DEUTERATED CANNABINOID COMPOUNDS

FIELD OF THE INVENTION

[001] This invention relates to deuterated tetrahydrocannabinol compounds, deuterated tetrahydrocannabivarin compounds, deuterated cannabigerol compounds, and deuterated cannabichromene compounds, methods for preparation thereof, compositions comprising the same, and uses thereof for the treatment or prevention of numerous diseases or disorders including, but not limited to, fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, aggression, fear, phobias, anxiety, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome- related disorders.

BACKGROUND OF THE INVENTION

[002] ((6a R,10aR)-delta-9-Tetrahydrocannabinol (THC) is metabolized in the liver by enzymes of the cytochrome P450 (CYP) hepatic mixed-function oxidase family. THC is oxidized by CYP to active, equipotent 11-OH-THC metabolite, which is then rapidly metabolized to the inactive THC-COOH metabolite, resulting in low concentrations of THC and 11-OH-THC in blood and much higher concentrations of THC-COOH, The presence of the carboxyl group of THC-COOH resu lts in a loss of biological activity, since THC-COOH can no longer bind tightly to cannabinoid receptors. Because THC is subject to extensive CYP-mediated first pass hepatic metabolism following oral administration, its oral bioavailability is low.

(THC)

[003] EPIDIOLEX (cannabidiol) has been approved for relief of spasticity in patients with multiple sclerosis. It is formulated in anhydrous ethanol, peppermint oil, and propylene glycol for buccal application. To date, no break-through in improving the bioavailability of THC has been reported. Current FDA approved THC product Dronabinol (Trade names: Marinol and Syndros), used as an appetite stimulant, is a synthetic form of THC dissolved in sesame oil that has an oral bioavailability of 10-20%.

[004] Cannabigerol (CBG) is one of cannabinoid compounds found in the plant genus cannabis. It acts on specific physiological systems and the results for medicinal use are promising. Endocannabinoid receptors are prevalent in eye structures. Cannabigerol is considered to be particularly effective in treating glaucoma because it reduces intraocular pressure. It is also effective in decreasing the inflammation characteristic of inflammatory bowel disease in animal experiments involving mice.

(CBG)

[005] Cannabigerol has shown to protect neurons in mice with Huntington’s disease, which is characterized by nerve cell degeneration in the brain. Further, it is shown to block receptors that cause cancer cell growth. For example, it inhibits the gro wth of colorectal cancer cells in mice and also inhibits tumors and chemically-induced colon carcinogenesis.

[006] Cannabichromene (CBC), also known as cannabichrome, pentylcannabichromene, or cannabinochromene, is one of major cannabinoids in Cannabis sativa L. and the second abundant cannabinoid in drug-type cannabis. Cannabichromene (CBC) outperforms other major cannabinoids in terms of anti-bacterial and anti-fungal activity. CBC also shows potent antiinflammatory activity in the carrageenan-induced rat paw edema assay.

(CBC)

[007] Deuterium has twice the mass of protium. A C-D bond is stronger than the corresponding C-’H bond. If a C- ^k H bond is broken during a rate-determining step in a chemical reaction (i.e., the step with the highest transition state energy), substituting a deuterium for that protium may lead to a decrease in the reaction rate. However, while deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been investigated, deuteration is inherently unpredictable. Deuterium incorporation can only produce an effect if the incorporated deuterium is broken during a rate -determining metabolic step. As a result, deuterium incorporation may produce no improvement in PK, PD, or toxicity profile. In addition, deuterium incorporation can lead to metabolic switching. Metabolic switching occurs when xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching can lead to different proportions of known metabolites as well as production of new metabolites. This new metabolic profile may impart more or less toxicity, or it may produce negative effects on PD and/or PD (Miwa et al., BioEssays 1987; 7(5), 215-19). Unsuccessful deuteration attempts have been reported. For example, nevirapine deuteration resulted in increased metabolism, rather than decreased metabolism (Harbeson and Tung, 2011, 46, Annu. Rep. Med. Chern, 403-417). Deuterated versions of tramadol were not found to be superior to the parent compound. (Id,, at 409-410). Because of the unpredictable outcomes of deuteration, the pharmacokinetic and metabolic behaviors of a particular compound after deuteration can be very different, and PK / PD outcomes cannot be predicted before the compound is synthesized and tested in a series of in vitro and in vivo PK / PD experiments.

[008] The present invention provides deuterated cannabinoid compounds or derivatives thereof. Such deuterated cannabinoid compounds will maintain the beneficial aspects of the corresponding non-isotopically enriched cannabinoids while substantially slowing metabolism and improving half-life and bioavailability’ (via oral or other routes of administration). A combination of deuterated cannabinoid compounds with additional therapeutic agents may exhibit a therapeutic synergistic or additive effect and allow for an improved safety profile of said therapeutic agents. The required therapeutically effective amount of the therapeutic agents may also be less than current recommended and approved dosages, thus minimizing the toxicity during treatments. Such a combination therapy may also prevent or delay the onset of drug resistance and reduce potentially the side effects that arise from the use of the therapeutic agents alone.

SUMMARY OF THE INVENTION

[009] In one aspect, the invention provides a deuterated compound of (6aR,10a/?)-delta-9- tetrahydrocannabinol (THC), or a derivative thereof, represented by the compound of formula (A)

wherein R ₁ -R ₃₀ are each independently H or D.

[0010] In another aspect, the invention provides a deuterated compound of (6aR,10aR)-delta-9- tetrahydrocannabinol (THC) represented by the compound of formula (I) wherein R ₁ -R ₁₄ are each independently H or D; and R ₁₅ is D or OH; provided that when R ₃ is H, R ₁₅ is OH.

[0011] In another aspect, the invention provides a deuterated compound of delta-9- tetrahydrocannabivarin (THCV) represented by the compound of formula (B)

wherein

R ₁ -R ₉ and R ₁₆ -R ₃₁ are each independently H or D; and R ₁₅ is D or OH.

[0012] In some embodiments, the invention provides a deuterated compound of delta-9- tetrahydrocannabivarin (THCV) represented by the compound of formula (II): wherein

R ₁ -R ₉ and R ₃₁ are each independently H or D; and R ₁₅ iS D or OH. [ 0013] In one aspect, the invention provides a deuterated compound of cannabigerol (CBG), or a derivative thereof, represented by a compound of formula (AA) wherein R ₁ -R ₃₂ are each independently H or D, provided that at least one of R ₁ -R ₁₇ is D.

[0014] In another aspect, the invention provides a deuterated compound of cannabigerol (CBG) represented by a compound of formula (Al) wherein R ₁ -R ₂₀ are each independently H or D, provided that at least one of R ₁ to R ₁₇ is D.

[0015] In one aspect, the invention provides a deuterated compound of cannabi chromene (CBC), or a derivative thereof, represented by a compound of formula (AAA)

wherein R ₁ -R30 are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D.

[0016] In another aspect, the invention provides a deuterated compound of cannabichromene

(CBC) represented by a compound of formula (AA1) wherein R ₁ -R2.5 are each independently H or D, provided that at least one of R ₁ -R2.5 is D.

[0017] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[0018] In a further aspect, the present invention provides a method of treating or preventing seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is an animal.

[0019] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.

[0020] In another aspect, the present invention provides a method of treating or preventing pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising adminis tering to said subject a therapeutically effective amount of a compound of the invention as described herein.

[0021] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome- related disorders. [0022] In another aspect, the present invention provides a method of treating or preventing pain or inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery, soft-tissue surgery, or dental surgery.

[0023] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety, aggression, compulsive disorders, phobias, epilepsy, or seizures. In some embodiments, the subject is a dog.

[0024] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the subject is a dog.

[0025] In another aspect, the present invention provides a method of heating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma. In some embodiments, the subject is a cat.

[0026] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) and at least one additional therapeutic agent,

wherein R ₁ -R30 are each independently H or D, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith- Magenis syndrome, major depressive disorder, primary' insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity', type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington’s disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.

[0027] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) and at least one additional therapeutic agent.

(B) wherein R ₁ -R9 and R16-R ₃₁ are each independently H or D; and R ₁₅ is D or OH. wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson’s disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof. [0028] In some embodiments, the compound of formula (B) is represented by a compound of formula (II) wherein

R ₁ -R ₉ and R ₃₁ are each independently H or D; and R ₁₅ is D or OH.

[0029] In some embodiments of the method of the invention comprising administering a compound of formula (A) or a compound of formula (B) and at least one additional therapeutic agent, the additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti-convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an anti-emetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti-dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an anti-osteoporosis agent, or a cardiovascular agent.

[0030] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome. [0031] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) and at least one additional therapeutic agent, wherein R ₁ -R32 are each independently H or D, provided that at least one of R ₁ -R ₁₇ is D, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith- Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, atention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof. [0032] In some embodiments, the compound of formula (AA) is represented by a compound of formula (Al) wherein R ₁ -R20 are each independently H or D, provided that at least one of Ri to R ₁₇ is D.

[0033] In some embodiments, said additional therapeutic agent is an analgesic agent, an antianxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti-convulsive agent, antiepileptics, an anti-inflammatory agent, an anti -depressant agent, an anti-emetic agent, an anti- ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodeeenerative diseases or disorders, an anti-dvskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an anti-osteoporosis agent, or a cardiovascular agent.

[0034] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent tor treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.

[0035] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) and at least one additional therapeutic agent,

(AAA) wherein R ₁ -Rso are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith- Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.

[0036] In some embodiments, the compound of formula (AAA) is represented by a compound of formula (AAI) OH

(AAT) wherein R ₁ -R ₂₅ are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D.

[0037] In some embodiments of the method of the invention, the additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti -depressant agent, an antiemetic agent, an anti -ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti- dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an antiosteoporosis agent, or a cardiovascular agent.

[0038] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent tor treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.

[0039] The details of one or more embodiments of the invention are set forth in the accompanying the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION OF THE PRESENT INVENTION [ 0040] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0041] The present invention relates to deuterated cannabinoid compounds. In some embodiments, the present invention relates to deuterated tetrahydrocannabinol compounds, deuterated tetrahydrocannabivarin compounds, deuterated cannabigerol compounds, and deuterated cannabichromene compounds. The deuterated compounds of the invention maintain the beneficial aspects of the corresponding non-isotopically enriched compounds while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half-life (T1/2.), lowering the maximum plasma concentration (Cmax) of the therapeutically efficacious dose or the minimum efficacious dose (MED), lowering the efficacious dose, prevent or slow metabolism, and improving oral bioavailability and bioavailability following other routes of administration.

[0042] In one aspect, the invention provides a deuterated compound of (6aR,10a/?)-delta-9~ Tetrahydrocannabinol (THC), or a derivative thereof, represented by a compound of formula (A): wherein R ₁ -R30 are each independently H or D. [0043] In some embodiments of the compound of formula (A), R ₁₅ is D or OH. In some embodiments, when R ₃ is H, R ₁₅ is OH. In some embodiments, Ri 5 is D or OH; provided that when R? is H, R ₁₅ is OH. In some embodiments, Ri and R2 are D, In some embodiments, R ₃ is D. In some embodiments, R4 and Rs are D. In some embodiments, R4-R14 are D. In some embodiments, Rs -R14 are D.

[0044] In another aspect, the invention provides a deuterated compound of (6aA’,10aR)-delta-9- Tetrahydrocannabinol (THC) represented by a compound of formula (I): wherein R ₁ -R14 are each independently H or D; and R ₁₅ is D or OH: provided that when R3 is H, R ₁₅ is OH.

[ 0045] In some embodiments of the compound of the invention of formula (I), Ri and R?, are D. In some embodiments, R ₃ is D. In some embodiments, Ri and Rs are D. In some embodiments,

R4-R14 are D. In some embodiments, Re -R14 are D.

[0046] In some embodiments, the compound of formula (I) is represented by compound 1-4, 1-6,

1-7, 1-14, 1-20, 1-24, 1-25, or 1-26:

[0047] In some embodiments, the compound of formula (I) or the compound of formula (A) is represented by any one of the following compounds:

[0048] In another aspect, the invention provides a deuterated compound of delta-9- tetrahydroeannabivarm (THCV) represented by a compound of formula (B):

(B) wherein R ₁ -R9 and Rie-Rsi are each independently H or D; and R ₁₅ is D or OH.

[0049] In some embodiments of the compound of formula (B), R ₁₅ is D. In some embodiments, R ₁₅ is OH. In some embodiments, R ₃ is D. In some embodiments, Ri and R2 are D. In some embodiments, R4 and R5 are D. In some embodiments, R4- Rs and Rsi are D. In some embodiments, R and R2 are D; and R ₁₅ is D. In some embodiments, R4 and Rs are D; and R ₁₅ is D. In some embodiments, R+- R9 are D; and R ₁₅ is D.

[0050] In some embodiments, the invention provides a deuterated compound of delta-9- tetrahydroeannabivarm (THCV) represented by a compound of formula (II):

wherein R ₁ -R9 and R ₃₁ are each independently H or D; and R ₁₅ IS D or OH.

[0051] In some embodiments of the compound of formula (II), R ₁₅ is D. In some embodiments, R ₁₅ is OH. In some embodiments, R3 is D. In some embodiments, Ri and R2 are D. In some embodiments, R4 and R5 are D. In some embodiments, Ra- Rs and R ₃ i are D. In some embodiments, R and R2 are D; and R ₁₅ is D. In some embodiments, R4 and Rs are D; and R ₁₅ is D. In some embodiments, R4- R9 are D; and R ₁₅ is D.

[ 0052] In some embodiments, the compound of formula (II) is represented by compound II-4, II-

6, 11-7, 11-14, 11-15, or 11-16:

[0053] In some embodiments, the compound of formula (B) or the compound of formula (II) is represented by any one of the following compounds:

[0054] In one aspect, the invention provides a deuterated compound of cannabigerol (CBG), or a derivative thereof, represented by the compound of formula (AA) wherein R ₁ -R32 are each independently H or D, provided that at least one of R.-R ₁₇ is D.

[0055] In some embodiments of the compound of formula (AA), R.-Rs are D. In some embodiments, R ₁ -Rs, R13, and R14 are D. In some embodiments, R ₁ -R ₁₇ are D. In some embodiments, R? and Rg are D. In some embodiments, R9-R ₁₇ are D. [0056] In another aspect, the invention provides a deuterated compound of cannabigerol (CBG) represented by the compound of formula (Al) wherein R ₁ -Rzo are each independently H or D, provided that at least one of R ₁ -Rn is D.

[0057] In some embodiments of the compound of formula (Al), Rt-Rs are D. In some embodiments, R ₁ -Ro, RB, and RM are D. In some embodiments, R ₁ -R ₁₇ are D. In some embodiments, R? and Rs are D. In some embodiments, R9-R1 ? are D.

[0058] In some embodiments, the compound of formula (Al) is represented by compound A8, A13, Al 8, A19, A20, or A21 :

[0059] In some embodiments, the compound of formula (Al) or the compound of formula (AA) is represented by any one of the following compounds:

[0060] In one aspect, the invention provides a deuterated compound of cannabichromene (CBC), or a derivative thereof, represented by a compound of formula (AAA)

wherein R ₁ -R30 are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D.

[0061] In some embodiments of the compound of formula (AAA), R ₁ -R13 are D. In some embodiments, R ₈ -Ru are D. In some embodiments, Rs~Ri3, R20, and R21 are D. In some embodiments, Rg-R?,4 are D. In other embodiments, R ₂₅ is D.

[0062] In another aspect, the invention provides a deuterated compound of cannabichromene

(CBC), or a deri vative thereof, represented by a compound of formula ( AAI)

OH

(AAI) wherein R ₁ -R ₂₅ are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D.

[0063] In some embodiments of the compound of formula (AAI), R ₁ -Ri 3 are D. In some embodiments, Rs~Ri3 are D. In some embodiments, RS-RB, R20, and R21 are D. In some embodiments, R ₈ -R?4 are D. In other embodiments, R2.5 is D. [0064] In some embodiments, the compound of formula (AAI) is represented by compound AA7,

AA 11 , AA 16, AA20, AA21 , AA22, AA23, or AA24:

(AA11)

(AA16),

(AA21),

[0065] In some embodiments, the compound of formula (AAI) or the compound of formula (AAA) is represented by any one of the following compounds:

[0066] In some embodiments, when a particular atomic position is designated as having deuterium or "D," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%.

[0067] In some embodiments, the compound of the invention as described herein is deuterium- enriched at every position represented D. In some embodiments, deuterium enrichment at any position represented as D in the compound of formula (II) or in the compound of formula (B) is at least about 1%; at least about 5%; at least about 10%; at least about 15%; at least about 20%; at least about 25%; at least about 30%; at least about 35%; at least about 40%; at least about 45%; at least about 50%; at least about 55%; at least about 60%; at least about 65%; at least about 70%; at least about 75%; at least about 80%; at least about 85%; at least about 90%; at least about 95%; at least about 98%; at least about 99%; or at least about 100%.

