WO2016105448A1 - Ligands du récepteur aux imidazolines de type 1 à utiliser en tant qu'agents thérapeutiques - Google Patents

Ligands du récepteur aux imidazolines de type 1 à utiliser en tant qu'agents thérapeutiques Download PDF

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WO2016105448A1
WO2016105448A1 PCT/US2015/000153 US2015000153W WO2016105448A1 WO 2016105448 A1 WO2016105448 A1 WO 2016105448A1 US 2015000153 W US2015000153 W US 2015000153W WO 2016105448 A1 WO2016105448 A1 WO 2016105448A1
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optionally substituted
pain
group
formula
hydrogen
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PCT/US2015/000153
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Darryl Rideout
Seth Lederman
Bruce DAUGHERTY
Leland J. GERSHELL
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Darryl Rideout
Seth Lederman
Daugherty Bruce
Gershell Leland J
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Publication of WO2016105448A1 publication Critical patent/WO2016105448A1/fr

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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Definitions

  • TTH Tension-type headaches
  • the pain of TTH may render a sufferer unable to attend activities, force them to stay home from work, or impair their ability to function at work.
  • tension headaches affect 90% of women and 70% of men. The pathogenesis of tension-type headache is poorly understood.
  • Migraine affects people of all races and both sexes with women accounting for 79% (61 % between 20 and 49 years of age) of physician visits for migraines and
  • TTH may be a mild form of migraine headache or may have a distinct etiology.
  • Recurrent TTH and migraine headache syndromes may be co-morbid and have been termed “mixed” headache syndrome.”
  • Nociceptive pain results from injury, compression, infection, inflammation, degeneration, metabolic or genetic pathology, or neoplasm affecting tissues including skin, muscles, joints, bones, and internal organs. Injury can include exposure to extreme temperatures, trauma, and physical exposure to blunt or sharp objects or physical exposure to caustic, irritating, or allergenic substances. Nociceptive pain can be acute or chronic.
  • Neuropathic pain results from injury, compression, infection, inflammation, degeneration, metabolic or genetic pathology, or neoplasm affecting nerves in the peripheral or central nervous system.
  • Traum can include exposure to extreme temperatures, trauma, and physical exposure to blunt or sharp objects or physical exposure to caustic, irritating, or allergenic substances.
  • Neuropathic pain can be acute or chronic.
  • Regional pain is pain associated with one or more areas of the body. Visceral pain is pain associated with one or more internal organs. Regional and visceral pain can be nociceptive or neuropathic or a combination of nociceptive and neuropathic.
  • CRPS complex regional pain syndromes
  • blood vessels are involved.
  • CRPS are chronic conditions characterized by pain, burning, swelling, sweating and skin color changes.
  • reflex sympathetic dystrophy type of CRPS nerve damage is either not present or represents a small component of the pathology.
  • causalgia type of CRPS nerve injury is present.
  • Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood issues. Research indicates that fibromyalgia amplifies painful sensations by affecting the way the brain processes pain signals. Symptoms of fibromyalgia sometimes begin after a physical trauma, surgery, infection, menopause, or significant psychological stress. In other cases, symptoms gradually accumulate over time. In many cases, fibromyalgia develops in people suffering for many years from chronic regional pain, including lower back pain or temporomandibular joint syndrome. The causes of fibromyalgia are unclear.
  • fibromyalgia The pathogenesis of fibromyalgia is believed to involve sensitization of the central nervous system (CNS) to perceiving painful stimuli v which is termed "central sensitization” or “centralization”. Centralization leads to the perception of widespread pain. Pain of this type is termed, “central neuropathic pain” or “central pain”. Centralization also leads to other symptoms, including visceral pain such as irritable bowel, TTH, and migraine. Centralization increases the sensitivity of the brain to light, sound, taste and odor stimuli. Non-restorative sleep is a key feature of fibromyalgia and disturbed sleep can exacerbate other symptoms. Fibromyalgia is estimated to impact 5- 15 million Americans age 18 or older.
  • Fibromyalgia is believed to be an extreme manifestation of symptoms, termed "fibromyalgia-ness" that can occur in lesser severity below the threshold that qualifies for the diagnosis of fibromyalgia by the American College of Rheumatology (ACR) 2010 criteria. Fibromyalgia and fibromyalgia-ness have overlap with other conditions including Gulf War Syndrome and Post-traumatic Stress Disorder (PTSD) and are sometimes co-morbid with these conditions. Allodynia, or pain due to a stimulus that does not usually provoke pain, is a prominent symptom in patients with neuropathic pain.
