) was determined in the presence of 10 μM unlabeled CP55,940. After drying the filter plate at 50°C for at least 60 minutes, the filter-bound radioactivity was determined by scintillation spectroscopy using a 1450 MicroBeta plate counter (Perkin Elmer, Boston, MA). From dose-response experiments, IC was obtained. 50 The values ​​were determined (Table 1, CB1 IC) 50 (See reference).

[0150] Preparation of CB2 membrane Membranes were prepared from CHO-K1 (Chinese hamster ovary) cells stably transfected with human CB2 receptor (catalog number ES-111-C, Perkin Elmer, Boston, MA). The cells were grown adherently and maintained at 37°C in a humid atmosphere of 5% CO2 in HAM F12 medium containing 10% fetal bovine serum (FBS), penicillin, streptomycin, and geneticin (G418), according to the manufacturer's instructions.

[0151] For membrane preparation, cells were washed with PBS, and the plate was scraped in a low-temperature homogenization buffer containing a protease inhibitor cocktail (25 mM HEPES (pH 7.4), 2 mM EDTA) (Sigma catalog number 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, the pellet was resuspended in the homogenization buffer, and stored at -80°C until use.

[0152] CB2 Radioactive Ligand Binding Assay In this experiment, 3H-labeled CP55,940, i.e., [3H]CP55,940 (Perkin Elmer, Boston, MA), was used as a radioligan for the CB2 receptor to determine the binding affinity of the compound to the CB2 receptor (Scheme 7, above).

[0153] Competitive coupling experiments (single dose and dose-response) were conducted by incubating 0.6 nM [3H]CP55,940 (specific activity 101 Ci / mmol, Perkin Elmer) and different concentrations of the compounds disclosed herein in membranes prepared as described above from CHO-K1 cells expressing human CB2 receptor (1 μg protein / well), 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 1 mM CaCl2, and 2 mg / mL BSA.

[0154] For single-dose experiments, compound stocks (typically 10 mM in DMSO) were diluted in a working stock in binding buffer to obtain final compound concentrations of 10 μM and 1 μM. For dose-response experiments, the test compounds were sequentially diluted to obtain the desired concentration range for IC50 determination. In each case, the compounds were pre-incubated on a membrane for 20 minutes before adding the radioactive ligand.

[0155] MultiScreen® is pre-soaked for 60 minutes in 50 mM Tris-HCl (pH 7.4) containing 0.33% polyethyleneimine (PEI) after incubation with a radioactive ligand at 37°C for 60 minutes. HTS + Incubation was terminated by rapidly filtering the assay mixture through a 96-well filter plate (Millipore, catalog number MSFCNXB). Nonspecific binding (NSB) was determined in the presence of 10 μM unlabeled CP55,940. After drying the filter plate at 50°C for at least 60 minutes, the filter-bound radioactivity was determined by scintillation spectroscopy using a 1450 MicroBeta plate counter (Perkin Elmer, Boston, MA). From dose-response experiments, IC was obtained. 50The values ​​were determined (Table 1, CB2 IC) 50 (See reference).

[0156] Some of the compounds in this disclosure showed selectivity for the CB2 receptor more than for the CB1 receptor (see, for example, Table 1). Again, Table 1 below shows the fold difference in selectivity between CB1 and CB2, with the fold difference indicated in the column for the receptor that showed a higher binding affinity (i.e., CB1 or CB2). If a 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. [Table 1]

[0157] Pathhunter® β-Arrestin Functional Assay Example 15: In the Pathhunter® β-arrestin system of DiscoveRx (Eurofins, Fremont, CA), a small peptide, ProLink® (PK), is fused to the intracellular sequence of a GPCR target, and a complementary peptide, the enzyme receptor (EA) fragment, is fused to β-arrestin. After binding to its specific ligand, the GPCR target recruits β-arrestin, forcing the complementation of the two β-galactosidase enzyme fragments (EA and PK) to produce a functional β-galactosidase enzyme. Enzyme activity, and therefore the amount of ligand bound to the GPCR, is detected by a single addition of a reagent cocktail to lyse cells and generate a chemiluminescent signal, and then analyzed using a conventional plate reader.