[0068] In some embodiments, deuterium enrichment at any position represented as D in the compound of the invention is from about 1% to about 100%; from about 1% to about 98%; from about 1% to about 90%; from about 1% to about 75%; from about 1% to about 50%; from about 1% to about 25%; from about 1% to about 20%; from about 1% to about 10%; from about 1% to about 5%; from about 5% to about 100%; from about 5% to about 99%; from about 5% to about 98%; from about 5% to about 90%; from about 5% to about 75%; from about 5% to about 50%; from about 5% to about 25%; from about 5% to about 20%; from about 5% to about 10%; from about 10% to about 100%; from about 10% to about 99%; from about 10% to about 98%; from about 10% to about 90%; from about 10% to about 75%; from about 10% to about 50%; from about 10% to about 25%; from about 10% to about 20%; from about 20% to about 100%; from about 20% to about 99%; from about 20% to about 98%; from about 20% to about 90%; from about 20% to about 75%; from about 20% to about 50%; from about 20% to about 25%; from about 25% to about 100’%; from about 25% to about 99%; from about 25% to about 98%; from about 25% to about 90%; from about 25% to about 75%; from about 25% to about 50%; from about 50% to about 100%; from about 50% to about 99%; from about 50% to about 98%; from about 50% to about 90%; from about 50% to about 75%; from about 75% to about 100%; from about 75% to about 99%; from about 75% to about 98%; from about 75% to about 90%; from about 90% to about 100%; from about 90% to about 99%; from about 90% to about 98%; from about 98% to about 100%; from about 98% to about 99%; or from about 99% to about 100%.

[0069] In some embodiments, the positions that are specifically deuterated as shown in the compounds of the invention as described herein are deuterium- enriched at about the same percentage. In other embodiments, the positions that are specifically deuterated as shown in the compounds of the invention as described herein are differentially deuterium enriched.

[0070] In some embodiments, the overall deuterium enrichment of the compounds of the invention as described herein is no less than 1%; no less than 5%; no less than 10%; no less than 15%; no less than 20%; no less than 25%; no less than 30%; no less than 35%; no less than 40%; no less than 45%; no less than 50%; no less than 55%; no less than 60%; no less than 65%; no less than 70%; no less than 75%; no less than 80%; no less than 85%; no less than 90%; no less than 95%; no less than 98%; no less than 99%; or no less than 100 %. Overall deuterium enrichment of the compounds of the invention can be determined using mass spectroscopy, according to methods known in the art.

[0071] As used herein, delta-9-tetrahydrocannabivarin (THCV or THV) is a homologue of (6a/?,10a/?)-delta-9-tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule.

[0072] The present invention further provides a pharmaceutical composition comprising a compound the invention as described herein and a pharmaceutically acceptable carrier.

[0073] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (A) of the invention as described herein and a pharmaceutically acceptable earner. In some embodiments, the invention provides a pharmaceutical composition comprising a compound of formula (B) of the invention as described herein and a pharmaceutically acceptable carrier. In certain embodiments, the invention provides a pharmaceutical composition comprising a mixture of a compound of formula (A) and a compound of formula (B) and a pharmaceutically acceptable carrier. [0074] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) of the invention as described herein and a pharmaceutically acceptable earner. In some embodiments, the invention provides a pharmaceutical composition comprising a compound of formula (II) of the invention as described herein and a pharmaceutically acceptable carrier. In certain embodiments, the invention provides a pharmaceutical composition comprising a mixture of a compound of formula (I) and a compound of formula (II) and a pharmaceutically acceptable carrier.

[0075] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (AA) of the invention and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising a compound of formula (Al) of the invention and a pharmaceutically acceptable carrier.

[0076] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (AAA) of the invention as described herein and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising a compound of formula (A Al) of the invention as described herein and a pharmaceutically acceptable carrier.

[ 0077] As used herein, "pharmaceutical composition" refers to a therapeutically effective amount of a compound of the present invention, together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or earners. Such compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g.; Tris-HCL, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzy l alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils). [0078] A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.

[0079] Numerous standard references are available that describe procedures for preparing various compositions or formulations suitable for administration of the compounds of the invention. Examples of methods of making formulations and preparations can be found in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Rachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

[0080] The mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.

[0081] The pharmaceutical compositions of the invention can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transderm ally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, intra ventricularly, intracranially, intravaginally, by inhalation, rectally, or intratumorally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces. Another method of administration is via aerosol formulation. The pharmaceutical compositions may be administered topically to body surfaces and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administrations, the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical earner.

[0082] Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdennal, spinal, intrathecal, intraarticular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for systemic delivery of active ingredients. Depending on the indication, in some embodiments, the formulations are suitable for oral or topical administration. [0083] As used herein "pharmaceutically acceptable carriers or diluents" are well known to those skilled in the art. The carrier or diluent may be a solid earner or diluent for solid formulations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.

[0084] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0085] In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For solid oral preparations such as, chewable, soft-chew, gummy, powders, capsules, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.

[0086] For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.

[0087] In some applications, it may be advantageous to utilize the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.

[0088] Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, orally disintegrating tablets or films, or lozenges, each containing a predetermined amount of the active ingredient. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.

[0089] A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable earner may be made by molding in a suitable machine.

[0090] A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient/ s). Such accessory ingredients) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

[0091] As used herein, flavorings can be added to all dosage forms when needed, including, but not limited to, solid oral forms and liquid oral forms.

[0092] Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which in some embodiments is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

[0093] Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be affected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired admini stration modality.

[0094] Nasal and other mucosal spray formulations (e.g. inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are in some embodiments adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.

[0095] Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids. [0096] Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.

[0097] In addition to the aforementioned ingredients, compositions of this invention may farther include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.

[0098] The formulations may be of immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.

[0099] For administration to mammals, it is expected that the physician will determine the actual dosage and duration of treatment, which will be most suitable for an individual and can vary with the age, weight, genetics and/or response of the particular individual.

[ 00100] The methods of the invention comprise administration of a compound at a therapeutically effective amount. The therapeutically effective amount may include various dosages.

[00101] A dosage unit of the compounds used in the present invention may comprise a single compound or mixtures thereof with additional therapeutic agents. A "‘dose'’ or "‘dosage unit” or “unit dosage” of a compound of the in vention as measured in milligrams refers to the milligrams of the compound of the invention, present in a preparation, regardless of the form of the preparation. A dosage unit may comprise a single compound or mixtures of compounds thereof.

[00102] In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.01-1.0 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.025-1.0 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.05-1.0 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.075-1.0 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.01 -0.075 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.01-0.05 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.01- 0.025 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.025-0.05 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 0.05-0.075 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1- 3000 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1-1000 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 10- 500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 50-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 5- 250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 10-250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 20-250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25- 250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-200 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-150 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25- 125 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-100 mg per day.

[00103] In other embodiments, a compound of the invention as described herein is administered at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 10-100 mg per day, 15-60 mg per day, 15-100 mg per day, 25-100 mg per day, 50-100 mg per day, 50-200 mg per day, 100-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mg per day, 500- 1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day.

[00104] In some embodiments, a compound of the invention as described herein is administered at a dosage of 25 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 40 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 50 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 67.5 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 75 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 80 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 100 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 125 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 250 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 300 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 500 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 600 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 1000 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 1500 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 2000 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 2500 mg per day. In one embodiment, a compound of the invention as described herein is administered at a dosage of 3000 mg per day.

[00105] The methods may comprise administering a compound at various dosages. For exampie, the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 nig, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.

[00106] Alternatively, the compound may be administered at a dosage of 0.1 mg/kg/day. The compound may be administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.

[00107] In some embodiments, a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, liquid suspensions, and granules.

[00108] In some embodiments, the pharmaceutical composition of the invention comprises from about 0.01 mg to about 250 mg compound of the invention as described herein. In some embodiments, the pharmaceutical composition of the invention comprises from about 0.05 mg to about 250 mg compound of the invention. In some embodiments, the pharmaceutical composition of the invention comprises from about 0. 1 mg to about 250 mg compound of the invention. In some embodiments, the pharmaceutical composition of the invention comprises from about 0.5 mg to about 250 mg compound of the invention. In some embodiments, the pharmaceutical composition of the invention comprises from about 1.0 mg to about 250 mg compound of the invention. In some embodiments, the pharmaceutical composition of the invention comprises from about 5 mg to about 250 mg compound of the invention. In some embodiment, the pharmaceutical composition of the invention comprises about 0.1 mg of compound of the invention. In some embodiment, the pharmaceutical composition of the invention comprises about 0,5 mg of compound of the invention. In some embodiment, the pharmaceutical composition of the invention comprises about 1.0 mg of compound of the invention. In some embodiment, the pharmaceutical composition of the invention comprises about 5.0 mg of compound of the invention. In some embodiment, the pharmaceutical composition of the invention comprises about 10 mg of compound of the invention. In another embodiment, the pharmaceutical composition of the invention comprises about 25 mg of compound of the invention. In another embodiment, the pharmaceutical composition of the invention comprises about 50 mg of compound of the invention. In another embodiment, the pharmaceutical composition of the invention comprises about 75 mg of compound of the invention. In another embodiment, the pharmaceutical composition of the invention comprises about 100 mg of compound of the invention. In another embodiment, the pharmaceutical composition of the invention comprises about 150 mg of compound of the invention. In another embodiment, the pharmaceutical composition of the invention comprises about 200 mg of compound of the invention.

[00109] The invention further provides a pharmaceutical composition comprising a compound of formula (1) or formula (II) for use in the treatment or prevention of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00110] The invention further provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is an animal.

[00111] The invention further provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[00112] The invention further provides a pharmaceutical composition comprising a compound of formula (I) or formula (IT) for use in the treatment or prevention of a disease or disorder selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm -related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer’s, Angelnian syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency.

[00113] The invention further provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the pain is chronic pain. In some embodiments, the pain is acute pain. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein.

[001 14] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) for use in the treatment or prevention of a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In other embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder.

[00115] In some embodiments, the compound of the invention is an analgesic agent. In some embodiments, the compound of the invention is an anti-anxiety agent. In some embodiments, the compound of the invention is an anti-cancer agent. In some embodiments, the compound of the invention is an anti-bacterial agent. In some embodiments, the compound of the invention is an anti-convulsive agent. In some embodiments, the compound of the invention is an antiinflammatory agent. In some embodiments, the compound of the invention is an anti-depressant agent. In some embodiments, the compound of the invention is an anti-emetic agent. In some embodiments, the compound of the invention is an anti-ischemic agent. In some embodiments, the compound of the invention is an anti-psychotic agent. In some embodiments, the compound of the invention is an anti-spasmodic agent. In some embodiments, the compound of the invention is a bone-stimulant agent. In some embodiments, the compound of the invention is an ocular hypotensive agent. In some embodiments, the compound of the invention is an immunosuppressive agent. [00116] The invention further provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00117] The invention further provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any’ combination thereof.

[00118] The invention further provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment or prevention of aggression, fear, phobias, generalized anxiety- disorder, or separation anxiety’ in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is an animal.

[001 19] The present invention further provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment or prevention of a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep -wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary’ insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency.

[ 00120] The present invention further provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment or prevention of pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Al) tor use in the treatment or prevention of pain in a subject in need thereof, comprising administering to said subject a therapeutically' effective amount of a compound of the invention as described herein. In some embodiments, the pain is chronic pain. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment or prevention of multiple sclerosis ill a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment or prevention of epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (AT) for use in the treatment or prevention of chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein.

[00121] The present invention further provides a pharmaceutical composition comprising a compound of formula (Al) for use in the treatment or prevention of a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, tor example, Parkinson's disease, Huntington's disease, and/or Alzheimer’s disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder.

[00122] In some embodiments, the compound of the invention is an analgesic agent. In some embodiments, the compound of the invention is an anti-anxiety agent. In some embodiments, the compound of the invention is an anti-cancer agent. In some embodiments, the compound of the invention is an anti-bacterial agent. In some embodiments, the compound of the invention is an anti -convulsive agent. In some embodiments, the compound of the invention is an antiinflammatory’ agent. In some embodiments, the compound of the invention is an anti- depressant agent. In some embodiments, the compound of the invention is an anti-emetic agent. In some embodiments, the compound of the invention is an anti-ischemic agent. In some embodiments, the compound of the invention is an anti-psychotic agent. In some embodiments, the compound of the invention is an anti-spasmodic agent. In some embodiments, the compound of the invention is a bone-stimulant agent. In some embodiments, the compound of the invention is an immunosuppressi ve agent.

[00123] The invention further provides a pharmaceutical composition comprising a compound of formula (AAA) for use in the treatment of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00124] The invention further provides a pharmaceutical composition comprising a compound of formula (AAA) for use in the treatment of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[00125] The invention further provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00126] The invention further provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of aggression, fear, phobias, generalized anxiety disorder, or separation anxiety in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is an animal.

[00127] The invention further provides a pharmaceutical composition comprising a compound of formula ( AAI) for use in the treatment of a disease or disorder, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[00128] The present invention further provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety’ disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety' disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency.

[00129] The present invention further provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiment, the pain is chronic pain. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of multiple sclerosis in a subject in need thereof) comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein.

[00130] The present invention further provides a pharmaceutical composition comprising a compound of formula (AAI) for use in the treatment or prevention of a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. Tn some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson’s disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder.

[00131] In some embodiments, the compound of the invention is an analgesic agent. In some embodiments, the compound of the invention is an anti-anxiety agent. In some embodiments, the compound of the invention is an anti-cancer agent. In some embodiments, the compound of the invention is an anti-bacterial agent. In some embodiments, the compound of the invention is an anti-convulsive agent. In some embodiments, the compound of the invention is an antiinflammatory agent. In some embodiments, the compound of the invention is an anti-depressant agent. In some embodiments, the compound of the invention is an anti-emetic agent. In some embodiments, the compound of the invention is an anti -ischemic agent. In some embodiments, the compound of the invention is an anti-psychotic agent. In some embodiments, the compound of the invention is an anti-spasmodic agent. In some embodiments, the compound of the invention is a bone-stimulant agent. In some embodiments, the compound of the invention is an immunosuppressive agent.

[00132] In some embodiments, the pharmaceutical composition of the invention is in the form of a capsule, a tablet, or a liquid suspension. In other embodiments, the pharmaceutical composition of the invention is in an oral dosage unit form.

[00133] The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.

[00134] In another embodiment, a pharmaceutical composition is prepared for once daily administration. In another embodiment, a pharmaceutical composition is prepared for more than once daily administration, for example, twice daily, three times daily, four times daily, etc.

[00135] In some embodiments, the compounds of the invention as described herein, or pharmaceutical compositions containing either or both, can provide an increased half-life in a mammal over the corresponding non-deuterated compound e.g., tetrahydrocannabinol or tetrahydrocannabivarin, as measured using an in vitro liver microsomal assay.

[00136] In some embodiments, the concentration of the compound of the invention as d escribed herein, in the pharmaceutical compositions of the present invention is about 100%, 90%, 80%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 22.5%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001%. It should be appreciated that the concentration of the compound of the invention in the pharmaceutical compositions described herein can also be expressed as range defined by any two of the concentrations as described here. It should be further appreciated that the concentration percentages as described herein can be on a weigh (/weight, weighVvolume, or a volume/volume basis. [00137] In some embodiments, the amount of the compound of the invention as described herein in the pharmaceutical compositions of the present invention is about 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 nig, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 090 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.9 mg, 0.8 mg, 0,7 mg, 0.6 mg, 0.5 mg, 0.4 mg, 0.3 mg, 0,2 mg, or 0,1 mg. It should be appreciated that the amount of the compound of the invention in the pharmaceutical compositions described herein can also be expressed as range defined by any two of the amounts as described here.

[00138] In some aspects, the administration of a compound of the invention provides one or more of the following: (1) a decrease in inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) an increase in average plasma levels of the compound or a decrease in average plasma levels of at least one metabolite of the compound per dosage unit; (3) a decrease in the inhibition of, and/or metabolism by at least one cytochrome P450 or monoamine oxidase isoform in the subject; (4) a decrease in metabolism via at least one polymorphically- expressed cytochrome P450 isoform in the subject; (5) at least one statistically-significant improvement in disorder-control and/or disorder-eradication endpoint; (6) an improvement in clinical effect during the treatment of the disorder, (7) prevention of recurrence, or delay of decline or appearance, of abnormal alimentary' or hepatic parameters as the primary clinical benefit, or (8) reduction or elimination of deleterious changes in any adverse event, including diagnostic hepatobiliary function endpoints, as compared to the corresponding non-deuterated compound, e.g., tetrahydrocannabinol or tetrahydrocannabivarin.

[00139] In certain embodiments, inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof, decreases; average plasma levels of the compound as disclosed herein increase; average plasma levels of a metabolite of the compound as disclosed herein decrease; inhibition of a cytochrome P450 or monoamine oxidase isoform by a compound as disclosed herein decrease; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed cytochrome P450 isoform decrease; by greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or by greater than about 50% as compared to the corresponding non-deuterated compound. In some embodiments, the compound of the invention can provide about a 40% or greater increase in halflife in a mammal over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 45% or greater increase in halt-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 70% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 75% or greater increase in half-life in a mammal over the corresponding non- deuterated compound. In certain embodiments, the percentage increase in half-life of the compound of the invention over the corresponding non-deuterated compoundcan be expressed as a range, such as between 40% and 75%; between 40% and 70%; between 40% and 45%; between 45% and 75%; between 45’% and 70%; or, between 70% and 75%.