  • ACR American College of Rheumatology
  • Allodynia is seen in various peripheral neuropathies and central pain disorders, and affects 15-50% of patients with neuropathic pain. Allodynia is classified according to the sensory modality (touch, ' pressure, pinprick, cold, and heat) that elicits the sensation. Allodynia can be co- morbid with fibromyalgia and can be a feature of fibromyalgia. Like fibromyalgia, the causes of allodynia are unclear. Centralization and allodynia can be acute as well as chronic. For example, migraine can be accompanied by acute symptoms of: nausea and vomiting, loss of appetite, abdominal pain, and sensitivity to light, odor, taste and sound. Pain, including widespread pain, can occur after traumatic brain injury (TBI) or in post-traumatic stress disorder (PTSD). When pain, TBI, and PTSD are all present, it is termed the "polytrauma triad".
  • TBI traumatic brain injury
  • PTSD post-traumatic stress disorder
  • benzodiazepines, nicotines, ketamines and opiates is associated with widespread pain and other symptoms. Widespread pain can persist for long periods of time after drug withdrawal. Regional pain syndromes including headaches can occur after medication discontinuation or even missed doses of a chronic regimen. For example, caffeine withdrawal headache is a headache syndrome associated with the discontinuation of caffeine.
  • medication overuse headache is a headache syndrome associated with use and withdrawal of medications.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • TNF tumor necrosis factor
  • Psychogenic pain is pain that results from psychological mechanisms including traumatic experiences, empathic reactions, or somatization. For example, loss of a loved friend or relative by death or other separation can result in widespread pain, regional pain, and other symptoms including reactive depression.
  • Psychiatric pain is pain that results from conditions that are believed to have biological causes.
  • endogenous depression or the depressed phases of bipolar disorder can be associated with the onset or exacerbation of widespread pain or regional pain disorders.
  • ergotamine and dihydroergotamine used in the treatment of migraine, interact with vascular receptors, a fact that has raised concerns about the cardiovascular safety of these pharmaceutical agents.
  • Other treatments for pain relief, such as ketamine, barbiturates, and opioids can lead to addiction.
  • Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant drug that is also useful in treating fibromyalgia and back pain, but has side effects that limit long term treatment in some patients.
  • SNRI norepinephrine reuptake inhibitor
  • gabapeninoids or alpha-2 delta ligands
  • pregabalin gabapentin and mirogabalin/DS-5565
  • antagonists of nerve growth factor receptor including tanezumab
  • blockers of voltage-gated sodium channels including Nay 1.7, Nay 1.8, and Nay 1.9
  • alcohol cannabinoids, including tetrahydrocannabinol (THC) and cannabidiol
  • THC tetrahydrocannabinol
  • cannabidiol cannabidiol
  • gamma-hydroxy butyrate gamma-hydroxy butyrate
  • Tramadol and tapentadol are pain treatments having both SNRI activity and mu-opioid activity.
  • Racemic tramadol combines the SNRI activity of one isomer with the opiate receptor activity of the other isomer.
  • Corticosteroids have been used to inhibit pain in
  • TNF-alpha blockers particularly antibodies against TNF- alpha, decrease pain in several autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, and psoriasis.
  • rheumatoid arthritis a chronic inflammatory disease characterized by rheumatoid arthritis
  • inflammatory bowel disease a chronic inflammatory disease characterized by rheumatoid arthritis
  • psoriasis pulmonary fibroblastsis
  • Each of the known treatments has side effects that limit use in some patients.
  • Racemic isometheptene has been used in the treatment of tension-type headache, vascular headache, and migraine headache, either alone or as one or more than one active ingredients in various combination drug products.
  • One theory of headache pathogenesis is that cranial vasodilation results in pressure on the pain producing areas surrounding blood vessels.
  • the effect of racemic isometheptene on relieving headache is believed to be due to isometheptene-induced cranial vasoconstriction which reduces the pressure on the pain producing areas surrounding blood vessels.
  • Racemic isometheptene has
  • Purified (R)-isometheptene has a significant binding affinity for the imidazoline- 1 (I
  • (R)-isometheptene binds preferentially to the bovine I i receptor versus the a-adrenergic receptor, with a Kj of 18 nM for the Ii receptor and a Kj of 2300 nM for the a-adrenergic receptor.
  • (S)- isometheptene the Kj was 1 100 nM for the I i receptor and 2700 nM for the a- adrenergic receptor. Studies have also suggested that (R)-isometheptene may have lower potential adverse effects to the cardiovascular system than (S)-isometheptene.
  • the imidazoline receptor system modulates sympathetic effects and three types of receptors have been identified: Ii, I 2 , and I 3 .