[0158] CB1 receptor response to ligand using DiscovRx cells Pathhunter® CHO-K1 CNR1 β-arrestin cells (DiscoverRx, catalog number 93-0959C2) that stably express the CB1 receptor (CB1R) were grown in HAM F12 medium containing 10% fetal bovine serum (FBS), 1% penicillin / streptomycin, 300 μg / mL hygromycin B, and 800 μg / mL genethicin (G418), and maintained in a 37°C incubator with 5% CO2.

[0159] For the CB1R dose-response assay, cells were seeded at a density of 40,000 cells / well in a 96-well white flat-bottom plate and incubated overnight at 37°C in 5% CO2. The following day, the compound stock (10 mM in DMSO) was sequentially diluted in DMSO (11 points, 3-fold dilution) and EC was performed. 50 (Agonist mode) or IC 50 The desired concentration range for determining the antagonist mode was obtained. In agonist mode, CP55,940 (CAS number 83002-04-4) was used, while in antagonist mode, the synthetic cannabinoid limonabane (CAS number 158681-13-1) was used as the reference compound.

[0160] After aspirating the culture medium from the plate wells and washing the cells with PBS, 49.5 μL (agonist mode) or 49 μL (antagonist mode) of PBS was added to each well, followed by 0.5 μL of the test compound or CP55,940. The cells were then incubated at 37°C for 90 minutes in agonist mode. Alternatively, in antagonist mode, the cells were incubated with the test compound or limonabane for 30 minutes (37°C), followed by EC (Emission Control). 80 The sample was further incubated for 90 minutes (37°C) with 0.5 μL of 2-AG (CAS number 53847-30-6) at a concentration (determined as a final concentration of 4 μM).

[0161] Incubation was completed by adding detection reagents equivalent to 50% of the assay volume (19 parts of 1% CHAPS, 5 parts of Emerald-II, and 1 part of Galacton-Star) to each well. After incubating the plates at room temperature in the dark for 1 hour, chemiluminescence detection was performed using a microplate reader.

[0162] The data were analyzed by generating nonlinear regression curves. The agonist response was normalized to the effect of the CP55,940 reference agonist, and the antagonist response was normalized to the effect of the Limonabant.

[0163] Compounds 12b and 36b of this disclosure were tested in agonist mode and found to exhibit minimal or no activity against the human CB1 receptor. Compound 36b was tested in antagonist mode and showed relative inhibition against approximately 3.0 μM of the human CB1 receptor compared to approximately 40% rimonabant. 50 It was found that this indicates...

[0164] Further biological examples Example 16: Simulated gastric juice (SGF) assay Dilute 626.5 μL of a solution containing 1.1× assay buffer (37.6 mM NaCl, pH 1.2-1.5) in a microcentrifuge tube with 70 μL of 10× pepsin solution (Sigma-Aldrich Co. catalog number: P7012, 80,000 U / mL in milliQ water). Incubate the resulting solution in an orbital mixer at 37°C and 1,200 rpm for 5 minutes before adding 3.5 μL of the test compound (2 mM, DMSO). Incubate the sample under the same conditions as long as necessary.

[0165] At the specified time, transfer a 150 μL sample aliquot to a microcentrifuge tube containing 24 μL of acid quench solution (0.5 M NaHCO3). Vortex the tube for 5 seconds, then add 348 μL of protein precipitate solution containing an internal standard (25 μM Glybrid, ACN). Vortex the tube again for 20 seconds and store on ice.

[0166] Finally, the tube is centrifuged at 5,000 × g and 4°C for 15 minutes. The remaining percentage of the test compound compared to time 0 is quantified in the supernatant by HPLC / LC-MS or LC-MS / MS to determine the half-life.

[0167] Example 17: TRP activation: Measurement of cation flux by intracellular calcium detection Transient receptor potential ion channels (TRPs) are non-selective ligand-gated cation channels that integrate various physical and chemical stimuli. When activated, these channels are Ca 2+ This leads to cation gating, resulting in changes in intracellular calcium concentration. The single-wavelength fluorescence indicator Fluo-4 acetoxymethyl (AM) is used to measure intracellular calcium flux and concentration in TRP-expressing, cannabinoid-stimulated cells. The Fluo-4 Direct® calcium assay kit (Molecular Probes, Invitrogen, Carlsbad, CA, USA) allows for direct addition of reagents to microplate wells containing cultured cells without requiring a medium removal or washing step, thus facilitating the targeted screening process.