[00140] In some embodiments, the compound of the invention can provide about a 30% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 35% or greater increase in halflife in a mammal over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 100% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 105% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the percentage increase in halflife of the compound of the invention over the corresponding non-deuterated compoundcan be expressed as a range, such as between 30% and 105%: between 30% and 100%: between 30% and 35%; between 35% and 105%; between 35% and 100%.

[00141] In certain embodiments, a pharmaceutical composition including the compound of the invention can provide about a 10% or greater increase in half- life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 20% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 30% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 40% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 50% or greater increase half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 60% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 70% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about an 80% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 90% or greater increase in half-life in a mammal over the corresponding non-deuterated compound. In certain embodiments, the pharmaceutical composition can provide about a 100% increase in half-life in a mammal over the corresponding non-deuterated compound.

[00142] In some embodiments, the percentage increase in half-life of a pharmaceutical composition including the compound of the invention over the corresponding non-deuterated compound is from about 10% to about 105%: from about 10% to about 100%; from about 10% to about 90%; from about 10% to about 80%; from about 10% to about 70%; from about 10% to about 60%; from about 10% to about 50%; from about 10% to about 40%; from about 10% to about 30%; from about 10% to about 20%; from about 20% to about 105%; from about 20% to about 100%; from about 20% to about 90%; from about 20% to about 80%; from about 20% to about 70%; from about 20% to about 60%; from about 20% to about 50%; from about 20% to about 40%; from about 20% to about 30%; from about 30% to about 105%; from about 30% to about 100%; from about 30% to about 90%; from about 30% to about 80%; from about 30% to about 70%; from about 30% to about 60%; from about 30% to about 50%; from about 30% to about 40%; from about 40% to about 105%; from about 40% to about 100%; from about 40% to about 90%; from about 40% to about 80%; from about 40% to about 70%; from about 40% to about 60%; from about 40% to about 50%; from about 50% to about 105%; from about 50% to about 100%; from about 50% to about 90%; from about 50% to about 80%; from about 50% to about 70%; from about 50% to about 60%; from about 60% to about 105%; from about 60% to about 100%; from about 60% to about 90%; from about 60% to about 80%; from about 60% to about 70%; from about 70% to about 105%; from about 70% to about 100%; from about 70% to about 90%; from about 70% to about 80%; from about 80% to about 105%; from about 80% to about 100%; from about 80% to about 90%; from about 90% to about 105%; or from about 90% to about 100%.

[00143] It should be appreciated that the disclosed percent increase in measured half-life in a mammal can also be expressed as a range including any of the previously described percent levels, in any combination, as well as including the specific percentages tailing within the ranges, such that increased half-life in a mammal can be expressed, in one embodiment, as a range of about 30% to about 40%, and it will be understood that such a described range includes percent values of 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, and 39%.

[00144] In some embodiments, the bioavailability of the compound of the invention is measured by AUC. In some embodiments, the compound of the invention can provide about a 20% or greater increase in bioavailability over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 40% or greater increase in bioavailability over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 70% or greater increase in bioavailability over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 80% or greater increase in bioavailability over the corresponding non- deuterated compound. In certain embodiments, the compound of the invention can provide about a 90% or greater increase in bioavailability over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 95% or greater increase in bioavailability over the corresponding non-deuterated compound. In certain embodiments, the compound of the invention can provide about a 100% increase in bioavailability over the corresponding non-deuterated compound. In certain embodiments, the percentage increase in bioavailability of the compound of the invention over the corresponding non-deuterated compound can be expressed as a range, such as between 20 and 100% between 40% and 100%; between 70% and 100%; between 40% and 45%; between 45% and 75%; between 45% and 70%; or, between 70% and 100%.

[00145] In some embodiments, the percentage increase in bioavailability of a pharmaceutical composition including the compound of the invention over the pharmaceutical composition comprising the corresponding non-deuterated compoundis from about 0.01 % to about 10%, or from about 0.01% to about 7.5%, or from about 0.01% to about 5%, or from about 0.01% to about 2.5%, from about 0.05% to about 10%, from about 0.05% to about 5%, from about 0.5% to about 10%, from about 1 .0% to about 10%, from about 2.5% to about 10%, from about 5.0% to about 10%, from about 1.0% to about 7.5%, from about 1.0% to about 5.0%, from about 10% to about 100%; from about 10% to about 90%; from about 10% to about 80%; from about 10% to about 70%; from about 10% to about 60%; from about 10% to about 50%; from about 10% to about 40%; from about 10% to about 30%; from about 10% to about 20%; from about 20% to about 100%; from about 20% to about 90%; from about 20% to about 80%; from about 20% to about 70%; from about 20% to about 60%; from about 20% to about 50%; from about 20% to about 40%; from about 20% to about 30%; from about 30% to about 100%; from about 30% to about 90%; from about 30% to about 80%; from about 30% to about 70%; from about 30% to about 60%; from about 30% to about 50%; from about 30% to about 40%; from about 40% to about 100%; from about 40% to about 90%; from about 40% to about 80%; from about 40% to about 70%; from about 40% to about 60%; from about 40% to about 50%; from about 50% to about 100%; from about 50% to about 90%; from about 50% to about 80%; from about 50% to about 70%; from about 50% to about 60%; from about 60% to about 90%; from about 60% to about 80%; from about 60% to about 70%; from about 70% to about 100%; from about 70% to about 90%; from about 70% to about 80%; from about 80% to about 100%; from about 80% to about 90%; or from about 90% to about 100%.

[00146] In some embodiments, the bioavailability of the compound of the invention is measured by ( max. In some embodiments, the compound of the invention can provide about a 40% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of the invention can provide about a 50% or greater increase in bioavai lability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of the invention can provide about a 80% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of the invention can provide about a 100% or greater increase in bioavailability’ over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of the invention can provide about a 125% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of the invention can provide about a 150% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of the invention can provide about a 200% increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the percentage increase in bioavailability' of the compound of the invention over the corresponding non-deuterated compound can be expressed as a range, such as between 20 and 200% between 40% and 200%; between 70% and 200%; between 40% and 100%; between 45% and 125%; between 45% and 150%; or, between 70% and 200%, [00147] In some embodiments, the bioavailability of the compound of the invention is measured by Crnax. In some embodiments, the compound of formula (I) can provide about a 40% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of formula (I) can provide about a 50% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of formula (I) can provide about a 80% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of formula (I) can provide about a 100% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of formula (I) can provide about a 125% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of formula (I) can provide about a 150% or greater increase in bioavailability over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the compound of formula (I) can provide about a 200% increase in bioavailability' over the corresponding non-deuterated compound, e.g., tetrahydrocannabinol. In certain embodiments, the percentage increase in bioavailability of the compound of formula (I) over the corresponding non-deuterated compound can be expressed as a range, such as between 20 and 200% between 40% and 200%; between 70% and 200%; between 40% and 100%; between 45% and 125%; between 45% and 150%; or, between 70% and 200%.

[00148] In some embodiments, the percentage increase in bioavailability of a pharmaceutical composition including the compound of the invention over the pharmaceutical composition comprising the corresponding non-deuterated compoundis from about 0.01% to about 10%, or from about 0.01% to about 7.5%, or from about 0.01% to about 5%, or from about 0.01% to about 2.5%, from about 0.05% to about 10%, from about 0.05% to about 5%, from about 0.5% to about 10%, from about 1.0% to about 10%, from about 2.5% to about 10%, from about 5.0% to about 10%, from about 1.0% to about 7.5%, from about 1.0% to about 5.0%, from about 10% to about 200%; from about 10% to about 150%; from about 10% to about 100%; from about 10% to about 70%; from about 10% to about 60%; from about 10% to about 50%; from about 10% to about 40%; from about 10% to about 30%; from about 10% to about 20%; from about 20% to about 200%; from about 20% to about 100%; from about 20% to about 90%; from about 20% to about 80%; from about 20% to about 70%; from about 20% to about 60%; from about 20% to about 50%; from about 20% to about 40%; from about 20% to about 30%; from about 30% to about 200%; from about 30% to about 150%; from about 30% to about 100%; from about 30% to about 80%; from about 30% to about 70%; from about 30% to about 60%; from about 30% to about 50%; from about 30% to about 40%; from about 40% to about 200%; from about 40% to about 150%; from about 40% to about 100%; from about 40% to about 80%; from about 40% to about 70%; from about 40% to about 60%; from about 40% to about 50%; from about 50% to about 200%; from about 50% to about 150%; from about 50% to about 100%; from about 50% to about 80%; from about 50% to about 70%; from about 50% to about 60%; from about 60% to about 200%; from about 60% to about 150%; from about 60% to about 100%; from about 60% to about 80%; from about 60% to about 70%; from about 70% to about 100%; from about 70% to about 90%; from about 70% to about 80%; from about 80% to about 200%; from about 80% to about 150%; or from about 90% to about 100%.

[00149] Plasma levels of the compound of the invention as described herein, or metabolites thereof, may be measured using the methods described by Li et al. Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950; De Francia et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(18+19), 1721-1726; Parise et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(20+21), 1894-1900; Pursche et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2007, 852(1-2), 208-216; Haouala et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(22), 1982-1996; and any references cited therein and any modifications made thereof.

[00150] Examples of cytochrome P450 isofonns in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S 1, CYP3A4, CYP3A5, CYP3A5P1 , CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F1 1, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1 , CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1 , CYP27B1, CYP39, CYP46, and CYP51.

[00151] Examples of monoamine oxidase isofonns in a mammalian subject include, but are not limited to, MAO A, and MAOB.

[00152] The inhibition of the cytochrome P450 isoform is measured by the method of Ko et al, British Journal of Clinical Pharmacology 2000, 49, 343-351. The inhibition of the MAOA isofonn is measured by the method of Weyler eZ al, J. Biol Chem. 1985, 260, 13199-13207. The inhibition of the MAOB isoform is measured by the method of Uebelhack et al, Pharmacopsychiatry 1998, 31, 187-192.

[00153] Examples of polymorphically-expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[00154] The metabolic activities of liver microsomes, cytochrome P450 isoforms, and monoamine oxidase isoforms are measured by the methods described herein.

[00155] Examples of improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to, major cytogenetic response, complete cytogenetic response, complete hematologic response, complete molecular remission, improved progression-free survival, increase in overall survival rate, tumor shrinkage, increased median overall survival time, improved overall response rate, and improved disease control rate.

[00156] Examples of diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase ("ALT”), serum glutamic-pyruvic transaminase ("SGPT”), aspartate aminotransferase ("AST" or "SGOT"), ALTZAST ratios, serum aldolase, alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP," "y-GTP," or "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5 '-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in "Diagnostic and Laboratory Test Reference", 4 ^th edition, Mosby, 1999.

[00157] In some embodiments, the present invention provides methods for treating cancer in a subject. In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. These methods can be achieved by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. In one embodiment, the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung tumors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma. In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+- ( ML).

[00158] In some embodiments, the present invention provides methods for treating a neurodegenerative disease or disorder in a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is an animal. In other embodiments, the subject is a human. These methods include administering to the mammal a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. In one embodiment, the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, or progressive muscular atrophy.

[00159] In some embodiments, the described methods of treatment can additionally include administering to the subject one or more additional therapeutic agents. Such other therapeutic agents may be administered, by a route and in an amoun t commonly used therefore, simultaneously or sequentially with a compound or composition of the present invention. In certain embodiments, the compounds disclosed herein can be combined with one or more alkylating agents, antimetabolite agents, mitotic inhibitors, tyrosine kinase inhibitors, topoisomerase inhibitors, cancer immunotherapy monoclonal antibodies, anti-tumor agents, and anti-cancer agents.

[00160] In some embodiments related to the methods of treating cancer in a subject, the compounds of the invention as described herein can be combined with one or more alkydating agents, including, but not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.

[00161] In some embodiments, the compounds of the invention as described herein can be combined with one or more anti -metabolite agents, including, but not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafor, camiofur, capecitabine and gemcitabine.

[00162] In some embodiments, the compounds of the invention as described herein can be combined with one or more mitotic inhibitors, including, but not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[00163] In some embodiments, the compounds of the invention as described herein can be combined with one or more tyrosine kinase inhibitors, including, but not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib. [00164] In some embodiments, the compounds of the invention as described herein can be combined with one or more topoisomerase inhibitors, including, but not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan,

[00165] In some embodiments, the compounds of the invention as described herein can be combined with one or more cancer immunotherapy monoclonal antibodies, including, but not limited to, rituximab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, and trastuzumab.

[00166] In some embodiments, the compounds of the invention as described herein can be combined with one or more anti-tumor agents, including, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea. [0096] In certain embodiments, the compounds disclosed herein can be combined with one or more anti-cancer agents, including, but not limited to, amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.

[00167] The compounds of the invention as descried herein can also be administered in combination with other classes of compounds, including, but not limited to, norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors ( D A R Is ), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotoninmorepinephrine-dopamine-reuptake-inhibit.ors (SNDRls), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP- ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethi azide, polythiazide, benzothiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g,, acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE HI inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L- asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; micro tubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.

[00168] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, multiple sclerosis, spasticity, Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette’s syndrome, or emesis, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00169] hi a further aspect, the present invention provides a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, 11-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, multiple sclerosis, spasticity, Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette’s syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00170] The invention further provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a compound of formula (I), wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette’s syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety’, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00171] The invention further provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a compound of formula (II), wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. [00172] The invention further provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a combination of the compound of formula (I) and the compound of formula (II), wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, multiple sclerosis, spasticity', Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00173] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1- 25, 1-26, U-4, II-6, 11-7, 11-14, 11-15, or 11-16, wherein said disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety' disorder, or separation anxiety' in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is an animal. In some embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a horse. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a ferret.

[00174] In a further aspect, the present invention provides a method of treating or preventing a subject suffering from a disease or disorder selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer’s, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity', type 2 diabetes, and testosterone insufficiency, wherein said method comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1- 14, 1-20, 1- 24, 1-25, 1-26, 11-4, II-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity’ disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. [00175] In another aspect, the present invention provides a method of treating or preventing pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-

25. 1-26, II-4, 11-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the pain is chronic pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-

6. 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, 11-4, JI-6, TI-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00176] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-

25, 1-26, II-4, 11-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In other embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00177] In another aspect, the present invention provides a method of treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1- 25, 1-26, II-4, IT-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgeiy, soft-tissue surgery, or dental surgery.

[00178] In another aspect, the present invention provides a method of treating or preventing pain or inflammation associated with osteoarthritis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, IT-4, IT-6, II-7, 11-14, II- 15, or II- 16, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00179] In yet another aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with orthopedic surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, IT-4, IT-6, TI-7, 11-14, 11-15, or IT-16, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00180] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with soft-tissue surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00181] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with dental surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00182] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, , e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1- 25, 1-26, II-4, II-6, IT-7, 11-14, 11-15, or 11-16, or any combination thereof, wherein said disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the subject is a dog. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In some embodiments, the causes of anorexia include, but are not limited to, secondary to chemo, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, and iatrogenic problems. In some embodiments, the anxiety is separation anxiety or generalized anxiety. In some embodiments, the aggression is dominance aggression, tear aggression, intraspecific aggression, or territorial aggression.

[00183] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, , e.g., a compound of formula (A) or (B), formula (I) or (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1- 25, 1-26, II-4, II-6, 11-7, 11-14, 11-15, or 11-16, or any combination thereof wherein said disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma. In some embodiments, the subject is a cat. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency.

[00184] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourete's syndrome, or emesis, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an ani-ma-h

[00185] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00186] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and Al H-A22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00187] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegen erative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00188] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[00189] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, or Rett syndrome.

[00190] The invention further provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to said subject a compound of fomulauAJd; wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is anxiety, infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00191] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety' disorder, seasonal affective disorder, attention deficit hyperactivity' disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary' insomnia circadian rhythm -related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity’ disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. hi some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00192] In another aspect, the present invention provides a method of treating or preventing pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A13, and A18-A22, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof. In some embodiments, the pain is chronic pain. In some embodiments, the pain is acute pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds 8, 13, and 18-22, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A 13, and A18-A22, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. [00193] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering io said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A13, and A18-A22, or any combination thereof, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. Tn some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. Tn some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. Tn some embodiments, the disease or disorder is cancer. Tn some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the subject in the method of the invention is a mammal. Tn other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00194] In another aspect, the present invention provides a method of treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and Al 8-A22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery, soft-tissue surgery, or dental surgery.

[00195] In another aspect, the present invention provides a method of treating or preventing pain or inflammation associated with osteoarthritis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A13, and A18-A22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00196] In yet another aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with orthopedic surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00197] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with soft-tissue surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, AI3, and A18-A22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00198] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with dental surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds 8, 13, and 18-22, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00199] In another aspect, the present invention provides a method of treating or preventing pain or inflammation associated with osteoarthritis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula OVA), or any one of compounds A8, A13, and A18-A22, or any combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00200] In yet another aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with orthopedic surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00201] hi a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with soft-tissue surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A13, and A18-A22, or any combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00202] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with dental surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as descried herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A13, and A18-A22, or any combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00203] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, A13, and A18-A22, or any combination thereof wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety, aggression, compulsive disorders, phobias, epilepsy, or seizures. In some embodiments, the subject is a dog. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In some embodiments, the anxiety is separation anxiety or generalized anxiety. In some embodiments, the aggression is dominance aggression, fear aggression, intraspecific aggression, or territorial aggression.