  • the best characterized is the 1 ) receptor, which has been connected with a cloned cDNTHIS D1SCLOSUREA.
  • I 2 and 1 3 are still described only as activities of activated membranes and may or may not correspond to single proteins.
  • Present understanding of the I i receptor is that of a cell- surface receptor mediating cellular responses, participating in cardiovascular control by the CNS, and providing a potential therapeutic target for multiple cardiovascular and metabolic disorders.
  • knockout mice lacking the I i receptor had a lower pain threshold than that of wild type in both hot-plate and tail- flick tests, indicating that nociceptive perception was potentiated in the knockout mice (See Zhang, L., et al., Generation and Primary Phenotypes of Imidazoline Receptor Antisera-Selected (IRAS) Knockout Mice, CAN Neuroscience and Therapeutics 19 (2013) 978-981 ).
  • an inflammatory disease or disorder an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions
  • an episodic tension-type headache a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode
  • epilepsy a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;
  • TMJ temporomandibular joint syndrome
  • TMJ lower back pain
  • interstitial cystitis Gulf War syndrome
  • visceral pain kidney stones
  • gout gout
  • neuropathic pain post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;
  • the compounds and compositions of this disclosure modulate the imidazoline-1 (I
  • the compounds and compositions of this disclosure are nitric oxidase inhibitors.
  • the compounds and compositions of this disclosure act as analgesics.
  • the compounds and compositions of the disclosure are used in conjunction simultaneously, separately, or sequentially with acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a
  • NSAID nonsteroidal anti-inflammatory drug
  • ibuprofen ibuprofen
  • naprosyn a cyclooxygenase-2 inhibitor
  • aspirin caffeine, dichloralphenazone, a triptan
  • a chemotherapeutic drug an antidepressant
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • gabapentinoid an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates or a combination of any of the foregoing therapeutics.
  • the compounds of this disclosure are selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1), formula (SC-12), formula (SC- 13), formula (SC-14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), or formula (SC-25), or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds.
  • the compounds of this disclosure are selected from a group of compounds having the formula 93, 96, 99-202, 212-217, 219-314, 318-354, 358-374, 376, or 378-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds.
  • the compounds of this disclosure are selected from a group of compounds having the formula 96, 111, 113-118, 123-129, 131, 133, 140-144, 146, 149, 150, 152, 153, 158, 160-167, 169, 170, 172, 176-178, 185, 187-189, 193, 195, 202, 212-217, 219, 220, 222-228, 231-233, 235, 236, 238-241, 247-249, 254, 258, 259, 284, 286, 289, 296, 298, 303, 304, 306, 308-314, 323-325, 328-330, 336-349, 358, 359, 361 , 364-366, 368, 372, 376, or 378-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds.
  • the compounds of the disclosure selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), formula 1, 54-93, 95-376, or 378-432, or a pharmaceutically acceptable salt, free base form, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, are useful as analgesics.
  • this disclosure relates to pharmaceutical compositions comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC- 05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC-14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC- 1 8), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds.
  • the pharmaceutical compositions described herein are useful as analgesics.
  • the disclosure of this application relates to a method of treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;
  • epilepsy a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;
  • TMJ temporomandibular joint syndrome
  • TMJ lower back pain
  • interstitial cystitis Gulf War syndrome
  • visceral pain kidney stones
  • gout gout
  • neuropathic pain post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;
  • the method described herein further comprises administering one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates
  • the disclosure of this application relates to a method of treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;
  • epilepsy a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;
  • TMJ temporomandibular joint syndrome
  • TMJ lower back pain
  • interstitial cystitis Gulf War syndrome
  • visceral pain kidney stones
  • gout gout
  • neuropathic pain post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;
  • a pharmaceutical composition comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC- 08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC-14), formula (SC- 15), formula (SC-16), formula (SC-17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SC- 22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95- 432, or a pharmaceutically acceptable salt,
  • the method further comprises administering one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a
  • additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a
  • NSAID non-steroidal antiinflammatory
  • gabapentinoid an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates, or a combination of any of the foregoing therapeutics simultaneously, separately, or sequentially with one or more compounds of this disclosure.
  • a medicament for treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy;
  • the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of acetaminophen, a ⁇ non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a
  • NSAID non-steroidal anti-inflammatory drug
  • ibuprofen ibuprofen
  • naprosyn a non-steroidal anti-inflammatory drug
  • cyclooxygenase-2 inhibitor aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an
  • an immunosuppressive agent an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a T F-alpha inhibitor, or one or more opiates.