[0168] Human embryonic kidney (HEK-293) cells were 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 were 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 were seeded into 96-well plates and polyethyleneimine (PEI) used to transiently transfect HEK-293 cells with an expression vector containing an open reading frame (ORF) of the TRP of interest. Transfection was performed using an empty expression vector as a negative control.

[0169] 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 over different periods. After incubation, fluorescence is measured using a microplate reader (excited at 494 nm and emitted at 516 nm).

[0170] Data analysis is performed by generating a nonlinear regression curve and all data points corrected for background fluorescence and negative control. The agonist response is normalized for the effect of the reference agonist, and the antagonist response is normalized for the EC of the reference agonist. 80 It was normalized.

[0171] Example 18: PPARγ activation: Nuclear hormone receptor activation assay Peroxisome proliferator-activated receptors (PPARs) are ligand-activating transcription factors for nuclear hormone receptors (NHRs). The Pathhunter® PPARγ protein interaction assay (DiscoverX, Fremont, CA, USA) reports NHR activation based on β-galactosidase complementarity, rendering a chemiluminescent signal.

[0172] The CHO-K1 PPARγ cell line (DiscoverX), which stably expresses the target receptor, is used. Cells are grown using reagents provided by the manufacturer (DiscoverX) and maintained in an incubator at 37°C in 5% CO2. Cells are harvested, seeded into a 96-well plate with a black skirt and clear bottom, allowed to adhere overnight, and then harvested. Subsequently, cells are incubated with cannabinoids and / or benchmark compounds such as troglitazone and rosiglitazone at 37°C in 5% CO2 for 30–90 minutes. Next, detection reagents (DiscoverX) provided by the manufacturer are added to the wells, the plate is incubated in the dark for 1 hour, and then chemiluminescence detection is performed using a microplate reader. Data analysis is performed by generating a nonlinear regression curve and all data points corrected for background luminescence and negative controls. The agonist response is normalized to the effect of the reference agonist, and the antagonist response is normalized to the EC of the reference agonist. 80 The values ​​were normalized. The basal activity of the cells was set to 0%.

[0173] Throughout this specification, numerous patents and printed publications are referenced. Each of these references and printed publications is incorporated herein by reference in its entirety.

[0174] Finally, it should be understood that the embodiments of the present invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be used are within the scope of the invention. Thus, alternative configurations of the present invention may be used in accordance with the teachings herein, not as examples but as examples. Accordingly, the present invention is not limited to those precisely shown and described.