[00204] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (Al), or a compound of formula (AA), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof wherein said disease or disorder is anorexia, anxiety, epilepsy, or glaucoma. In some embodiments, the subject is a cat. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary' anorexia, e.g., secondary’ to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency.

[00205] In some embodiments, the method of the invention further comprises the administration of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is antiemetics or analgesics. In some embodiments, the analgesic is carprofen, meloxicam, carbamazepine, gabapentin, pregabalin, acetaminophen, acetylsalicyclic acid, ibuprofen, or naproxen. In some embodiments, the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, and palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.

[00206] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00207] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[00208] In a further aspect, the present invention provides a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AAI 1, AAI 6, and AA20-AA24, or any combination thereof

[00209] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.

[00210] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[0021 1] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, or Rett syndrome.

[00212] The invention further provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to said subject a compound of formula (AAI), wherein the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.

[00213] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AA16, and AA20-AA24, wherein said disease or disorder is aggression, fear, phobias, generalized anxiety disorder, or separation anxiety in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein. In some embodiments, the subject is an animal. In some embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a horse. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a ferret.

[00214] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AAI 6, and AA20-AA24, or any combination thereof, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jetlag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary' insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivitydisorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[ 00215 ] In another aspect, the present invention provides a method of treating or preventing pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g. , a compound of formula (AAI), or a compound of formula (AAA), or any one of compound A.A7, A.A1 1, AA16, and A.A20-A.A24, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AAI 1 , AA 16, and AA20- AA24, or any combination thereof. In some embodiments, the pain is chronic pain. In some embodiments, the pain is acute pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AAI 6, and AA20-AA24, or any combination thereof. Tn some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AAI 1, AAI 6, and AA20-AA24, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AA16, and AA20-AA24, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00216] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AAI 1 , AA16, and AA20-AA24, or any combination thereof, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity', and metabolic syndrome -related disorders. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington’s disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00217] In another aspect, the present invention provides a method of treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AAI 1 , AAI 6, and AA20-AA24, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperati ve pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery , soft-tissue surgery', or dental surgery ¹ .

[00218] In another aspect, the present invention provides a method of treating or preventing pain or inflammation associated with osteoarthritis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA1 1 , AA16, and AA20-AA24, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00219] In yet another aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with orthopedic surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AA16, and AA20-AA24, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00220] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with soft-tissue surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AAI 6, and AA20-AA24, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00221] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with dental surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AAI 6, and AA20-AA24, or any combination thereof. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00222] In another aspect, the present invention provides a method of treating or preventing pain or inflammation associated with osteoarthritis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA1 1 , AA16, and AA20-AA24, or any combination thereof. Tn some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00223] In yet another aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with orthopedic surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11, AAI 6, and AA20-AA24, or any combination thereof. In some embodiments, the subject is a human. Tn some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00224] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with soft-tissue surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA1 1, AA16, and AA20-AA24, or any combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00225] In a further aspect, the present invention provides a method of treating or preventing a postoperative pain or inflammation associated with dental surgery in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA1 1, AA16, and AA20-AA24, or any combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse or a cat.

[00226] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11 , AA16, and AA20-AA24, or any combination thereof, wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety, aggression, compulsive disorders, phobias, epilepsy, or seizures. IN some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In some embodiments, the anxiety is separation anxiety or generalized anxiety. In some embodiments, the aggression is dominance aggression, fear aggression, intraspecific aggression, or territorial aggression.

[00227] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compound AA7, AA11 , AA16, and AA20-AA24, or any combination thereof, wherein said disease or disorder is anorexia, anxiety, epilepsy, or glaucoma. In some embodiments, the subject is an animal. In some embodiments, the subject is a cat. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency.

[ 00228] In some embodiments, the method of the invention further comprises the administration of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is antiemetics or analgesics. In some embodiments, the analgesic is meloxicam, carprofen, carbamazepine, gabapentin, pregabalin, acetaminophen, acetylsalicyclic acid, ibuprofen, or naproxen. In some embodiments, the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, and palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.

[00229] In some embodiments, the method of the invention further comprises the administration of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is carprofen, meloxicam, fluoxetine hydrochloride, comipramine hydrochloride, or phenobarbital

[00230] The present invention further provides a combination therapy. The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic disorder described in the present invention. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. Tn addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drag combination in treating the disorders described herein.

[00231 ] The present invention relates to a novel method for the treatment of a disease or disorder in a subject currently receiving a therapeutic agent by administering a compound of formula (A) or a compound of formula (B) in combination with the therapeutic agent.

[00232] It is one aspect of the invention that a combination therapy that includes a deuterated compound of formula (A) or formula (B) and at least one additional therapeutic agent as described herein exhibits a therapeutic synergistic or additive effect. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (A) or formula (B).

[00233] It is another aspect of the invention that a combination of a deuterated tetrahydrocannabinol compound of formula (A) or a deuterated tetrahydrocannabivarm compound of formula (B) with at least one additional therapeutic agent as described herein may minimizing toxicity during treatments and result in a decrease in the onset of resistance development.

[00234] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) and at least one additional therapeutic agent,

wherein R ₁ -R30 are each independently H or D,

[00235] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jetlag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.

[00236] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia nervosa, dementia, cachexia, HIV wasting syndrome, Tourette’s syndrome, or emesis, or any combination thereof.

[00237] In some embodiments, the disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer’s, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency .

[00238] In some embodiments, the disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.

[00239] In some embodiments, the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.

[00240] In some embodiments, the disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma.

[00241] In some embodiments, the compound of formula (A) is a deuterated compound of (6aR, 10aR)-delta-9-Tetrahydrocannabinol (THC), or a derivative thereof,

[00242] In some embodiments of the compound of formula (A), R ₁₅ is D or OH. In some embodiments, when R3 is H, R ₁₅ is OH. In some embodiments, R ₁₅ is D or OH; provided that when Rs is H, R ₁₅ is OH. In some embodiments, Ri and R2 are D. In some embodiments, Ri is D. In some embodiments, R4 and Rs are D. In some embodiments, R4-R14 are D. In some embodiments, Rs -Ri4 are D. [00243] In some embodiments, the compound of formula (A) is represented by a compound of formula (I): wherein

Rj~Ri4 are each independently H or D; and

Ri 5 is D or OH; provided that when Rs is H, Ri s is OH.

[00244] In some embodiments of the compound of formula (A) or (I), Ri and R2 are D. In some embodiments, Rs is D. In some embodiments, R4 and Rs are D. In some embodiments, R4-Ri4 are D. In some embodiments, Rs -RM are D.

[00245] In some embodiments, the compound of formula (A) or (I) is represented by compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26:

[00246] In another aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) and at least one additional therapeutic agent.

(B) wherein R ₁ -R9 and R ₁₅ -Rn are each independently H or D; and R ₁₅ is D or OH,

[00247] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourete's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jetlag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington’s disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.

[00248] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia nervosa, dementia, cachexia, HIV wasting syndrome, Tourette’s syndrome, or emesis, or any combination thereof.

[00249] In some embodiments, the disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smifh-Magenis syndrome, major depressive disorder, primary' insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer’s, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency .

[00250] In some embodiments, the disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.

[00251] In some embodiments, the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.

[00252] In some embodiments, the disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the disease or disorder is anorexia, anxiety', epilepsy, osteoarthritis, or glaucoma.

[00253] In some embodiments, the compound of formula (B) is a deuterated compound of delta- 9-tetrahydrocannabivarin (THCV), or a derivative thereof.

[00254] In some embodiments of the compound of formula (B), R ₁₅ is D. In some embodiments, R ₁₅ is OH. In some embodiments, Rs is D. In some embodiments, Ri and Re are D. In some embodiments, R4 and R5 are D. In some embodiments, R4- R9 and R ₃₁ are D. In some embodiments, Ri and R2 are D; and R ₁₅ is D. In some embodiments, R4 and Rs are D; and R ₁₅ is D. In some embodiments, Rt- R9 are D; and R ₁₅ is D. [00255] In some embodiments, the compound of formula (B) is represented by a compound of formula (II): wherein R ₁ -R9 and Rs; are each independently H or D; and R ₁₅ is D or OH.

[00256] In some embodiments of the compound of formula (B) or (II), R ₁₅ is D. In some embodiments, R ₁₅ is OH. In some embodiments, R3 is D. In some embodiments, Ri and R2 are D.

In some embodiments, R4 and R5 are D. In some embodiments, R<- R9 and R ₃₁ are D. In some embodiments, Ri and R? are D; and R ₁₅ is D. In some embodiments, R4 and Rs are D; and R ₁₅ is

D. In some embodiments, R+- R9 are D; and R ₁₅ is D.

[00257] In some embodiments, the compound of formula (B) or (II) is represented by compound

II-4, 11 -6, II-7, II- 14, 11- I 5 , or 11-16:

(IT- 16). [00258] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) or formula (B) and at least one additional therapeutic agent.

[00259] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A) as described herein and at least an additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the compound of formula (A) is the compound of formula (I), or any one of compounds 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, and I- 26, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00260] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (B) as described herein and at least an additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound 11-4, 11-6, 11-7, 11-14, 11-15, or 11-16, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non- human animal.

[00261] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A) as described herein and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any' combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment andprevention of the disease or disorder. In some embodiments, the compound of formula (A) is the compound of formula (I), or any' one of compounds 1-4, 1-6, 1- 7, 1-14, 1-20, 1-24, 1-25, and 1-26, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00262] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (B) as described herein and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any' combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound IT-4, II-6, TI-7, IT-14, U-15, or 11-16, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00263] In a farther aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A), or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1- 24, 1-25, 1-26, 11-4, II-6, TI-7, IT- 14, IT- 15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivitydisorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivitydisorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a nonhuman animal.

[00264] In another aspect, the present invention provides a method for treating or preventing pain, multiple sclerosis, epilepsy, chemo-related nausea, vomiting, and anorexiain a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, 11- 7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent. In some embodiments, the pain is chronic pain. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, 11-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent. In some embodiments, the pain is chronic pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (1), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, IT-6, II-7, IT-14, 11-15, or II- 16, or any compound as descried herein, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (1), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1- 26, 11-4, 11-6, 11-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, IT-4, II-6, IT-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00265] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1- 6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, 11-4, 11-6, 11-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In some embodiments, the causes of anorexia include, but are not limited to, secondary to chemo, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, and iatrogenic problems. [00266] In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is anxiety. In some embodiments, the disease or disorder is aggression. In some embodiments, the disease or disorder is a compulsive disorder. In some embodiments, the disease or disorder is noise phobias. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog.

[00267] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is anxiety. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In certain embodiments, the subject is a cat.

[00268] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, 1- 6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.

[00269] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, I- 6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent, wherein the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia. In some embodiments, the disease or disorder is pain. In some embodiments, the pain is chronic pain. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is chemo-related nausea, vomiting, and anorexia. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non- human animal.

[00270] In another aspect, the present invention provides a method of treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (A) as described herein, or a compound of formula (B), or a compound of formula (I), or a compound of formula (II), or compound 1-4, I- 6, 1-7, 1-14, 1-20, 1-24, 1-25, 1-26, II-4, II-6, 11-7, 11-14, 11-15, or 11-16, or any compound as descried herein, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used tor the treatment or prevention of pain or inflammation. In some embodiments, the additional therapeutic agent is as described anywhere herein tor the treatment and prevention of pain or inflammation. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In other embodiments, the subject is a horse or a cat. In some embodiments, the subject is a dog. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery, soft-tissue surgery, or dental surgery.

[00271] In some embodiments, the ‘‘therapeutic agent” as used herein refers to an agent or a drug that is capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. The “therapeutic agent” can be any agent or drug as known in the art or being currently developed. In some embodiments, the terms “therapeutic agent” and “therapeutic drug” are used interchangeably. In some embodiments, the “therapeutic agent” refers to the “additional therapeutic agent” as used herein.

[00272] In some embodiments of the method of the invention, the additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an antiemetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti- dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an antiosteoporosis agent, or a cardiovascular agent.

[00273] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.

[00274] In one aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an analgesic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an analgesic agent. In some embodiments, the disease or disorder is pain, e.g., acute pain or chronic pain. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1- 6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00275] In one aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an analgesic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an analgesic agent. In some embodiments, the disease or disorder is pain, e.g., acute pain or chronic pain. In some embodiments, the compound of formula (B) is the compound of (II), or compound II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00276] In some embodiments, the analgesic agent is an opioid analgesic agent or a nonopioid analgesic agent. In some embodiments, the non-opioid analgesic agent is meloxicam, acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiproten, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, carbamazepine, gabapentin, or pregabalin. In certain embodiments, the analgesic agent is naproxen sodium or magnesium. In some embodiments, the analgesic is carbamazepine, gabapentin, pregabalin, acetaminophen, ibuprofen, or naproxen.

[00277] In some embodiments, the opioid analgesic agent is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol. In some embodiments, the opioid analgesic agent is hydrocodone bitartrate or oxycodone hydrochloride. In some embodiments, the opioid analgesic agent is a naturally occurring opiate, such as an alkaloid occurring in the opium poppry. In certain embodiments, the naturally occurring opiate is morphine, codeine, narcotine, papaverine, narceine, or thebaine.

[00278] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and a therapeutic agent for treatment of a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, Tourette's syndrome, or progressive muscular atrophy. In some embodiments, the neurodegenerative disease or disorder is Parkinson’s disease, Alzheimer's disease, or Huntington's disease. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00279] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and a therapeutic agent for treatment of a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, Tourette's syndrome, or progressive muscular atrophy. In some embodiments, the neurodegenerative disease or disorder is Parkinson's disease, Alzheimer's disease, or Huntington's disease. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, IT-6, TI-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00280] In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanins (e.g., anthocyanin cyanidin-3-O-glucoside), levodopa, pergolide (PERMAX™), ephenedrine sulfate (EPHEDRINE™), pemoline CYLERT™), mazindol (SANOREX™), d,l-a-methylphenethylamine (ADDERALL™) methylphenydate (RITALIN™), pramipexole (MIRAPEX™), modafinil (PROVIGIL™), or ropinirole (REQUIP™). In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanin, levodopa, pergolide, ephenedrine sulfate, pemoline, mazindol, a-methylphenethylamine, methylphenidate, pramipexole, modafinil, or ropinirole.

[00281 ] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-dyskensia agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti- dyskensia agent. In some embodiments, the disease or disorder is a movement disorder or Parkinson disease. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00282] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti -dyskensia agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti dyskensia agent. In some embodiments, the disease or disorder is a movement disorder or Parkinson disease. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound 11-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00283] In some embodiments, the anti-dyskensia agent is selected from baclofen (Lioresal™), botulinum toxin (Botox™), clonazepam (Klonopin™), and diazepam (Valium™). In other embodiments, an anti-dyskensia agent is baclofen, botulinum toxin, clonazepam, or diazepam.

[00284] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an immunosuppressive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an immunosuppressive agent. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is lupus or rheumatoid arthritis. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00285] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an immunosuppressive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an immunosuppressive agent. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is lupus or rheumatoid arthritis. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, 11-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00286] In some embodiments, the immunosuppressive agent is azathioprine, cyclophosphamide, bromocriptine, glutaraldehyde, cyclosporin A, prednisone, prednisolone, methylprednisone, dexamethasone, heterologous anti-lymphocyte globulin, deoxyspergualin, or rapamycin.

[00287] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-spasmodic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti- spasmodic agent. In some embodiments, the disease or disorder is irritable bowel syndrome, abdominal pain, or bladder dysfunction. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00288] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-spasmodic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antispasmodic agent. In some embodiments, the disease or disorder is irritable bowel syndrome, abdominal pain, or bladder dysfunction. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound 11-4. 11-6. 11- 7. 11-14, 11-15, or 11-16, or any compounds as described herein.

[00289] In some embodiments, the anti-spasmodic agent is carbamatepine, oxcarbazepine, ferbocate, fiirboc acid, paroxamine, fibapramine, laxamide, talapanib, retigabine, levethiracetam, tobinamide, zonisamide. barbiturates, benzodiazepines, or hydantoin.

[00290] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-diabetic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidiabetic agent. In some embodiments, the disease or disorder is diabetes. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, I- 20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00291 ] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-diabetic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidiabetic agent. In some embodiments, the disease or disorder is diabetes. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, 11-6. II-7, 11-14, II- 15, or 11-16, or any compounds as described herein. [00292] In some embodiments, the anti-diabetic agent is mefluminine hydrochloride, acarbose, miglitol, human insulin, pig insulin, bovine insulin, nateglinide, reglinide, glimepiride, glibenclamide, chlorpromide, tolazamide, or glipben.

[00293] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is seizure, neuropathic pain, or epilepsy. In some embodiments, the disease or disorder is a seizure associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00294] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is seizure, neuropathic pain, or epilepsy. In some embodiments, the disease or disorder is a seizure associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound 11-4, II-6, II--7, 11-14, 11- 15, or 11-16, or any compounds as described herein.