  • a pharmaceutical composition comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC-1 3), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, is used for the manufacture of a medicament for treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an inflammatory disease or
  • epilepsy a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;
  • TMJ temporomandibular joint syndrome
  • TMJ lower back pain
  • interstitial cystitis Gulf War syndrome
  • visceral pain kidney stones
  • gout gout
  • neuropathic pain post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;
  • the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of acetaminophen, a ⁇ non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a
  • NSAID non-steroidal anti-inflammatory drug
  • ibuprofen ibuprofen
  • naprosyn a non-steroidal anti-inflammatory drug
  • cyclooxygenase-2 inhibitor aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an
  • immunosuppressive agent an immunomodulatory agent, a cardiovascular disease.
  • treatment agent an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.
  • one or more compounds selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds is used in treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurode
  • epilepsy a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;
  • TMJ temporomandibular joint syndrome
  • TMJ lower back pain
  • interstitial cystitis Gulf War syndrome
  • visceral pain kidney stones
  • gout gout
  • neuropathic pain post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;
  • the one or more compounds are used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a
  • cyclooxygenase-2 inhibitor aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an
  • an immunosuppressive agent an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.
  • a pharmaceutical composition comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, is used in treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disorder, or
  • the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of
  • acetaminophen a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), a gabapentinoid, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.
  • NSAID non-steroidal anti-inflammatory drug
  • ibuprofen ibu
  • the disclosure of this application relates to a method of modulating an imidazoline-1 (Ii) receptor, comprising contacting the I ] receptor with one or more compounds selected from a group of compounds having the formula (SC- 01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC-13), formula (SC-14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds.
  • the disclosure of this application relates to a method of modulating an imidazoline-1 (Ii) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of one or more compounds selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 1 8), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of
  • the disclosure of this application relates to a method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of one or more compounds selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, simultaneously
  • dichloralphenazone a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an
  • an antiproliferative agent an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.
  • Figure 1 illustrates data related to analgesic activity using the Formalin Test, late phase (licking score) in a mouse of compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate.
  • Figure 2 illustrates data related to analgesic activity using the Tail-flick Test in a mouse of compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate.
  • Figures 3A-B illustrate data- from the TAAR1 cAMP assay for compound 9 mucate salt, (R)-isometheptene mucate (isomer 2),. and compound 27 mucate salt, (S)- isometheptene mucate (isomer 1 ).
  • Figure 4 illustrates data from tactile sensory testing in STA rats using von Frey monofilaments for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate.
  • STA rats treated with compound 9 mucate salt showed a dramatic increase in threshold values versus STA rats treated with compound 27 mucate salt or the control rats, demonstrating the analgesic effect of compound 9 mucate salt.
  • FIGs 5A-D illustrate data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1), on arterial blood pressure (BP) and heart rate.
  • D Heart rate
  • Figures 6A-D illustrate data related to analgesic efficacy in a rat chronic constrictive nerve injury (CCI) model of neuropathic pain of (S)-isometheptene mucate
  • Figure 8 illustrates data related to analgesic activity using the Hot Plate Test in a mouse of compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate.
  • Figures 9 ⁇ - ⁇ illustrate expression of the imidazoline-l receptor in CHO cells.
  • Figures lOA-C illustrate a functional assay for the imidazoline- 1 receptor in PC- 12 cells or a cell line stably expressing the imidazoline-1 receptor to evaluate the impact of imidazoline-1 receptor agonists and antagonists on forskolin-stimulated cAMP induction.
  • Figures 11A-D illustrate preliminary human pharmacokinetic studies using racemic isometheptene and compound 9 mucate salt, (R)-isometheptene mucate.
  • B) Cohort 1 with 70 mg racemic isometheptene (n 3).
  • D) Cohort 2 with 70 mg racemic isometheptene (n 3).
  • Figures 12A-D illustrate preliminary human pharmacokinetic studies using racemic isometheptene and compounds mucate salt, (R)-isometheptene mucate.
  • D) Cohort 3 with 70 mg racemic isometheptene (n 3).
  • Figure 13 illustrates effects of 1 mg/kg of R- or S-isometheptene mucate on
  • Figure 15 illustrates effects of 30 mg/kg of R- or S-isometheptene mucate on trigeminial sensitivity in the STA rat model. The data were from tactile sensory testing in STA rats using von Frey monofilaments for compound 9 mucate salt, (R)- isometheptene mucate, and compound 27 mucate, (S)-isometheptene mucate. STA rats treated with compound 9 mucate showed an increase in threshold values versus STA rats treated with compound 27 mucate or the control rats, demonstrating the analgesic effect of compound 9 mucate.