Claims

1. Structural formula: [Formula 1] or an enantiomer, diastereomer, racemate, or tautomer thereof, or a pharma- ceutically acceptable salt, solvate, or hydrate of said compound, enantiomer, diastereomer, racemate, or tautomer, During the ceremony, [chemical 2] The part is, [C3] and R 1a and R 1b But independently, Hydrogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 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 1c R 1d and R 1c and R 1d are independently hydrogen, C 1 -C 4 Alkyl, or -C(O)(C 1 -C 4 alkyl) or Or R 1a and R 1b together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; R 2 But hydrogen, halo, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, —CO 2 H, -(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), -(C 0 -C 4 alkyl)-OC(O)O-(C 1 -C 6 alkyl), -OR 2a , -(C 1 -C 4 Alkyl) OR 2a , -SR 2a , -(C 1 -C 4 Alkyl)SR 2a , -NR 2b R 2c , -(C 1 -C 4 alkyl)NR 2b R 2c , -(C 1 -C 4 alkyl)C(O)NR 2b R 2c , -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, -(C 0 -C 4 alkyl)-heterocycloalkyl, or, when attached to an appropriately saturated ring, is oxo; R 2a , R 2b and R 2c are independently hydrogen, C 1 -C 4Alkyl, or -C(O)(C 1 -C 4 alkyl), R 3 is hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, -(OCH 2 CH 2 ) 0-6 O (C 1 -C 8 alkyl), -(C 0 -C 4 alkyl)-NR 3a R 3b , -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl or -(C 0 -C 4 alkyl)-heterocycloalkyl, R 3a and R 3b are each independently hydrogen or C 1 -C 6 is alkyl, R 4 is -aryl, -heteroaryl, -cycloalkyl, or -heterocycloalkyl, provided that said heterocycloalkyl is [C17] or its esters, R 5 is hydrogen, C 1 -C 8 Alkyl, -(C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), -C(O)(C 1 -C 4 alkyl), -C(O)O(C 1 -C 4 alkyl), -C(O)NH 2, -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 Alkyl) 2 , -(C 1 -C 4 alkyl)C(O)O(C 1 -C 4 alkyl), or -(C 1 -C 4 alkyl)OC(O)(C 1 -C 4 alkyl), During the ceremony, Each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, 1 or 2 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 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 of which is independently boron, nitrogen, oxygen, or sulfur, is saturated or partially unsaturated, and optionally contains 1 or 2 fused cycloalkyl or aryl 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 being boron, nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms each independently being boron, 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 independently, oxo, C 1 -C 4 Alkyl, -Cl, -F, -Br, -CN, -SF 5 , -N 3 , nitro, -SR A , -S(O) 1-2 R A , -OR A , -C 1 -C 4 Alkyl-OR A , -NR B R A , -C 1 -C 4 Alkyl-NR B R A , -C(O)R A , -C(O)NR B R A , -NR B C(O)R A , -C(S)NR B R A , -NR B C(S)R A , -CO 2 R A , -OC(O)R A , -C(O)SR A , -SC(O)R A , -C(S)OR A , -OC(S)R A , -C(S)SR A , -SC(S)R A , -S(O) 1-2 OR A , -OS(O) 1-2 R A, -S(O) 1-2 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 , -NR B S (O) 1-2 N.R. B R A , unsubstituted phenyl, or 5-6 membered unsubstituted heteroaryl; Each R 8 is independently an optionally substituted C 1 -C 4 Alkyl, -Cl, -F, -Br, -CN, -SF 5 , -N 3 , nitro, -SR A、-S(O) 1-2 R A 、-OR A 、-C 1 -C 4 アルキル-OR A 、-NR B R A 、-C 1 -C 4 アルキル-NR B R A 、-C(O)R A 、-C(O)NR B R A 、-NR B C(O)R A 、-C(S)NR B R A 、-NR B C(S)R A 、-CO 2 R A 、-OC(O)R A 、-C(O)SR A 、-SC(O)R A 、-C(S)OR A 、-OC(S)R A 、-C(S)SR A 、-SC(S)R A 、-S(O) 1-2 OR A 、-OS(O) 1-2 R A 、-S(O) 1-2 NR B R A 、-NR B S(O) 1-2 R A 、-OCO 2 R A 、-OC(O)NR B R A 、-NR B CO 2 R A 、-NR B C(O)NR B R A 、-SCO 2 R A 、-OC(O)SR A 、-SC(O)SR A 、-SC(O)NR B R A 、-NR B C(O)SR A , -OC(S)OR A , -OC(S)NR B R A , -NR B C(S)OR A , -NR B C(S)NR B R A , -SC(S)OR A , -OC(S)SR A , -SC(S)SR A , -SC(S)NR B R A , -NR B C(S)SR A , -NR B C (NR B ) N.R. B R A , -NR B S (O) 1-2 N.R. B R A , unsubstituted phenyl, or 5-6 membered unsubstituted heteroaryl; 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).

2. The part [C4] but, [C5] 2. The compound of claim 1,

3. R 1a and R 1b each independently represents hydrogen, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, hydroxy, halo, -O(C 1 -C 4 alkyl), -C(O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, or -(C 0 -C 4 alkyl)-heterocycloalkyl; R 1a and R 1b together with the carbon atom form a cycloalkyl ring containing 3 to 6 carbon ring members; R 1a and R 1b but both are methyl; R 1a is methyl, R 1b is hydrogen; R 1a and R 1b but both are hydrogen; R 1a is hydrogen, R 1b -NR 1c R 1d or R 1a and R 1b 3. The compound according to claim 1 or 2, wherein together with the carbon atom forms a cyclopentyl.

4. R 2 But hydrogen, halo, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, -CO 2H, -(C 0 -C 4 alkyl)-C(O)O(C 1 -C 6 alkyl), -OR 2a , -(C 1 -C 4 Alkyl) OR 2a , -SR 2a , -(C 1 -C 4 Alkyl)SR 2a , -NR 2b R 2c , -(C 1 -C 4 alkyl)NR 2b R 2c , -(C 1 -C 4 alkyl)C(O)NR 2b R 2c , -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, -(C 0 -C 4 alkyl)-heterocycloalkyl, oxo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, -hydroxy, -(C 0 -C 2 alkyl)-C(O)O(C 1 -C 6 Alkyl), C 2 -C 4 alkenyl, optionally substituted with hydroxy 1 -C 4 Alkyl, -CO 2 H, -C(O)O(C 1 -C 4 alkyl), methyl, ethyl, propyl, or -CH 2 The compound according to any one of claims 1 to 3, wherein said compound is OH.