[00295] In some embodiments, the anti-convulsant agent or anti-epileptic agent is phenobarbital, pentobarbital, nitronazapine, clozapine acid salt, diazapine, saigabin, gabapentin, phenytoin, 5,5- diphenylhydantoin, carbamatepine, oxcarbazepine, falbockate, falbock acid, bifarin Pockic acid, paroxamide, tibamay, levethiracetam, tobinamide, zonisamide, lamtidine, mesylamine, ethoxyl , or ruitijiabin. In some embodiments, the anti-convulsant agent or anti-epileptic agent is brivaracetam, carbamzepine, clobazam, rancedon, ethosuximide, non-ammonia ester, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin sodium salt, pregabalin, desoxyphenobarbital, rotigotine, rufinamide, seletracetam, talampanel, tiagabine, topiramate, sodium valproate, vigabatrin, or zonisamide. In some embodiments, the anticonvulsant agent or anti-epileptic agent is arbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, tiagabine, valproic acid, or zonisamide. In some embodiments, the anti-convulsant agent or anti-epileptic agent is Epidiolex®.

[ 00296] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-psychotic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antipsychotic agent. In some embodiments, the disease or disorder is schizophrenia, psychosis, or bipolar disorder. In some embodiments, the compound of formula (A) is the compound of formula

(I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00297] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-psychotic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antipsychotic agent. In some embodiments, the disease or disorder is schizophrenia, psychosis, or bipolar disorder. In some embodiments, the compound of formula (B) is the compound of formula

(II), or compound TI-4, 11-6, II-7, 11-14, 11-15, or II- 16, or any compounds as described herein.

[00298] In some embodiments, the anti-psychotic agent is risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, or raclopride.

[ 00299] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is high cholesterol, lipid abnormalities, obesity, or a metabolic syndrome-related disorder. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1- 6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein. [ 00300] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is any? one that can be treated or prevented as known in the art by a cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is high cholesterol, lipid abnormalities, obesity, or a metabolic syndrome-related disorder. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, II- 7, II- 14, 11-15, or 11-16, or any compounds as described herein.

[00301] In some embodiments, the cholesterol/lipid lowering agent is pravastatin, lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, cholestyramine, colestipol, gemfibrozil, clofibrate, fenofibrate, benzafibrate, rosiglitazone, or ezetimibe.

[00302] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-inflammatory agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-inflammatory agent. In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the disease or disorder is severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, headaches, digestive disorders, or a fever. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00303] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-inflammatory agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-inflammatory agent. Tn some embodiments, the disease or disorder is an inflammatory’ disease. In some embodiments, the disease or disorder is severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, headaches, digestive disorders, or a fever. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, IT-7, 11- 14. 11-15, or 11-16, or any compounds as described herein.

[00304] In some embodiments, the anti-inflammatory agent is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, naproxen, ketoprofen, ceiecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, ciidanac, oxpinac, niefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen.

[00305] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-bacterial agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antibacterial agent. In some embodiments, the disease or disorder is a bacterial infection. In some embodiments, the disease or disorder is a skin or eye infection, tuberculosis, or a urinary tract infection. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00306] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-bacterial agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antibacterial agent. In some embodiments, the disease or disorder is a bacterial infection. In some embodiments, the disease or disorder is a skin or eye infection, tuberculosis, or a urinary' tract infection. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, IT-7, II- 14, II- 15, or 11-16, or any compounds as described herein.

[00307] In some embodiments, the anti-bacterial agent is selected from the group consisting of erythromycin, aji azithromycin, clarithromycin, telithromycin, penicillin G, penicillin V, methicillin, toluene oxazinmycin, o-chloropenicillin, diclofenac, phenoxypenicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, Piperacillin, azlocillin, ternocillin, cepalothin, cefepime, cefacyclohexene, ceftizodine, cefazolin, cefotaxazole, cephalosporin, cephalosporin IV, cefprozil, cloxacromycin, loracarbef, cefotaxime, cefmetazole, ceftazidime cefotaxime, cefizoxirne, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, cetazide, ceftibuten, cefdinir, cefpirome, cefepime, aztreonam, imipenem, meropenem, meropenem penicillin (ertapenem), doricane (doripenem), cephalosporin ceftobiprole and ceftaroline, citric acid, porphyrin, norfloxacin, pelloxacin, enoxacin, oufumycin, levofloxacin, ciprofloxacin, tiproxoxacin temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, and rafosa trovafloxacin), clinafloxacin, gatifloxacin, moxifloxacin, sitar Sitafloxacin, garenoxacin, gemifloxacin, pazufloxacin, p-aminobenzoic acid, sulfadiazine, sulfonamide azole, sulfamethine oxazole and sulfonamide, streptomycin, neomycin, kenmycin, baromycin, gentamicin, tobramycin, butyl Amine kanamycin, netilmicin, spectinomycin, perillamycin, dardamycin and ezeparin, tetracycline, chlortetracycline, chlorotetracycline, go Mechlorin, minocycline, oxy tetracycline, methicillin, tigcycline, doxycycline, rifampicin, rifampin, rifapentine, rifabutin, bezoxazinorifamycin and rifaximin, lincomycin, kesendamycin, telavancin, vancomycin, ticlosin, daptomycin, quinupristin and darfapolis Daflopristin, linoleide, polymyxin, colistin, colin, trimethoprim, and bacitracin.

[00308] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-emetic. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antiemetics. In some embodiments, the disease or disorder is vomiting, nausea, motion sickness, or the side effects of opioid analgesics, general anesthetics, and'or chemotherapy directed against cancer. In some embodiments, the compound of formula (A) is the compound of formula

(I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00309] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-emetic. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antiemetics. In some embodiments, the disease or disorder is vomiting, nausea, motion sickness, or the side effects of opioid analgesics, general anesthetics, and/or chemotherapy directed against cancer. In some embodiments, the compound of formula (B) is the compound of formula

(II), or compound 11-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00310] In some embodiments, the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidoi, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol. [ 00311] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-depressant. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidepressant. In some embodiments, the disease or disorder is an obsessive-compulsive disorder (OCD), depression, panic disorder, an anxiety disorder, bipolar disorder, postraumatic stress disorder (PTSD), phobias, or social anxiety disorder. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or I- 26, or any compounds as described herein.

[00312] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-depressant. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidepressant. In some embodiments, the disease or disorder is an obsessive-compulsive disorder (OCD), depression, panic disorder, an anxiety disorder, bipolar disorder, posttraumatic stress disorder (PTSD), or social anxiety disorder. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, IT-6, II-7, 11-14, 11-15, or IT-16, or any compounds as described herein.

[00313] In some embodiments, the anti-depressants is selected from the group consisting of adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, eianopramine, cinioxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, Htoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, fluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine, and zometapine. In some embodiments, the anti-depressant agent is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the anti-depressant agent is fluoxetine. [00314] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-anxiety agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antianxiety agent. In some embodiments, the disease or disorder is generalized anxiety disorder, social phobia, anxiety, obsessive-compulsive disorder (OCD), panic disorder, and depression. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1- 6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00315] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-anxiety agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antianxiety agent. In some embodiments, the disease or disorder is generalized anxiety disorder, social phobia, anxiety, obsessive-compulsive disorder (OCD), panic disorder, and depression. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, II-7, 11-14, II- 15, or 11-16, or any compounds as described herein.

[00316] In some embodiments, the anti-anxiety agent is comipramine hydrochloride, fluoxetine hydrochloride, salprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam prazepam, buspirone, flesinoxan, gepirone and ipsapirone, pindolol, carbamazepine, lamotrigine, valproate, clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, vigabatrin, or barbiturates.

[00317] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and a sleeping agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a sleeping agent. In some embodiments, the disease or disorder is insomnia, sleepwalking, night terrors, a movement disorder that interrupts sleep, such as restless legs syndrome (RLS) and periodic limb movement disorder. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein. [00318] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and a sleeping agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a sleeping agent. In some embodiments, the disease or disorder is insomnia, sleepwalking, night terrors, a movement disorder that interrupts sleep, such as restless legs syndrome (RLS) and periodic limb movement disorder. In some embodiments, the compound of formula (B) is the compound of formula (11), or compound 11-4, II-6, 11-7, 11-14, 11- 15, or 11-16, or any compounds as described herein.

[00319] In some embodiments, the sleeping agent is zolpidem, alpidem, zopiclone, or indiflon.

[00320] In some embodimen ts, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an orexigenic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an orexigenic agent. In some embodiments, the disease or disorder is anorexia . In some embodiments, a compound of formula (A) as described herein and an orexigenic agent can stimulate appetite and produce weight gain in older persons. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[ 00321 ] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an orexigenic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an orexigenic agent. In some embodiments, the disease or disorder is anorexia. In some embodiments, a compound of formula (A) as described herein and an orexigenic agent can stimulate appetite and produce weight gain in older persons. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00322] In some embodiments, the orexigenic agent is megestrol or oxandrolone.

[00323] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an ocular hypotensive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an ocular hypotensive agent. In some embodiments, the disease or disorder is glaucoma. In some embodiments, a compound of formula (A) as described herein and an ocular hypotensive agent can lower intraocular pressure (IOP). In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00324] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an ocular hypotensive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an ocular hypotensive agent. In some embodiments, the disease or disorder is glaucoma. In some embodiments, a compound of formula (A) as described herein and an ocular hypotensive agent can lower intraocular pressure (TOP). In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00325] In some embodiments, the ocular hypotensive agent includes, but is not limited to, bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, pilocarpine, brimonidine, latanoprost, travoprost, or bimatoprost.

[ 00326] In some embodiments, the present invention provides a method tor treating or preventing osteoporosis in a subject in need thereof, comprising administering io the subject a compound of formula (A) as described herein and an anti-osteoporosis agent. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1- 24, 1-25, or 1-26, or any compounds as described herein.

[00327] In some embodiments, the present invention provides a method for treating or preventing osteoporosis in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-osteoporosis agent. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, 11-7, 11-14, II- 15, or II- 16, or any compounds as described herein. [00328] In some embodiments, the anti-osteoporosis agent includes, but is not limited to alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, bazedoxifene, teriparatide, abaloparatide, and denosumab.

[00329] In some embodimen ts, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and an anti-migraine agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antimigraine agent. In some embodiments, the disease or disorder is migraine headache or migraine pain. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00330] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and an anti-migraine agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antimigraine agent. In some embodiments, the disease or disorder is migraine headache or migraine pain. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound 11-4, IT-6, II-7, 11-14, IT-15, or 11-16, or any compounds as described herein.

[00331] In some embodiments, the anti-migraine agent is sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, probatriptan, or almotriptan.

[00332] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A) as described herein and a cardiovascular agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cardiovascular agent. In some embodiments, the disease or disorder includes, but is not limited to, arrhythmias, blood clots, coronary artery disease, high or low blood pressure, high cholesterol, heart failure, and stroke. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00333] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (B) as described herein and a cardiovascular agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cardiovascular agent. Tn some embodiments, the disease or disorder includes, but is not limited to, arrhythmias, blood clots, coronary artery’ disease, high or low blood pressure, high cholesterol, heart failure, and stroke. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00334] As used herein, in some embodiments, the term “cardiovascular agents” refer to medicines that are used to treat medical conditions associated with the heart or the circulatory’ system (blood vessels). In some embodiments, the cardiovascular agent is avasimibe, pactimibe, captopril, enalapril, enalaprilat, tradolapril, moexipril, ramipril, hinapril, perindopril, lisinopril, benazepril, fosinopril, eplerenone, aldactone, doxazosin, methykiofu, clonidine, prazosin, terazosin, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, or tocainide.

[00335] In some embodiments, the present invention provides a method tor treating or preventing cancer, comprising administering to a subject in need thereof a compound of formula (A) as described herein and an anti-cancer agent. In some embodiments, the compound of formula (A) is the compound of formula (I), or compound 1-4, 1-6, 1-7, 1-14, 1-20, 1-24, 1-25, or 1-26, or any compounds as described herein.

[00336] In some embodiments, the present invention provides a method tor treating or preventing cancer, comprising administering to a subject in need thereof a compound of formula (B) as described herein and an anti-cancer agent. In some embodiments, the compound of formula (B) is the compound of formula (II), or compound II-4, II-6, II-7, 11-14, 11-15, or 11-16, or any compounds as described herein.

[00337] In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung minors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma. In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML). [00338] In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is adrimycin, doxorubicin, 5-fluorouracil, cytosine arabinoside(“Ara-C”), cyclophosphamide, thiotepa, taxotere (docetaxel), bulsulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycine, esperamicins, or melphalan.

[00339] In some embodiments, the anti-cancer agent is a cytostatic drug. In some embodiments, the cytostatic drag is busulfan, chlorambucil, cyclophosphamide, melphalan, carmustine, lomustine, 5-fluorouracil, gemcitabine, pemetrexed, doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, paclitaxel, docetaxel, vinblastine, vincristine, etoposide, cisplatin, carboplatin, or oxaliplatin.

[00340] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkylating agent includes, but is not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.

[ 00341] In some embodiments, the anti-cancer agent is a cancer immunotherapy monoclonal antibody. In some embodiments, the cancer immunotherapy monoclonal antibody is rituximab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, or trastuzumab.

[00342] In some embodiments, the anti-cancer agent is an anti-tumor agent. In some embodiments, the anti-tumor antibiotic agent includes, but is not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea.

[00343] In certain embodiments, the anti-cancer agent is selected from the group consisting of amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.

[00344] In some embodiments, the anti-cancer agent is an anti-metabolite agent. In some embodiments, the anti-metabolite agent includes, but is not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur, capecitabine, and gemcitabine.

[00345] In some embodiments, the anti-cancer agent is a mitotic inhibitor. In some embodiments, the mitotic inhibitor includes, but is not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[00346] In some embodiments, the anti-cancer agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor includes, but is not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.

[00347] In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.

[00348] In some embodiments of the method of the invention, the additional therapeutic agent is selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, anti atherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti -infective agents, antiviral agents, antibacterial agents, antiviral agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischemic preconditioning and/or myocardial stunning, or a combination thereof.

[ 00349] In some embodiments of the method of the invention, the additional therapeutic agent is selected from norepinephrine reuptake inhibitors (NRIs) such as atornoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as itetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti -platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethi azide, polythiazide, benzothiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE HI inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L- asparaginase; famesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplalin, and carboplatin.

[00350] The present invention relates to a novel method for the treatment of a disease or disorder in a subject currently receiving a therapeutic agent by administration a deuterated cannabigerol compound of formula (AA) in combination with the therapeutic agent.

[00351] It is one aspect of the invention that a combination therapy that includes a deuterated cannabigerol compound of formula (AA) and at least one additional therapeutic agent as described herein exhibits a therapeutic synergistic or additive effect. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (AA). It is another aspect of the invention that a combination of a deuterated cannabigerol compound of formula (AA) with at least one additional therapeutic agent as described herein may allow for an improved safety profile of the additional therapeutic agent during treatments and result in a decrease in the onset of resistance development. In another aspect, the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (AA) in the treatment. Such combination therapy may allow for at least the same efficacy as, or a higher efficacy than, the treatment using the therapeutic agent alone, with an improved safety profile of the therapeutic agent. In another aspect, the therapeutically effective amount of the therapeutic agent administered to the subject is the same as the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (AA) in the treatment. Such combination therapy may allow for an increased efficacy with the same safety' profile of the therapeutic agent. [00352] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) and at least one additional therapeutic agent, wherein R ₁ -R32 are each independently H or D, provided that at least one of R.-R ₁₇ is D, wherein said disease or disorder is seiected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith- Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm -related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome -related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.

[00353] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) and at least one additional therapeutic agent,

wherein R ₁ -R32 are each independently H or D, provided that at least one of R ₁ -R ₁₇ is D, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, or any combination thereof; or wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; or wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders; or wherein the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia, or wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety; or wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, autoimmune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety’, aggression, compulsive disorders, noise phobias, epilepsy, or seizures; or wherein said disease or disorder is anorexia, anxiety, epilepsy, or glaucoma.

[00354] In some embodiments, the compound of formula (AA) is a deuterated compound of cannabigerol (CBG), or a derivative thereof.

[00355] In some embodiments of the compound of formula (AA), R ₁ -Re are D. In some embodiments, R ₁ -Ro, RB, and RM are D. In some embodiments, R ₁ -R ₁₇ are D. In some embodiments, R? and Rs are D. In some embodiments, R9-R1 ? are D.

[00356] In some embodiments, the compound of formula (AA) is represented by the compound of formula (Al) wherein R ₁ -R20 are each independently H or D, provided that at least one of R ₁ -Rn is D.

[00357] In some embodiments of the compound of formula (Al), R ₁ -Re are D. In some embodiments, R ₁ -R0, RB, and R14 are D. In some embodiments, R ₁ -R ₁₇ are D. In some embodiments, R? and Rs are D. Tn some embodiments, R9-R ₁₇ are D. [00358] In some embodiments, the compound of formula (AA) or (Al) is represented by compound A8, A13, A18, Al 9, A20, or A21:

[00359] In one aspect, the invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) and at least one additional therapeutic agent.