  • Figure 16 illustrates trigeminal sensitivity in the inflammatory soup model.
  • Figure 17 illustrates effects of 1 mg/kg of R- or S-isometheptene mucate on trigeminial sensitivity in the STA rat model.
  • Figure 18 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1), on mean arterial blood pressure (mmHg).
  • Figure 19 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1 ), on systolic arterial blood pressure (mmHg).
  • Figure 20 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1), on diastolic arterial blood pressure (mmHg).
  • Figure 21 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1 ), on heart rate (bpm).
  • Figure 22 illustrates a model of 11 -imidazoline receptor signaling pathways.
  • Figure 23 illustrates data of activation via phosphorylation of ERK in human Ii - imidazoline receptor transfected 293T cells after treatment with compound 9 mucate salt, (R)-isometheptene mucate, or compound 27 mucate salt, (S)-isometheptene mucate.
  • Figure 24 illustrates periorbital allodynia after treatment with compound 9 mucate salt, (R)-isometheptene mucate, in a NO donor-evoked medication overuse headache rat model.
  • Figure 25 illustrates hindpaw allodynia after treatment with compound 9 mucate salt, (R)-isometheptene mucate, in a NO donor-evoked medication overuse headache rat model.
  • Figure 26 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on ipsilateral paw withdrawal threshold (PWT) in a rat chronic constructive nerve injury model of neuropathic pain.
  • PWT ipsilateral paw withdrawal threshold
  • Figure 27 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on ipsilateral paw withdrawal threshold (PWT) 15 minutes post administration in a rat model of bortezomib-induced neuropathy.
  • Figure 28 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, or compound 27 mucate salt, (S)-isometheptene mucate, on naloxone-precipitated withdrawal test in mice.
  • Figure 29 illustrates the effect of a positive control, diclofenac, on sodium
  • FIG. 30 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on sodium monoiodoacetate (MIA)-induced osteoarthritic pain.
  • Figure 31 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, and diclofenac on sodium monoiodoacetate (MIA)-induced osteoarthritic pain.
  • Figure 32 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on fecal boli in a naloxone-precipitated withdrawal test in mice.
  • Figure 33 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on diarrhea in a naloxone-precipitated withdrawal test in mice.
  • Figure 34 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on salivation in a naloxone-precipitated withdrawal test in mice.
  • Figure 35 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on teeth chattering in a naloxone-precipitated withdrawal test in mice.
  • Figure 36 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on wet dog shakes in a naloxone-precipitated withdrawal test in mice.
  • Figure 37 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on writhing in a naloxone-precipitated withdrawal test in mice.
  • Figure 38 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on weight loss in a naloxone-precipitated withdrawal test in mice.
  • compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also may consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions are conducted
  • analgesic refers to a painkiller or a drug that is able to provide relief from pain.
  • agonist refers to a molcule that activates a receptor to provoke a biological response.
  • Agonists may bind directly to a receptor to activate it or they may activate a receptor through another mechanism, such as through second messengers like cAMP and pErk.
  • antagonist refers to a receptor ligand that blocks or dampens agonist- mediated responses rather than provoking a biological response upon binding to a receptor.
  • Imidazoline- 1 Receptor-Independent Isometheptene Pain Modulatory pathway or "IRIPM pathway” refer to a pain perception pathway mediated by isometheptene that is independent of the imidazoline- 1 (li) receptor.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula
  • acylaminoalkyl refers to an alkyl group substituted with an acylamino group.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, ter/-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkoxyaryl refers to an aryl group substituted with an alkoxy group and may be represented by the general formula aryl-O-alkyl.
  • alkoxycycloalkyl refers to a cycloalkyl group substituted with an alkoxy group and may be represented by the general formula cycloalkyl-O-alkyl.
  • alkanediyl refers to an optionally substituted divalent radical derived from a straight chained or branched non-aromatic hydrocarbon.
  • alkenediyl refers to an optionally substituted divalent radical derived from an aliphatic group containing at least one double bond.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls,” the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.
  • substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkyl group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, «-propyl, /_?o-propyl, »-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C)-C 6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl) as used throughout the application, examples, and embodiments is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF 3 , -CN, and the like.
  • C x . y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Cx.yalkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C 2-y alkenyl and C 2-y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylaryloxydiyl refers to an optionally substituted divalent radical derived from an aryloxy group substituted with an alkyl group.
  • alkylcycloalkylalkanediyl refers to an optionally substituted divalent radical derived from an alkyl group substituted with a carbocycle group which is substituted with an alkyl group.