5. R 2a , R 2b and R 2c are independently hydrogen, C 1 -C 4 Alkyl, or -C(O)CH 3 4. The compound of claim 3,

6. R 3 is hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, -(OCH 2 CH 2 ) 0-6 OCH 3 , -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4 alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, -(C 0 -C 4 alkyl)-heterocycloalkyl, 3 -C 6 Alkyl, C 1 -C 10 Alkyl, C 1 -C 8 Alkyl, -(C 1 -C 4 alkyl)-heteroaryl, -(C 1 -C 4 alkyl)-heterocycloalkyl, C 4 -C 9 Alkyl, -(C 1 -C 2 alkyl)-heteroaryl, -(C 1 -C 2 The compound of any one of claims 1 to 5, wherein the heterocycloalkyl is n-propyl, n-pentyl, or 1,1-dimethylheptyl.

7. R 3 But -(C 0 -C 4 alkyl)-aryl, -(C 0 -C 4alkyl)-heteroaryl, -(C 0 -C 4 alkyl)-cycloalkyl, or -(C 0 -C 4 alkyl)-heterocycloalkyl; The heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms which are nitrogen, oxygen, or sulfur, and 0 to 4 R 7 is replaced by said heterocycloalkyl is piperidinyl, pyrrolidinyl, azetidinyl, or aziridinyl; or The heterocycloalkyl is azetidinyl, and independently is selected from the group consisting of oxo, C 1 -C 4 Alkyl, -Cl, -F, -Br, -C(O)R A , -C(O)CH 3 , or -CO 2 R A One to two R 7 is substituted with R A But H or C 1 -C 3 The compound according to any one of claims 1 to 5, which is alkyl.

8. R 5 is hydrogen, C 1 -C 6 Alkyl, -(C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), -C(O)(C 1 -C 4 alkyl), -C(O)O(C 1 -C 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), or -C(O)N(C 1 -C 4 Alkyl) 2 The compound according to any one of claims 1 to 7,

9. The compound has the formula: [C14] 2. The compound of claim 1,

10. Cycloalkyl or heterocycloalkyl is 0 to 3 R 7 and the aryl or heteroaryl is substituted with 0 to 3 R 8 cycloalkyl or heterocycloalkyl is substituted with 0 to 2 R 7 and the aryl or heteroaryl is substituted with 0 to 2 R 8 cycloalkyl or heterocycloalkyl is substituted with 1 to 2 R 7 and the aryl or heteroaryl is substituted with 1 to 2 R 8 or wherein cycloalkyl or heterocycloalkyl is unsubstituted and aryl or heteroaryl is unsubstituted.

11. 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 , -C 1 -C 4 Alkyl-OR A , -NR B R A , -C 1 -C 4 Alkyl-NR B R A , -C(O)R A , -C(O)NR B R A , -NR B C(O)R A , -C(S)NR B R A , -NR B C(S)R A , -CO 2 R A , -OC(O)R A , -C(O)SR A , -SC(O)R A , -C(S)OR A , -OC(S)R A , -C(S)SR A , -SC(S)R A , -S(O) 1-2 OR A , -OS(O) 1-2 R A , -S(O) 1-2 N.R. B R A , -NR B S (O) 1-2 R A , unsubstituted phenyl, or 5-6 membered unsubstituted heteroaryl; or R 7 independently, oxo, C 1 -C 4 Alkyl, -Cl, -F, -Br, -CN, -OR A , -C 1 -C 4 Alkyl-OR A , -C 1 -C 3 Alkyl-OR A , -NR B R A , -C 1 -C 4 Alkyl-NR B R A , -C 1 -C 3 Alkyl-NR B R A , -C(O)R A , -C(O)NR B R A , -NR B C(O)R A , -CO 2 R A , -OC(O)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 11. The compound of any one of claims 1 to 10, wherein the aryl group is aryl, unsubstituted phenyl, 5-6 membered unsubstituted heteroaryl, or unsubstituted pyridyl.