[00360] In another aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (AA) as described herein and at least an additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. Tn some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. [00361] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (AA) as described herein and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00362] In a further aspect, the present invention provides a method for treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00363] In a farther aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA), or a compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00364] In another aspect, the present invention provides a method for treating or preventing pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any combination thereof. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula ( AA) as described herein, or a compound of formula (Al), or any one of compounds A8, AI3, and A18- A22, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the pain is chronic pain. In other embodiments, the pain is acute pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, A 13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. Tn some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00365] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent, wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is aggression. In some embodiments, the disease or disorder is fear. In some embodiments, the disease or disorder is phobias, e.g., noise phobias. In some embodiments, the disease or disorder is generalized anxiety disorder. In some embodiments, the disease or disorder is separation anxiety. In some embodiments, the subject is an animal. In other embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.

[00366] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. Tn some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the disease or disorder is a neoplastic disease. In some embodiments, the disease or disorder is a degenerative disorder. In some embodiments, the disease or disorder is an auto-immune disease. In other embodiments, the disease or disorder is allergies. In other embodiments, the disease or disorder is a metabolic disorder. In some embodiments, the disease or disorder is infection. In other embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is trauma. In other embodiments, the disease or disorder is toxicity. In some embodiments, the disease or disorder is nutritional imbalance. In some embodiments, the disease or disorder is an idiopathic condition. In some embodiments, the disease or disorder is an iatrogenic problem. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is anxiety. In some embodiments, the anxiety is separation anxiety or generalized anxiety. In some embodiments, the disease or disorder is aggression. In some embodiments, the aggression is dominance aggression, fear aggression, intraspecific aggression, or territorial aggression. In some embodiments, the disease or disorder is a compulsive disorder. In some embodiments, the disease or disorder is noise phobias. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is seizures. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.

[00367] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or any’ one of compounds A8, A13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, anxiety, epilepsy, or glaucoma. In some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency. In some embodiments, the disease or disorder is anxiety. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In certain embodiments, the subject is a cat. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.

[00368] In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or a compound of formula (Al), or any one of compounds A8, A 13, and A18-A22, or any combination thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. Tn some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington’s disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. Tn some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. Tn some embodiments, the disease or disorder is cancer. Tn some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment andprevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00369] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or a compound of formula (Al), or any one of compounds 8, 13, and 18-22, or any combination thereof, and at least one additional therapeutic agent, wherein the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia,. In some embodiments, the disease or disorder is pain. In some embodiments, the pain is chronic pain. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is chemo-related nausea, vomiting, and anorexia. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the additional therapeutic agent is the one as know' n in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00370] In another aspect, the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or a compound of formula (Al), or any one of compounds A8, A13, and AI8-A22, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of pain or inflammation. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of pain or inflammation. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery', soft-tissue surgery, or dental surgery.

[00371 ] In another aspect, the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AA) as described herein, or a compound of formula (Al), or a compound of formula (Al), or any one of compounds 8, 13, and 18-22, or any' compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the therapeutic agent in the method of the invention is an analgesic agent including drugs and agents that provide pain relief. In some embodiments, the therapeutic agent is a non-steroidal anti-inflammatory’ drug (NSAID). In some embodiments, the non-steroidal antiinflammatory drug (NSAID) is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen. In some embodiments, the non-steroidal antiinflammatory drug (NSAID) is meloxicam, carprofen, deracoxib, or firocoxib. In certain embodiments, the non-steroidal anti-inflammatory drug (NSAID) is meloxicam. In other embodiments, the non-steroidal anti-inflammatory drug (NSAID) is carprofen. In some embodiments, the subject is a human. In other embodiments, the subject is an animal. In certain embodiments, the subject is a dog. In some embodiments, the subject is a cat.

[00372] In some embodiments of the method of the invention, the additional therapeutic agent is an analgesic agent, an anti-anxiety' agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an antiemetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti- dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an antiosteoporosis agent, or a cardiovascular agent.

[00373] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent tor treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.

[00374] In one aspect, in the method of the invention, the deuterated compound as described herein can be used to treat the adverse effects resulting from the treatment with the additional therapeutic agent as described herein. Such adverse effects include, but are not limited to, vomiting, dizziness, drowsiness, dry mouth, swollen tongue, loss of balance or coordination, and unsteadiness.

[00375] In one aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an analgesic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an analgesic agent. In some embodiments, the disease or disorder is pain such as acute pain or chronic pain. In some embodiments, the compound of formula ( AA) is the compound of formula (Al), or any one of compounds A8, A 13, and Al 8-A22, or any compounds as described herein.

[00376] In some embodiments, the analgesic agent is an opioid analgesic agent or a nonopioid analgesic agent. In some embodiments, the non-opioid analgesic agent is acetaminophen, aspirin, ibuprofen, meloxicam, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, carbamazepine, gabapentin, or pregabalin. In certain embodiments, the analgesic agent is naproxen sodium or magnesium. In some embodiments, the analgesic is carbamazepine, gabapentin, pregabalin, acetaminophen, ibuprofen, meloxicam, or naproxen.

[00377] In some embodiments, the opioid analgesic agent is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol. Tn some embodiments, the opioid analgesic agent is hydrocodone bitartrate or oxycodone hydrochloride. In some embodiments, the opioid analgesic agent is a naturally occurring opiate, such as an alkaloid occurring in the opium poppy. In certain embodiments, the naturally occurring opiate is morphine, codeine, narcotine, papaverine, narceine, or thebaine.

[00378] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and a therapeutic agent for treatment of a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, Tourette's syndrome, or progressive muscular atrophy. In some embodiments, the neurodegenerative disease or disorder is Parkinson's disease, Alzheimer's disease, or Huntington's disease. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and Al 8-A22, or any compounds as described herein.

[00379] In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanins (e.g., anthocyanin cyanidin-3-O-glucoside), levodopa, pergolide (PERMAX™), ephenedrine sulfate (EPHEDRINE™), pemoline CYLERT™), mazindol (SANOREX™), d,l-a-methylphenethylamine (ADDERALL™) methylphenydate (RITALIN™), pramipexole (MIRAPEX™), modafinil (PROVIGIL™), or ropinirole (REQUIP™). In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanin, levodopa, pergolide, ephenedrine sulfate, pemoline, mazindol, a-methylphenethylamine, methylphenidate, pramipexole, modafinil, or ropinirole.

[ 00380] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (A A) as described herein and an anti-dyskensia agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-dyskensia agent. In some embodiments, the disease or disorder is a movement disorder or Parkinson disease. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and Al 8-A22, or any compounds as described herein.

[00381] In some embodiments, the anti-dyskensia agent is selected from baclofen (LIORESAL ™), botulinum toxin (BOTOX™), clonazepam (KLONOPIN™), and diazepam (VALRJM™). In other embodiments, an anti-dyskensia agent is baclofen, botulinum toxin, clonazepam, or diazepam.

[00382] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an immunosuppressive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an immunosuppressive agent. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is lupus or rheumatoid arthritis. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00383] In some embodiments, the immunosuppressive agent is azathioprine, cyclophosphamide, bromocriptine, glutaraldehyde, cyclosporin A, prednisone, methylprednisone, dexamethasone, heterologous anti -lymphocyte globulin, deoxy spergualin, or rapamycin.

[00384] In some embodimen is, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-spasmodic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-spasmodic agent. In some embodiments, the disease or disorder is irritable bowel syndrome, abdominal pain, or bladder dysfunction. In some embodiments, the compound of formula (AA) is the compound of formula (AT), or any one of compounds A8, A13, and A18-A22, or any compounds as described herein.

[00385] In some embodiments, the anti-spasmodic agent is carbamatepine, oxcarbazepine, terbocate, furboc acid, paroxamine, fibapramine, laxamide, talapanib, retigabine, levethiracetam, tobinamide, zonisamide. barbiturates, benzodiazepines, or hydantoin.

[00386] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-diabetic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidiabetic agent. In some embodiments, the disease or disorder is diabetes. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and Al 8-A22, or any compounds as described herein.

[00387] In some embodiments, the anti-diabetic agent is mefluminine hydrochloride, acarbose, miglitol, human insulin, pig insulin, bovine insulin, nateglinide, reglinide, glimepiride, glibenclamide, chlorpromide, tolazamide, or glipben.

[00388] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is seizure, neuropathic pain, or epilepsy. In some embodiments, the disease or disorder is a seizure associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. In some embodiments, the compound of formula (AA) is the compound of formula ( AT), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00389] In some embodiments, the anti-convulsant agent or anti-epileptic agent is pentobarbital, nitronazapine, clozapine acid salt, diazapine, saigabin, gabapentin, phenytoin, 5,5- diphenylhydantoin, carbarn atepine, oxcarbazepine, falbockate, falbock acid, bifarin Pockic acid, paroxamide, fibamay, levethiracetam, tobinamide, zonisamide, lamtidine, mesylamine, ethoxyl , or ruitijiabin. In some embodiments, the anti-convulsant agent or anti-epileptic agent is brivaracetam, carbamzepine, clobazam, rancedon, ethosuximide, non-ammonia ester, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin sodium salt, pregabalin, desoxyphenobarbital, rotigotine, rufinamide, seletracetam, talampanel, tiagabine, topiramate, sodium valproate, vigabatrin, or zonisamide. In some embodiments, the anticonvulsant agent or anti-epileptic agent is arbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, tiagabine, valproic acid, or zonisamide. In some embodiments, the anti-convulsant agent or anti-epileptic agent is Epidiolex®. [00390] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-psychotic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-psychotic agent. In some embodiments, the disease or disorder is schizophrenia, psychosis, or bipolar disorder. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00391] In some embodiments, the anti-psychotic agent is risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, or raclopride.

[00392] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is high cholesterol, lipid abnormalities, obesity, or a metabolic syndrome-related disorder. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A 13, and Al 8-A22, or any compounds as described herein.

[00393] In some embodiments, the cholesterol/lipid lowering agent is pravastatin, lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, cholestyramine, colestipol, gemfibrozil, clofibrate, fenotibrate, benzatibrate, rosiglitazone, or ezetimibe.

[00394] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-inflammatory agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-inflammatory agent. In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the disease or disorder is severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, headaches, digestive disorders, or a fever. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A 13, and Al 8-A22, or any compounds as described herein.

[00395] In some embodiments, the anti-inflammatory agent is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, meloxicam, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, prarnoprofen, rnuroprofen, trioxaprofen, suprofen, arninoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen.

[00396] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-bacterial agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antibacterial agent. In some embodiments, the disease or disorder is a bacterial infection. In some embodiments, the disease or disorder is a skin or eye infection, tuberculosis, or a urinary tract infection. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and Al 8-A22, or any compounds as described herein.

[00397] In some embodiments, the anti-bacterial agent is selected from the group consisting of erytliromycin, aji azithromycin, clarithromycin, telithromycin, penicillin G, penicillin V, methicillin, toluene oxazinmycin, o-chloropenicillin, diclofenac, phenoxypenicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, Piperacillin, azlocillin, temocillin, cepalothin, cefepime, cefacyclohexene, ceftizodine, cefazolin, cefotaxazole, cephalosporin, cephalosporin IV, cefprozil, cloxacromycin, loracarbef, cefotaxime, cefinetazole, ceftazidime cefotaxime, cefizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, cetazide, ceftibuten, cefdinir, cefpirome, cefepime, aztreonam, imipenern, meropenem, rneropenem penicillin (ertapenem), doricane (doripenem), cephalosporin ceftobiprole and ceftaroiine, citric acid, porphyrin, norfloxacin, pefloxacin, enoxacin, oufumycin, levofloxacin, ciprofloxacin, tiproxoxacin temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, and rufosa trovafloxacin), clinafloxacin, gatifloxacin, moxifloxacin, sitar Sitafloxacin, garenoxacin, gemifloxacin, pazufloxacin, p-aminobenzoic acid, sulfadiazine, sulfonamide azole, sulfamethine oxazole and sulfonamide, streptomycin, neomycin, kenmycin, baromycin, gentamicin, tobramycin, butyl Amine kanamycin, netilmicin, spectinomycin, perillamycin, dardamycin and ezeparin, tetracycline, chlortetracycline, chlorotetracycline, go Mechlorin, minocycline, oxytetracycline, methicillin, tigcycline, doxycycline, rifampicin, rifampin, rifapentine, rifabutin, bezoxazinorifamycin and rifaximin, lincomycin, kesendamycin, telavancin, vancomycin, ticlosin, daptomycin, quinupristin and darfapolis Daflopristin, linoleide, polymyxin, colistin, colin, trimethoprim, and bacitracin.

[00398] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula ( AA) as described herein and an anti-emetic. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antiemetics. In some embodiments, the disease or disorder is vomiting, nausea, motion sickness, or the side effects of opioid analgesics, general anesthetics, and/or chemotherapy directed against cancer. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and A18-A22, or any compounds as described herein,

[00399] In some embodiments, the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.

[ 00400] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-depressant. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidepressant. In some embodiments, the disease or disorder is an obsessive-compulsive disorder (OCD), depression, panic disorder, an anxiety disorder, bipolar disorder, posttraumatic stress disorder (PTSD), phobias, or social anxiety disorder. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00401] In some embodiments, the anti-depressant is selected from the group consisting of adinazolam, alaproclate, amineptine, aniitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, nietapramine, nietralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, fluorxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine, and zometapine. In some embodiments, the anti-depressant agent is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the anti-depressant agent is fluoxetine.

[00402] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-anxiety agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antianxiety agent. In some embodiments, the disease or disorder is generalized anxiety disorder, social and other phobias, anxiety, obsessive-compulsive disorder (OCD), panic disorder, and depression. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or anyone of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00403] In some embodiments, the anti-anxiety agent is salprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam prazepam, buspirone, flesinoxan, gepirone and ipsapirone, pindolol, carbamazepine, lamotrigine, valproate, zolpidem; clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, vigabatrin, or barbiturates.

[00404] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and a sleeping agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a sleeping agent. In some embodiments, the disease or disorder is insomnia, sleepwalking, night terrors, a movement disorder that interrupts sleep, such as restless legs syndrome (RLS) and periodic limb movement disorder. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00405] In some embodiments, the sleeping agent is zolpidem, alpidem, zopiclone, or indiflon.

[00406] In some embodimen ts, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an orexigenic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an orexigenic agent. In some embodiments, the disease or disorder is anorexia . In some embodiments, a compound of formula (AA) as described herein and an orexigenic agent can stimulate appetite andproduce weight gain in older persons. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A 13, and A18- A22, or any compounds as described herein.

[00407] In some embodiments, the orexigenic agent is megestrol or oxandrolone.

[00408] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an ocular hypotensive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an ocular hypotensive agent. In some embodiments, the disease or disorder is glaucoma. In some embodiments, a compound of formula (AA) as described herein and an ocular hypotensive agent can lower intraocular pressure (IOP). In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, A13, and AI8-A22, or any compounds as described herein.

[00409] In some embodiments, the ocular hypotensive agent includes, but is not limited to, bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, pilocarpine, brimonidine, latanoprost, travoprost, or bimatoprost.

[00410] In some embodiments, the present invention provides a method for treating or preventing osteoporosis in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-osteoporosis agent. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein. [00411] In some embodiments, the anti-osteoporosis agent includes, but is not limited to alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, bazedoxifene, teriparatide, abaloparatide, and denosumab.

[00412] In some embodimen ts, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) as described herein and an anti-migraine agent. Tn some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antimigraine agent. In some embodiments, the disease or disorder is migraine headache or migraine pain. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00413] In some embodiments, the anti-migraine agent is sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, probatriptan, or almotriptan.

[ 00414] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AA) or a compound of formula (Al) as described herein and a cardiovascular agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cardiovascular agent. In some embodiments, the disease or disorder includes, but is not limited to, arrhythmias, blood clots, coronary artery disease, high or low blood pressure, high cholesterol, heart failure, and stroke.

[00415] As used herein, in some embodiments, the term ‘"cardiovascular agents” refer to medicines that are used to treat medical conditions associated with the heart or the circulatory system (blood vessels). In some embodiments, the cardiovascular agent is avasimibe, pactimibe, captopril, enalapril, enalaprilat, tradolapril, moexipril, ramipril, hinapril, perindopril, lisinopril, benazepril, fosinopril, eplerenone, aldactone, doxazosin, methyldofu, clonidine, prazosin, terazosin, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, or tocainide.

[ 00416] In some embodiments, the present invention provides a method for treating or preven ting cancer, comprising administering to a subject in need thereof a compound of formula (AA) as described herein and an anti-cancer agent. In some embodiments, the compound of formula (AA) is the compound of formula (Al), or any one of compounds A8, Al 3, and A18-A22, or any compounds as described herein.

[00417] In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, coion tumors, lung tumors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma. In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Pli+ CML).

[00418] In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is adrimycin, doxorubicin, 5-fluorouracil, cytosine arabinoside(“Ara-C”), cyclophosphamide, thiotepa, taxotere (docetaxel), bulsulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycine, esperamicins, or melphalan.

[00419] In some embodiments, the anti-cancer agent is a cytostatic drug. In some embodiments, the cytostatic drag is busulfan, chlorambucil, cyclophosphamide, melphalan, carmustine, lomustine, 5-fluorouracil, gemcitabine, pemetrexed, doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, paclitaxel, docetaxel, vinblastine, vincristine, etoposide, cisplatin, carboplatin, or oxaliplatin.