  • alkylcycloalkenylalkanediyl refers to an optionally substituted divalent radical derived from an alkyl group substituted with a cycloalkenyl group which is substituted with an alkyl group.
  • alkylheterocyclylalkanediyl refers to an optionally substituted divalent radical derived from an alkyl group substituted with a heterocyclyl group which is substituted with an alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkylthiodiyl refers to an optionally substituted divalent radical derived from an alkylthio.
  • An example is 2-thiapent- 1 ,5-diyl.
  • alkynediyl refers to an optionally substituted divalent radical derived from an aliphatic group containing at least one triple bond.
  • An example is but-2-yne- l ,4- diyl.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls,” the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group wherein each R independently represent a hydrogen or hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 12 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that is-represented by wherein each R 30 independently represents a hydrogen or a hydrocarbyl group, or two
  • R are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 12 atoms in the ring structure.
  • aminoalkanediyl refers to an optionally substituted divalent radical derived from an aminoalkane group.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aminoalkylaminodiyl refers to an optionally substituted divalent radical derived from an amino group substituted with an aminoalkyl group.
  • aminoalkylaryloxyalkoxyaryl refers to an alkoxyaryl group substituted with an aryloxy group that has been substituted with an aminoalkyl group.
  • arylalkanediyl refers to an optionally substituted divalent radical derived from an alkyl group substituted with an aryl group.
  • arylalkyl or “aralkyl,” as used herein, refers to an alkyl group substituted with an aryl group.
  • arylheteroalkyl refers to a heteroalkyl group substituted with an aryl group.
  • aryl as used herein includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons or heteroatoms are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, thienylpyridine, isothiazole, 2-thienyl, 3-thienyl, benzothiophenyl, benzisothiazole, 3-amino-4-pyridine, thiophene, isoquinoline, pyrrazole, pyrrolidine, benzimidazole, indole, indazole, pyrimidine, 2,3- dihydrobenzo[6]thiophene, thiochromane, and the like.
  • arylalkoxy refers to an alkoxy group substituted with an aryl group.
  • arylamino refers to an aryl group having an amino attached thereto.
  • aryloxy refers to an aryl group having an oxygen attached thereto.
  • aryloxyalkyl refers to an alkyl group having an aryloxy attached thereto.
  • aryloxyalkoxy refers to an alkoxy group having an aryloxy attached thereto.
  • carboxylate is art-recognized and refers to a group wherein R and R independently represent hydrogen or a hydrocarbyl group, such an alkyl group, or R 29 and R 30 taken together with the intervening atom(s) complete ; heterocycle having from 4 to 12 atoms in the ring structure.
  • carbamoylaminoalkyl refers to an aminoalkyl group having a carbamoyl attached thereto.
  • carbocycle refers to a saturated or unsaturated ring in which.each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8- 12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term "fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Carbocycles include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1 ,5- cyclooctadiene, 1 ,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1 ,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4.1.0]hept-3 ⁇ ene.
  • Carbocycles may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
  • Carbocyclylalkyl or "cycloalkylalkyl,” as used herein, refer to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OC0 2 -R
  • cyano is art-recognized and refers to the group— CN.
  • cyanato is art-recognized and refers to the group— O— CN.
  • cycloalkanediyl refers to an optionally substituted divalent radical derived from a cyclic hydrocarbon which is completely saturated.
  • a "cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • cycloalkenyl is a cyclic hydrocarbon containing one or more double bonds.
  • cycloalkylacyl refers to an acyl group substituted with a cycloalkyl group.
  • cycloalkylalkanediyl refers to an optionally substituted divalent radical derived from an alkyl group substituted with a carbocycle group.
  • cycloalkylalkylamino refers to an alkylamino group substituted with a cycloalkyl group.
  • cycloalkylaminoalkyl refers to an aminoalkyl group-substituted with a cycloalkyl group.
  • cycloalkylheteroalkanediyl refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a carbocycle group.
  • 1 , 1 -dialkylcycloalkanediyl refers to an optionally substituted divalent radical derived from a cycloalkyl ring structure modified at the same position with two alkyl groups.
  • esters refers to a group -C(0)OR 3 ° wherein R 30 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O- heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • heteroalkanediyl refers to an optionally substituted divalent radical derived from a saturated or unsaturated chain of carbon atoitis and at least one heteroatom.
  • heteroalkenediyi refers to an optionally substituted divalent radical derived from a chain of carbon atoms containing at least one double bond and at least one heteroatom.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroalkylcycloalkylheteroalkanediyl refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a carbocycle group which is substituted with a heteroalkyl group.