12. R 8 But independently, C 1 -C 4 Alkyl, -Cl, -F, -Br, -CN, -SF 5 , -N 3 , nitro, -SR A , -S(O) 1-2 R A , -OR A , -C 1 -C 4 Alkyl-OR A , -NR B R A , -C 1 -C 4 Alkyl-NR B R A , -C(O)R A , -C(O)NR B R A , -NR B C(O)R A , -C(S)NR B R A , -NR B C(S)R A , -CO 2 R A , -OC(O)R A , -C(O)SR A , -SC(O)R A , -C(S)OR A , -OC(S)R A , -C(S)SR A , -SC(S)R A , -S(O) 1-2 OR A , -OS(O) 1-2 R A , -S(O) 1-2 N.R. B R A , -NR B S (O) 1-2 R A , unsubstituted phenyl, 5-6 membered unsubstituted heteroaryl, -C 1 -C 3 Alkyl-OR A, -C 1 -C 3 Alkyl-NR B R A or unsubstituted pyridyl.

13. each alkyl is unsubstituted; and / or each cycloalkyl is cyclopropane, cyclobutane, cyclopentane, or cyclohexane; and / or each heterocycloalkyl is a monocyclic or bicyclic heterocycloalkyl; and / or each aryl is phenyl; and / or The compound of any one of claims 1 to 12, wherein each heteroaryl is a monocyclic or bicyclic heteroaryl.

14. 2. The compound of claim 1 , 6,6,9-trimethyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-tetrazol-5-yl)-6H-benzo[c]chromen-1-ol, 5-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)-1,3,4-oxadiazol-2(3H)-one, 6,6,9-trimethyl-2-(5-methyl-4H-1,2,4-triazol-3-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrol-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrol-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridin-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidin-4-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrazin-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidin-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridin-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidin-5-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridin-4-yl)-6H-benzo[c]chromen-1-ol, 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-2-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazol-5-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazol-4-yl)-6H-benzo[c]chromen-1-ol, 2-(indolin-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(1H-benzo[d]imidazol-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(9H-purin-8-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxetan-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxetan-3-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxiran-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(aziridin-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(aziridin-1-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(1H-indol-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(4-(pyridin-3-yl)phenyl)-6H-benzo[c]chromen-1-ol, 2-(isoxazol-5-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(4,5-dihydrooxazol-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(4H-pyran-4-yl)-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(1-methyl-1H-pyrazol-5-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrazol-4-yl)-6H-benzo[c]chromen-1-ol, 2-(benzo[b]thiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(4-methylthiophen-2-yl)-3-pentyl-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-tetrazol-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)-1,3,4-oxadiazol-2(3H)-one, 6,6,9-trimethyl-2-(5-methyl-4H-1,2,4-triazol-3-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrol-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrrol-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridin-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidin-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrazin-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidin-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridin-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyrimidin-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(pyridin-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(furan-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiophen-3-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazol-5-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(thiazol-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(indolin-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(1H-benzo[d]imidazol-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(9H-purin-8-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxetan-2-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxetan-3-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(oxiran-2-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(aziridin-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(aziridin-1-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(1H-indol-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(4-(pyridin-3-yl)phenyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(isoxazol-5-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(4,5-dihydrooxazol-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(4H-pyran-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-2-(1-methyl-1H-pyrazol-5-yl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(benzofuran-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 6,6,9-trimethyl-3-pentyl-2-(1H-pyrazol-4-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, 2-(benzothiophen-2-yl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol, or The compound of claim 1 which is 6,6,9-trimethyl-2-(4-methyl-2-thienyl)-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol.

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or an enantiomer, diastereomer, racemate, or tautomer thereof, or a pharma- ceutically acceptable salt, solvate, or hydrate of said compound, enantiomer, diastereomer, racemate, or tautomer, and a pharma- ceutically acceptable excipient, diluent, or carrier.

16. A composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for use in the treatment or prevention of a disease associated with cannabinoid receptors.

17. 17. The composition or pharmaceutical composition for use according to claim 16, wherein the cannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or μ-opioid receptor.

18. The disease is acute pain, ADHD / ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's disease, anorexia, 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, keloid, leukodystrophy. , hepatic fibrosis, liver cirrhosis, pulmonary fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea, neuropathic pain, 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, sleep disorders, spinocerebellar ataxia, systemic fibrosis, systemic sclerosis, heat injury, tobacco use disorder / nicotine dependence, Tourette's syndrome, tumor, or trigeminal neuralgia.

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