[00420] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkylating agent includes, but is not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.

[ 00421] In some embodiments, the anti-cancer agent is a cancer immunotherapy monoclonal antibody. In some embodiments, the cancer immunotherapy monoclonal antibody is rituximab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, or trastuzumab.

[00422] In some embodiments, the anti-cancer agent is an anti-tumor agent. In some embodiments, the anti-tumor agent includes, but is not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea. [00423] In certain embodiments, the anti-cancer agent is selected from the group consisting of amsacrine, asparaginase, altretamine, hydroxy carbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.

[00424] In some embodiments, the anti-cancer agent is an anti-metabolite agent. In some embodiments, the anti-metabolite agent includes, but is not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur, capecitabine, and gemcitabine.

[00425] In some embodiments, the anti-cancer agent is a mitotic inhibitor. In some embodiments, the mitotic inhibitor includes, but is not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[00426] In some embodiments, the anti-cancer agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor includes, but is not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.

[00427] In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.

[00428] In some embodiments of the method of the invention, the additional therapeutic agent is selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, anti atherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischemic preconditioning and/or myocardial stunning, or a combination thereof. [00429] In some embodiments, an additional therapeutic agent is selected from norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARTs), such as methylphenidate; serotonin-norepmephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethi azide, polythiazide, benzothiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE HI inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L- asparaginase; famesyl -protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble I'NF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.

[00430] The present invention relates to a novel method for the treatment of a disease or disorder in a subject currently receiving a therapeutic agent by administration a deuterated cannabichromene compound of formula (AAA) in combination with the therapeutic agent.

[00431] It is one aspect of the invention that a combination therapy that includes a deuterated cannabichromene compound of formula (AAA) and at least one additional therapeutic agent as described herein exhibits a therapeutic synergistic or additive effect. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (AAA). It is another aspect of the invention that a combination of a deuterated cannabichromene compound of formula (AAA) with at least one additional therapeutic agent as described herein may allow for an improved safety profile of the additional therapeutic agent during treatments and result in a decrease in the onset of resistance development. In another aspect, the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (AAA) in the treatment. Such combination therapy may allow for at least the same efficacy as, or a higher efficacy than, the treatment using the therapeutic agent alone, with an improved safety profile of the therapeutic agent. In another aspect, the therapeutically effective amount of the therapeutic agent administered to the subject is the same as the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of formula (AAA) in the treatment. Such combination therapy may allow for an increased efficacy with the same safety profile of the therapeutic agent.

[00432] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) and at least one additional therapeutic agent,

(AAA) wherein R ₁ -R30 are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety', migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity ¹ , Alzheimer’s disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson’s disease, Huntingtoil’s disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.

[00433] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) and at least one additional therapeutic agent, wherein R ₁ -R30 are each independently H or D, provided that at least one of R ₁ -R ₂₅ is D, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, vomiting, and emesis, or any combination thereof; or wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary' insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer’s, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity', type 2 diabetes, and testosterone insufficiency; or wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders; or wherein the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia, or wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety; or wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures; or wherein said disease or disorder is anorexia, anxiety, epilepsy, or glaucoma.

[00434] In some embodiments, the compound of formula (AAA) is a deuterated compound of cannabichromene (CBC), or a derivative thereof.

[00435] In some embodiments of the compound of formula (AAA), R ₁ -RB are D. In some embodiments, RS-RB are D. In some embodiments, RS-RB, Rao, and R21 are D. In some embodiments, R8-R24 are D. In other embodiments, R2.5 is D.

[00436] In some embodiments, the compound of formula (AAA) is represented by a compound of formula (AAI)

wherein R ₁ -Rzs are each independently H or D, provided that at least one of R ₁ -R2.5 is D.

[00437] In some embodiments of the compound of formula (AAA) or (AAI), R ₁ -RB are D. In some embodiments, RS-RB are D. In some embodiments, RS-RB, R20, and R21 are D. In some embodiments, R ₈ -R24 are D. In other embodiments, R ₂₅ is D.

[00438] In some embodiments, the compound of formula (AAA) or (AAI) is represented by any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24:

(AA22),

[00439] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) and at least one additional therapeutic agent.

[00440] In another aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (AAA) as described herein and at least an additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA16, and AA20- A A24, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00441] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (AAA) as described herein and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00442] In a further aspect, the present invention provides a method for treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (AAA) as described herein, e.g., a compound of formula (AAI), or a compound of formula (AAA), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy- induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00443] In a farther aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA), or a compound of formula (AAI), or a compound of formula (AAI), or any one of compounds AA7, AA 11, AAI 6, and AA20- AA24. or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of non-AA24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non- AA24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an atention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00444] In another aspect, the present invention provides a method for treating or preventing pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as d escribed herein, or a compound of formula (AAI), or any one of compound s AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AA I I, AAI 6, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the pain is chronic pain. In some embodiments, the pain is acute pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AAI 1 , AAI 6, and AA20-AA24, or any combination thereof, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00445] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24, or any compounds as described herein, or any combination thereof, and at least one additional therapeutic agent, wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is aggression. In some embodiments, the disease or disorder is fear. In some embodiments, the disease or disorder is phobias, e.g., noise phobias. In some embodiments, the disease or disorder is generalized anxiety disorder. In some embodiments, the disease or disorder is separation anxiety. In some embodiments, the subject is an animal. In other embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.

[00446] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24, or any compounds as described herein, or any combination thereof, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, iatrogenic problems, glaucoma, anxiety', aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary’ anorexia. In some embodiments, the anorexia is a secondary' anorexia, e.g., secondary' to chemo. In other embodiments, the disease or disorder is a neoplastic disease. In some embodiments, the disease or disorder is a degenerative disorder. In some embodiments, the disease or disorder is an auto-immune disease. In other embodiments, the disease or disorder is allergies. In other embodiments, the disease or disorder is a metabolic disorder. In some embodiments, the disease or disorder is infection. In other embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is trauma. In other embodiments, the disease or disorder is toxicity'. In some embodiments, the disease or disorder is nutritional imbalance. In some embodiments, the disease or disorder is an idiopathic condition. In some embodiments, the disease or disorder is an iatrogenic problem. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is anxiety. In some embodiments, the anxiety? is separation anxiety or generalized anxiety. In some embodiments, the disease or disorder is aggression. In some embodiments, the aggression is dominance aggression, fear aggression, intraspecific aggression, or territorial aggression. In some embodiments, the disease or disorder is a compulsive disorder. In some embodiments, the disease or disorder is noise phobias. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is seizures. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.

[00447] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or any one of compounds AA7, AA1 1, AA16, and AA20-AA24, or any compounds as described herein, or any combination thereof, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, anxiety, epilepsy, or glaucoma. In some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency. In some embodiments, the disease or disorder is anxiety'. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In certain embodiments, the subject is a cat. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.

[00448] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or a compound of formula (AAA), or any one of compounds AA7, AAI 1, AA 16, and AA20-AA24, or any combination thereof and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Alzheimer’s disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntingtons disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal.

[00449] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or a compound of formula (AAA), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent, wherein the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo- related nausea, vomiting, and anorexia. In some embodiments, the disease or disorder is pain. In some embodiments, the pain is chronic pain. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is chemo-related nausea, vomiting, and anorexia. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. [00450] In another aspect, the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or a compound of formula (AAA), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of pain or inflammation. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of pain or inflammation. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is an animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery, soft-tissue surgery', or dental surgery’.

[00451 ] In another aspect, the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (AAA) as described herein, or a compound of formula (AAI), or a compound of formula (AAA), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the therapeutic agent in the method of the invention is an analgesic agent including drugs and agents that provide pain relief. In some embodiments, the therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID). In some embodiments, the non-steroidal anti-inflammatory drug (NSAID) is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, meloxicam, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen. In some embodiments, the non-steroidal anti-inflammatory drug (NSAID) is meloxicam, carprofen, deracoxib, or firocoxib. In certain embodiments, the non-steroidal anti-inflammatory drug (NSAID) is meloxicam. In other embodiments, the non-steroidal anti-inflammatory drug (NSAID) is carprofen. In some embodiments, the subject is a human. In other embodiments, the subject is an animal. In certain embodiments, the subject is a dog. In some embodiments, the subject is a cat.

[00452] In some embodiments of the method of the invention, the additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an antiemetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti- dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an antiosteoporosis agent, or a cardiovascular agent.

[ 00453] In some embodiments, the additional therapeutic agent is an agent tor treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent tor treating Ret syndrome.

[00454] In one aspect, in the method of the invention, the deuterated compound as described herein can be used to treat the adverse effects resulting from the treatment with the additional therapeutic agent as described herein. Such adverse effects include, but are not limited to, vomiting, dizziness, drowsiness, dry mouth, swollen tongue, loss of balance or coordination, and unsteadiness.

[00455] In one aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an analgesic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an analgesic agent. In some embodiments, the disease or disorder is pain such as acute pain or chronic pain. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1 , AAI 6, and AA20-AA24, or any compounds as described herein.

[00456] In some embodiments, the analgesic agent is an opioid analgesic agent or a nonopioid analgesic agent. In some embodiments, the non-opioid analgesic agent is acetaminophen, aspirin, ibuprofen, meloxicam, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, carbamazepine, gabapentin, or pregabalin. In certain embodiments, the analgesic agent is naproxen sodium or magnesium. In some embodiments, the analgesic is carbamazepine, gabapentin, pregabalin, acetaminophen, ibuprofen, meloxicam, or naproxen.

[00457] In some embodiments, the opioid analgesic agent is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol. In some embodiments, the opioid analgesic agent is hydrocodone bitartrate or oxycodone hydrochloride. In some embodiments, the opioid analgesic agent is a naturally occurring opiate, such as an alkaloid occurring in the opium poppy. In certain embodiments, the naturally occurring opiate is morphine, codeine, narcotine, papaverine, narceine, or thebaine.

[00458] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and a therapeutic agent for treatment of a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the neurodegenerative disease or disorder is Alzheimer’s disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, Tourette’s syndrome, or progressive muscular atrophy. In some embodiments, the neurodegenerative disease or disorder is Parkinson's disease, Alzheimer's disease, or Huntington's disease. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24, or any compounds as described herein. [00459] In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanins (e.g., anthocyanin cyanidin-3-O-glucoside), levodopa, pergolide (PERM AX™), ephenedrine sulfate (EPHEDRINE™), pemoline CYLERT™), mazindol (SANOREX ^rM ), dj-a-methylphenethylamine (ADDERALL™) methylphenydate (RITALIN™), pramipexole (MIRAPEX™), modafinil (PROVIGIL™), or ropinirole (REQUIP™). In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanin, levodopa, pergolide, ephenedrine sulfate, pemoline, mazindol, a-methylphenethylamine, methylphenidate, pramipexole, modafinil, or ropinirole.

[00460] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-dyskensia agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-dyskensia agent. In some embodiments, the disease or disorder is a movement disorder or Parkinson disease. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, A A 16, and AA20-AA24, or any compounds as described herein.

[00461] In some embodiments, the anti-dyskensia agent is selected from baclofen (LIORESAL™), botulinum toxin (BOTOX™), clonazepam (KLONOPIN™), and diazepam (VALIUM™). In other embodiments, an anti-dyskensia agent is baclofen, botulinum toxin, clonazepam, or diazepam.

[00462] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an immunosuppressive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an immunosuppressive agent. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is lupus or rheumatoid arthritis. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1, AA16, and AA20-AA24, or any compounds as described herein. [00463] In some embodiments, the immunosuppressive agent is azathioprine, cyclophosphamide, bromocriptine, glutaraldehyde, cyclosporin A, prednisone, methylprednisone, dexamethasone, heterologous anti -lymphocyte globulin, deoxy spergualin, or rapamycin.

[00464] In some embodimen ts, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-spasmodic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-spasmodic agent. In some embodiments, the disease or disorder is irritable bowel syndrome, abdominal pain, or bladder dysfunction. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA 16, and AA20-AA24, or any compounds as described herein.

[00465] In some embodiments, the anti-spasmodic agent is carbamatepine, oxcarbazepine, ferbocate, furboc acid, paroxamine, fibapramine, laxamide, talapanib, retigabine, levethiracetam, tobinarnide, zonisamide. barbiturates, benzodiazepines, or hydantoin.

[00466] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-diabetic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-diabetic agent. In some embodiments, the disease or disorder is diabetes. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24, or any compounds as described herein.

[00467] In some embodiments, the anti-diabetic agent is mefluminine hydrochloride, acarbose, miglitol, human insulin, pig insulin, bovine insulin, nateglinide, reglinide, gliniepiride, glibenclamide, chlorpromide, tolazamide, or glipben.

[00468] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is seizure, neuropathic pain, or epilepsy. In some embodiments, the disease or disorder is a seizure associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein.

[00469] In some embodiments, the anti-convulsant agent or anti-epileptic agent is pentobarbital, nitronazapine, clozapine acid salt, diazapine, saigabin, gabapentin, phenytoin, 5,5- diphenylhydantoin, carbarn atepine, oxcarbazepine, falbockate, falbock acid, bifarin Pockic acid, paroxamide, fibamay, levethiracetam, tobinamide, zonisamide, lamtidine, mesylamine, ethoxyl , or ruitijiabin. In some embodiments, the anti-convulsant agent or anti-epileptic agent is brivaracetam, carbamzepine, clobazam, rancedon, ethosuximide, non-ammonia ester, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin sodium salt, pregabalin, desoxyphenobarbital, rotigotine, rufinamide, seletracetam, talampanel, tiagabine, topiramate, sodium valproate, vigabatrin, or zonisamide. In some embodiments, the anticonvulsant agent or anti-epileptic agent is arbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, tiagabine, valproic acid, or zonisamide. In some embodiments, the anti-convulsant agent or anti-epileptic agent is Epidiolex®.

[00470] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-psychotic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-psychotic agent. In some embodiments, the disease or disorder is schizophrenia, psychosis, or bipolar disorder. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1, AAI 6, and AA20-AA24, or any compounds as described herein.

[00471] In some embodiments, the anti-psychotic agent is risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, or raclopride.

[00472] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is high cholesterol, lipid abnormalities, obesity, or a metabolic syndrome-related disorder. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI I, AA16, and AA20-AA24, or any compounds as described herein.

[00473] In some embodiments, the cholesterol/lipid lowering agent is pravastatin, lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, cholestyramine, colestipol, gemfibrozil, clofibrate, fenofibrate, benzafibrate, rosiglitazone, or ezetimibe.

[00474] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-inflammatory' agent. In some embodiments, the disease or disorder is any? one that can be treated or prevented as known in the art by an anti-inflammatory agent. In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the disease or disorder is severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, headaches, digestive disorders, or a fever. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein,

[00475] In some embodiments, the anti-inflammatory’ agent is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, meloxicam, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen.

[00476] In some embodimen ts, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-bacterial agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-bacterial agent. In some embodiments, the disease or disorder is a bacterial infection. In some embodiments, the disease or disorder is a skin or eye infection, tuberculosis, or a urinary tract infection. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA16, and AA20-.AA24, or any compounds as described herein.

[00477] In some embodiments, the anti-bacterial agent is selected from the group consisting of erythromycin, azithromycin, clarithromycin, telithromycin, penicillin G, penicillin V, methicillin, toluene oxazinmycin, o-chloropenicillin, diclofenac, phenoxypenicillin, ampicillin, amoxicillin, carbenicillin, ticarciilin, mezlocillin, Piperacillin, azlociilin, temociliin, cepaiothin, cefepime, cefacyclohexene, ceftizodine, cefazolin, cefotaxazole, cephalosporin, cephalosporin IV, cefprozil, cloxacromycin, loracarbef, cefotaxime, cefinetazole, ceftazidime cefotaxime, cefizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, cetazide, ceftibuten, cefdinir, cefpirome, cefepime, aztreonam, imipenem, meropenem, meropenem penicillin (ertapenem), doricane (doripenem), cephalosporin ceftobiprole and ceftaroline, citric acid, porphyrin, norfloxacin, petloxacin, enoxacin, oufumycin, levofloxacin, ciprofloxacin, tiproxoxacin temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, and rufosa trovafloxacin), clinailoxacin, gatifloxacin, moxifloxacin, sitar Sitafloxacin, garenoxacin, gemifloxacin, pazufloxacin, p-aminobenzoic acid, sulfadiazine, sulfonamide azole, sulfamethine oxazole and sulfonamide, streptomycin, neomycin, kenmycin, baromycin, gentamicin, tobramycin, butyl Amine kanamycin, netilmicin, spectinomycin, perillamycin, dardamycin and ezeparin, tetracycline, chlortetracycline, chlorotetracycline, go Mechlorin, minocycline, oxytetracycline, methicillin, tigcycline, doxycycline, rifampicin, rifampin, rifapentine, rifabutin, bezoxazinorifamycin and rifaximin, lincomycin, kesendamycin, telavancin, vancomycin, ticlosin, daptomycin, quinupristin and darfapolis Daflopristin, linoleide, polymyxin, colistin, colin, trimethoprim, and bacitracin.

[00478] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-emetic. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antiemetics. Tn some embodiments, the disease or disorder is vomiting, nausea, motion sickness, or the side effects of opioid analgesics, general anesthetics, and/or chemotherapy directed against cancer. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds A.A7, AA11, AAI 6, and AA20-.AA24, or any compounds as described herein. [00479] In some embodiments, the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.