  • heteroalkylcycloalkenylheteroalkanediyl refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a cycloalkenyl group which is substituted with a heteroalkyl group.
  • heteroalkylheterocyclylheteroalkanediyl refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a heterocyclyl group which is substituted with a heteroalkyl group.
  • heteroaryl and heterotaryl include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls,
  • heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroarylalkyl refers to an alkyl group substituted with a hetaryl group.
  • heteroarylalkoxy refers to an alkoxy group substituted with a heteroaryl group.
  • heteroarylamino refers to a heteroaryl group having an amino attached thereto.
  • heteroaryloxy refers to a heteroaryl group having an oxygen attached thereto.
  • heteroaryloxyalkyl refers to an alkyl group having a heteroaryloxy attached thereto.
  • heteroaryloxyalkoxy refers to an alkoxy group having a heteroaryloxy attached thereto.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkanediyl refers to an optionally substituted divalent radical derived from a ring structure including at least one heteroatom.
  • heterocyclylheteroalkanediyl refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a ring structure including at least one heteroatom.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, azepane, and the like.
  • heterocyclylalkyi refers to an alkyl group substituted with a heterocycle group.
  • heterocyclylalkylamino refers to an alkylamino group substituted with a heterocycle group.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyl refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • isocyano is art-recognized and refers to the group— N + C ⁇ .
  • isothiocyanate is art-recognized and refers to the group -NCS.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • nitro is art-recognized and refers to the group represented by -N0 2 .
  • nitroso is art-recognized and refers to the group represented by -NO.
  • oxyalkoxydiyl refers to an optionally substituted divalent radical derived from an alkoxy group substituted with oxygen at the end of the alkyl chain.
  • phosphono is art-recognized and refers to the group represented by— P(0)(OH) 2 .
  • phosphonato is art-recognized and refers to the group represented by— P(0)(0-) 2 .
  • phosphinato is art-recognized and refers to the group represented by— P(0)(CT).
  • phospho is art-recognized and refers to the group represented by— P0 2 .
  • phosphino is art-recognized and refers to the group represented by— PH 2 .
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings".
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sil refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
  • sulfate is art-recognized and refers to the group -OSO 3 H, or a
  • R and R independently represents hydrogen or hydrocarbyl, such as alkyl, or R 29 and R 30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 12 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(0)-R 30 , wherein R 30 represents a hydrocarbyl.
  • sulfonate or “sulfo” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • sulfone or “alkylsulfonyl” are art-recognized and refer to the
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thiocarbamoyl is art-recognized and efers to the group— (CS)— NH 2 .
  • thiocyanate is art-recognized and refers to the group -SCN.
  • thioester refers to a group -C(0)SR 30 or -SC(0)R 30 wherein R 30 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula
  • R 29 R 29 wherein R 29 and R 30 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 29 taken together with R 30 and the intervening atom(s) complete a heterocycle having from 4 to 12 atoms in the ring structure.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, but not limited to, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol - derivatives and allyl ethers.
  • Optional or “optionally” means that the subsequently described circumstance may or may not occur, so that the application includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the application includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • the term “stability,” “stable,” “stable compound,” or “stable structure” in the context of a chemical structure refers to the chemical state when a system is in its lowest energy state, or in chemical equilibrium with its environment. Thus, a stable compound (or, e.g.
  • a compound containing a number of atoms or substitutions that are stable is not particularly reactive in the environment or during normal use, and retains its useful properties on the timescale of its expected usefulness.
  • a stable compound is sufficiently robust to survive isolation, and as appropriate, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the free base form of the compound is also contemplated and the disclosed salt form should not be considered as limiting. All such free base forms are intended to be included in the embodiments of this disclosure, even where a salt form of a compound of this disclosure is specifically indicated.
  • derivative refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • analogue refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analogue is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • small molecule is an art-recognized term. In some embodiments, this term refers to a molecule, which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.
  • Healthcare providers refers to individuals or organizations that provide healthcare services to a person, community, etc.
  • Examples of “healthcare providers” include doctors, hospitals, continuing care retirement communities, skilled nursing facilities, sub acute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMO's.
  • IC 5 o half maximal inhibitory concentration
  • concentration of a substance e.g., a compound or a drug
  • a biological process or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • EC50 half maximal effective concentration refers to the concentration of a compound, moleule, or drug, which induces a response halfway between the baseline and maximum after a specified exposure time.
  • health and normal are used interchangeably herein to refer to a subject or particular cell or tissue that is devoid (at least to the limit of detection) of a disease condition.