[00480] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-depressant. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antidepressant. In some embodiments, the disease or disorder is an obsessive-compulsive disorder (OCD), depression, panic disorder, an anxiety' disorder, bipolar disorder, posttraumatic stress disorder (PTSD), phobias, or social anxiety' disorder. In some embodiments, the compound of formula (AAA) is the compound of formula (AAT), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein.

[00481] In some embodiments, the anti-depressants is selected from the group consisting of adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflu carbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine, and zometapine. In some embodiments, the anti-depressant agent is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the anti-depressant agent is fluoxetine.

[00482] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-anxiety agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an antianxiety agent. In some embodiments, the disease or disorder is generalized anxiety disorder, social and other phobias, anxiety, obsessive-compulsive disorder (OCD), panic disorder, and depression. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein.

[00483] In some embodiments, the anti-anxiety agent is salprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam prazepam, buspirone, flesinoxan, gepirone and ipsapirone, pindolol, carbamazepine, lamotrigine, valproate, zolpidem; clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, vigabatrin, or barbiturates.

[00484] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and a sleeping agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a sleeping agent. In some embodiments, the disease or disorder is insomnia, sleepwalking, night terrors, a movement disorder that interrupts sleep, such as restless legs syndrome (RLS) and periodic limb movement disorder. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein.

[00485] In some embodiments, the sleeping agent is zolpidem, alpidem, zopiclone, or indiflon.

[00486] In some embodiments, the present invention provides a method tor treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an orexigenic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an orexigenic agent. In some embodiments, the disease or disorder is anorexia. In some embodiments, a compound of formula (AAA) as described herein and an orexigenic agent can stimulate appetite and produce weight gain in older persons. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1, AA16, and AA20-AA24, or any compounds as described herein.

[00487] In some embodiments, the orexigenic agent is megestrol or oxandrolone. [00488] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an ocular hypotensive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an ocular hypotensive agent. In some embodiments, the disease or disorder is glaucoma. In some embodiments, a compound of formula (AAA) as described herein and an ocular hypotensive agent can lower intraocular pressure (IOP). In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AA16, and AA20-AA24, or any compounds as described herein.

[00489] In some embodiments, the ocular hypotensive agent includes, but is not limited to, bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, pilocarpine, brimonidine, latanoprost, travoprost, or bimatoprost.

[ 00490] In some embodiments, the present invention provides a method for treating or preventing osteoporosis in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti -osteoporosis agent. In some embodiments, the compound of formula (AAA) is the compound of formula (AAI), or any one of compounds AA7, AAI 1 , AAI 6, and AA20-AA24, or any compounds as described herein.

[00491] In some embodiments, the anti-osteoporosis agent includes, but is not limited to alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, bazedoxifene, teriparatide, abaloparatide, and denosumab.

[00492] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) as described herein and an anti-migraine agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-migraine agent. In some embodiments, the disease or disorder is migraine headache or migraine pain. In some embodiments, the compound of formula ( AAA) is the compound of formula (AAI), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein.

[00493] In some embodiments, the anti-migraine agent is sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, probatriptan, or almotriptan. [00494] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (AAA) or a compound of formula (AAI) as described herein and a cardiovascular agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an cardiovascular agent. In some embodiments, the disease or disorder includes, but is not limited to, arrhythmias, blood clots, coronary artery disease, high or low blood pressure, high cholesterol, heart failure, and stroke.

[00495] As used herein, in some embodiments, the term “cardiovascular agents” refer to medicines that are used to treat medical conditions associated with the heart or the circulatory system (blood vessels). In some embodiments, the cardiovascular agent is avasimibe, pactimibe, captopril, enalapril, enalaprilat, tradolapril, moexipril, ramipril, hinapril, perindopril, lisinopril, benazepril, fosinopril, eplerenone, aldactone, doxazosin, niethyldofo, clonidine, prazosin, terazosin, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, or tocainide.

[00496] In some embodiments, the present invention provides a method for treating or preventing cancer, comprising administering to a subject in need thereof a compound of formula (AAA) as described herein and an anti-cancer agent. In some embodiments, the compound of formula (AAA) is the compound of formula (AV), or any one of compounds AA7, AA11, AAI 6, and AA20-AA24, or any compounds as described herein.

[00497] In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung humors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma. In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML).

[00498] In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is adrimycin, doxorubicin, 5-fluorouracil, cytosine arabinoside(“Ara-C”), cyclophosphamide, thiotepa, taxotere (docetaxel), bulsulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinoreibine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycine, esperamicins, or melphalan.

[00499] In some embodiments, the anti-cancer agent is a cytostatic dmg. Tn some embodiments, the cytostatic drug is busuifan, chlorambucil, cyclophosphamide, melphalan, carmustine, lomustine, 5-fluorouracil, gemcitabine, pemetrexed, doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, paclitaxel, docetaxel, vinblastine, vincristine, etoposide, cisplatin, carboplatin, or oxaliplatin.

[00500] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkydating agent includes, but is not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busuifan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.

[00501] In some embodiments, the anti-cancer agent is a cancer immunotherapy monoclonal antibody. In some embodiments, the cancer immunotherapy monoclonal antibody is rituximab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, or trastuzumab.

[00502] In some embodiments, the anti-cancer agent is an anti-tumor agent. In some embodiments, the anti-tumor agent includes, but is not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea,

[00503] In certain embodiments, the anti-cancer agent is selected from the group consisting of amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.

[00504] In some embodiments, the anti-cancer agent is an anti-metabolite agent. In some embodiments, the anti-metabolite agent includes, but is not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafor, carmofor, capecitabine, and gemcitabine. [ 00505] In some embodiments, the anti-cancer agent is a mitotic inhibitor. In some embodiments, the mitotic inhibitor includes, but is not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[00506] In some embodiments, the anti-cancer agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor includes, but is not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.

[00507] In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.

[00508] In some embodiments of the method of the invention, the additional therapeutic agent is selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatheroscl erotic agents, anticoagulants, antithrombotic agents, protlirombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischemic preconditioning and/or myocardial stunning, or a combination thereof.

[00509] In some embodiments, an additional therapeutic agent is selected from norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors ( D ARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRls), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-AA74AA7), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethiazide, polythiazide, benzothiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L- asparaginase; famesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/anti androgens, progestins, and luteinizing hormone -releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyl lotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX- 2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.

[00510] Where the compound of the invention as described herein is administered in combination with an additional therapeutic agent, typically a daily dosage may be about 0.1 to about 1 milligrams of the compound of the invention per kilogram of patient body weight and, in the case of the additional therapeutic agent, the usual dosage of the therapeutic agent when administered alone may be reduced by about 10-90% when administered with a compound of the invention as described herein. In some embodiments, the compound of the invention any compounds as described herein.

[0051 1] In some embodiments of the method of the invention, the therapeutically effective amount of the additional therapeutic agent administered to the subject is less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention as described herein. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 10% to 90% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 20% to 80% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 20% to 70% less than the therapeutically effective amount of the therapeutic agent wiien administered in the absence of the compound of the invention. In some embodiments, the compound of the invention is any compounds as described herein.

[00512] In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 10% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention as described herein. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 20% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 30% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 40% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 50% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 5%, or 15%, or 25%, or 35%, or 45%, or 55% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the compound of the invention. In some embodiments, the compound of the invention is any compounds as described herein.

[00513] In some embodiments, the additional therapeutic agent and a compound of the invention as described herein are administered in combination administered concurrently. In other embodiments, the additional therapeutic agent and the compound of the invention are administered concurrently.

[00514] In some embodiments, the present invention further provides a combination therapy. The term “administered in combination” or “combination therapy” means the administration of the compound of the invention as described herein, and one or more additional therapeutic agents to treat a therapeutic disorder described in the present invention. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of active ingredient in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the diseases or disorders described herein.

[00515] It is another aspect of the invention that the therapeutic agent and the compound of the invention are formulated in the same pharmaceutical composition. Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, at least one additional therapeutic agent, and a pharmaceutically acceptable earner. In some embodiments, the compound of the invention is any compounds as described herein.

[00516] In some embodiments, the additional therapeutic agent is formulated in a first pharmaceutical composition and the compound of the invention as described herein is formulated in a second pharmaceutical composition.

[00517] In another aspect, the present invention provides a kit comprising a first compartment containing a first pharmaceutical composition comprising a therapeutic agent as described herein and a second compartment containing a second pharmaceutical composition comprising a compound of the invention.

[00518] When the compound of the invention as described herein and the additional therapeutic agents are combined in a single dosage unit they may be formulated such that the physical contact between the active ingredients is minimized to reduce a potential chemical interaction between the combined active ingredients. For example, one or both active ingredients may be enteric coated. In some embodiments, the active ingredient(s) may be coated with a material that affects a sustained release throughout the gastrointestinal tract. In some embodiments, the compound of the invention may not be coated.

[ 00519] As used herein, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.

[00520] As used herein, in some embodiments, the term "deuterium enrichment" is used to describe an above -natural amount of deuterium contained at any position of the compounds of the invention as described herein, designated by the letter "D" (or by the designation "2H"). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[00521] In some embodiments, an approximate percentage is used to quantitatively define the amount of deuterium enrichment at a certain position of the described chemical structure, such as, for example, "deuterium enrichment is no less than about 10%." Where such quantitative approximations are used in this invention, they are meant to describe a percentage of the described compounds in an aggregate composition of like compounds that contain deuterium at the identified position D instead of protium. [00522] In each of the foregoing and each of the following embodiments, it is to be understood that the formulas also include any and all hydrates and/or solvates of the compound formulas. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulas are to be understood to include and represent those various hydrates and/or solvates.

[00523] As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the sol vent is water, the solvate is referred to as "hydrate.” Pharmaceutically acceptable solvates and hydrates are complexes that, for example, may include from 1 to about 100, or from 1 to about 10, or from one to about 2.3 or 4 molecules of water or a solvent. In some embodiments, the hydrate may be a channel hydrate. It should be understood that the term “compound” in this application covers the compound and solvates of the compound, as well as mixtures thereof.

[00524] In some embodiments, the term “hydrate” includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like.

[00525] "Subject" refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, and hamsters), lagomorphs (e.g., rabbit), swine (e.g., pig and miniature pig), equine, ferrets, parrots, canine, feline, bovine, ovine, caprine, and camelids. The terms "subject" and "patient" are used interchangeably herein when referencing, for example, a mammalian subject, such as a human patient.

[00526] Thus, besides being useful for human treatment, the compounds of the invention and formulations comprising the same as disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals. In some embodiments, the animals include horses, dogs, and cats.

[00527] In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog.

[00528] The term “treatment” or “treating” as used herein refers to the administering of a therapeutic effective amount of the composition of the present invention which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above.

[00529] In some embodiments, the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00530] The present invention also includes “pharmaceutically' acceptable salts” of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds -wherein the parent compound is modified by converting an existing acid or base moiety' to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the compound of the invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compound of the invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; for example, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

[00531] The pharmaceutically acceptable salts of the compound of the invention can be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin. [00532] Possible pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977; incorporated herein by reference.

[00533] Typically, a pharmaceutically acceptable salt form of a compound can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base functionality with a suitable organic or inorganic acid.

[00534] Suitable acids for preparation of the pharmaceutically acceptable salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.

[00535] Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[00536] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[00537] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, IH-imidazole, L-lysine, morpholine, 4-(2- hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l -(2- hydroxyethyl)-pyrrolidine, pyridine, quinnclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)-l ,3-propanediol, and tromethamine.

[00538] The invention further includes derivatives of the compound of the invention. The term “derivatives” includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.

[00539] The invention further includes metabolites of the compound of the invention. The term “metabolite” means any substance produced from another substance by metabolism or a metabolic process.

[00540] The invention further includes pharmaceutical products of the compound of the invention. The term “pharmaceutical product” means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.

[00541] The invention further includes prodrugs of the compound of the invention. The term “■prodrug” means a substance which can be converted in vivo into a biologically active agent by such reactions as hydrolysis, esterification, de-esterification, activation, salt formation and the like.

[00542] It is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,'' it will be understood that the particular value forms another embodiment. .411 ranges are inclusive and combinable. Further, reference to values stated in ranges includes each and every value within that range. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any combination. [00543] The invention further provides processes for the preparation of compounds of the invention as described herein. For example, the compound of the invention can be prepared using methods known in the art, including, for example, by referring to the following Schemes.

[00544] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.

Example 1: Preparation of Compounds of Invention

[00545] Schemes 1 - 6 provide processes for the preparation of compounds (1-4), (1-6), (1-7),

(1-14) and (1-20):

Scheme 2: Process for the preparation of compound (1-4)

P-594952-PC

Scheme 4: Process for the preparation of compound (I- 7)

Scheme 5: Process for the preparation of compound (1-14)

Scheme 6: Process for the preparation of compound (1-20)

[00546] Schemes 7- 11 provide processes for the preparation of compounds (II--4), (II-6), (II-7), and (II- 16):

Deuterium Exchange catalysed by transition metals (such as Pd-C)

6 d ₃ -THC

Scheme 9: Process for the preparation of compound (11-7)

1) CD ₃ MgBr

2) H ₃ O ⁺

Scheme 10: Process for the preparation of compound (II-7)

Scheme 1 1 : Process for the preparation of compound (11-16)

[00548] Scheme 12 provides processes for the preparation of compound (1-24):

[00549] The processes for the preparation of compounds of the invention can further follow the procedures disclosed in Molecules, 2014, 19, 13526-13540 and Can J. Chem 1982, 60, 2804, which are herein incorporated by reference.

Example 2: Preparation of Compounds of Invention

[00550] The invention further provides the processes for the preparation of compounds of the present invention. Schemes Al -A3 provide processes for the preparation of compounds (A8), (Al 3), and (Al 8).

Scheme Al: Process for the preparation of compound (A8)

Scheme A2: Process for the preparation of compound (A13)

Scheme A3: Process for the preparation of compound (Al 8)

[00551] The process tor the preparation of compounds can also follow the procedure disclosed in Can. J. Chem. 193, 61 , 1053 and Recuelldes Trav. Chim. Des Pays-Bas, 1981, 100(9), 342-343, which are herein incorporated by reference.

Example 3: Preparation of Compounds of Invention

[00552] The invention further provides the processes for the preparation of compounds of the present invention. Schemes AA1- AA4 provide processes for the preparation of compounds (AA7), (AA11), (AA16) and (AA20).

Scheme AA1 : Process for the preparation of compound (AA7)

Scheme AA2: Process for the preparation of compound (AA11)

Scheme AA3: Process for the preparation of compound (AA16)

Scheme A A4: Process for the preparation of compound (AA20)

[00553] The process for the preparation of compounds can also follow the procedure disclosed in J. Pharm. Sei. 1982, 71(12), 1319-1323, which are herein incorporated by reference.

Example 4: Biological Activity Assays

In vitro Liver Microsomal Stability Assay

[00554] Liver microsomal stability’ assays are conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium chloride). Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay? mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Final concentration of acetonitrile in the assay? should be <1%. Aliquots (50 pL) are taken out at times 0, 15, 30, 45, and 60 minutes, and diluted with ice cold acetonitrile (200 pL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 minutes to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for LC/MS/MS analysis of the degradation half- life of the test compounds.

In Vitro Metabolism Using Human Cytochrome P450 Enzymes

[00555] The cytochrome P450 enzymes are expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, Calif.). A 0.25 milliliter reaction mixture containing 0.8 milligrams per milliliter protein, 1.3 millimolar NADP ⁴ , 3.3 millimolar glucose-6-phosphate, 0.4 U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound as disclosed herein, the corresponding non-isotopically enriched compound or standard or control in 100 millimolar potassium phosphate (pH 7.4) is incubated at 37° C. for 20 minutes. After incubation, the reaction is stopped by the addition of an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 minutes. The supernatant is analyzed by HPLC/MS/MS.

Monooamine Oxidase B Inhibition and Oxidative Turnover

[00556] The procedure is earned out as described in Uebelhack et al., Pharmacopsychiatry, 1998, 31(5), 187-192, which is hereby incorporated by reference in its entirety. CB2 Radioligand Binding Assay

[00557] The procedure is earned out as described in Yao et al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety.

CB 1 Radioligand Binding Assay

[00558] The procedure is carried out as described in Yao et al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety'.

CB2 Cyclase Functional Assay

[00559] The procedure is carried out as described in Yao et al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety.

CB1 cAMP Assay

[00560] The procedure is earned out as described in Steffens et al., Brit. J Pharmacol. 2004, (141), 1 193-1203, which is hereby incorporated by reference in its entirety.

Pharmacokinetics (PK) in rats or mice

[00561] Rats or mice receive a single intravenous dose of THC or deuterated compounds at a dose of 1 mg/kg body weight, or a single oral dose of THC or deuterated compounds at a dose of 10-50 mg/kg body weight Plasma samples are collected at different times following dosing and the plasma concentrations of THC or deuterated compounds is determined by HPLC-MS/MS analysis using standards methods. Clearance, half-life, volume of distribution and oral bioavailability' are calculated from the plasma concentration-time course data using established methods.

[00562] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.