  • Embodiments of this disclosure relate to compounds that, in some embodiments, are useful for treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyal
  • the compounds of this disclosure are ligands of the imidazoline-1 (L) receptor.
  • the compounds of this disclosure modulate the I i receptor.
  • the compounds of this disclosure modulate the I i receptor to reduce pain.
  • the compounds of this disclosure activate the Ii receptor to reduce pain.
  • the compounds of this disclosure reduce pain through a pathway that is independent of the I i receptor (the Imidazoline-1 Receptor-Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).
  • the compounds in accordance with the various embodiments of this disclosure can be used alone or simultaneously, separately, or sequentially in combination with each other or with acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine,
  • NSAID non-steroidal anti-inflammatory drug
  • ibuprofen ibuprofen
  • naprosyn a cyclooxygenase-2 inhibitor
  • aspirin caffeine
  • dichloralphenazone a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an
  • an antiproliferative agent an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates, or a combination of any of the foregoing therapeutics for the treatment of the conditions disclosed herein.
  • Analgesic and pain reduction activity of the compounds of this disclosure that is modulated through the Ii receptor can be evaluated by determining trigeminal von Frey thresholds in spontaneous trigeminal allodynia (STA) rats, as described herein.
  • Therapeutic activity of the compounds described herein can also be evaluated using rats in an inflammatory soup model of chronic migraine and an opiate-like dependence model with the naloxone-precipitated withdrawal (Saelens) test in mice.
  • the analgesic potential of the compounds described herein can also be evaluated using a monosodium iodacetate (MIA) induced model of osteoarthritic pain in adult male rats.
  • MIA monosodium iodacetate
  • sumatriptan-induced medication overuse headache can be triggered by nitric oxide (NO) donors in rats.
  • NO nitric oxide
  • Analgesic and pain reduction activity of the compounds described herein that are modulated through the IRIPM pathway can be evaluated in a rat chronic constrictive nerve injury (CCI) model of neuropathic pain or a rat model of bortezomib-induced neuropathy, also described herein. Additionally, the analgesic and pain reduction activity of the compounds described herein that is modulated through the IRIPM pathway can be identified using the mouse formalin, hot plate, and tail-flick tests. Binding of the compounds described herein to the I
  • CCI chronic constrictive nerve injury
  • Evaluation of the impact of 11 receptor agonists and antagonists on forskolin-stimulated cAMP induction can be conducted using a functional assay for the Ii receptor with PC- 12 cells or a transiently- expressing or stably-expressing I
  • the compounds of this disclosure are represented by general formula (SC-01 ):
  • SC-01 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • L 1 is a 4 to 10 carbon atom linker selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl,
  • heterocyclylalkanediyl cycloalkylalkanediyl, cycloalkylheteroalkanediyl, alkenediyl, alkynediyl, alkylthiodiyl, and 1 , 1 -dialkylcycloalkanediyl;
  • W is selected from the group consisting of N and CH;
  • Y is selected from the group consisting of CH 2 , NH, O, and S;
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, alkoxycycloalkyl, cycloalkyl, and heterocyclyl;
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl; wherein L 1 can be linked with R 1 , R 2 or both R 1 and R 2 to form a monocyclic,
  • bicyclic, or polycyclic ring wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted heterocyclyl;
  • L 1 can be linked with R 1 or R 2 to form a moiety selected from the group
  • W is N and Y is CH 2 . In some embodiments when W is N and Y is CH 2 . In some embodiments when W is N and
  • Y is CH 2 , R 1 and R 2 are each hydrogen. In some embodiments when W is N, Y is CH 2 , and R 1 and R 2 are each hydrogen, L 1 is an optionally substituted cycloalkanediyl. In some embodiments W is N, Y is CH 2 , R 2 is hydrogen, and L 1 is linked with R 1 to form a monocyclic optionally substituted heterocyclyl. In some embodiments W is CH and Y is NH. In some embodiments when W is CH and Y is NH, R 1 and R 2 are each an optionally substituted alkyl. In some
  • W is CH
  • Y is NH
  • R 1 and R 2 are each an optionally substituted alkyl
  • L 1 is an optionally substituted 1 , 1 -dialkylcycloalkanediyl.
  • W is N and Y is NH.
  • R 1 is an optionally substituted alkenyl and R 2 is hydrogen.
  • W is N, Y is NH, R 1 is an optionally substituted alkenyl, and R 2 is hydrogen, L 1 is an optionally substituted alkanediyl.
  • R 1 is an optionally substituted cycloalkyl. In certain such embodiments, R 1 is an optionally substituted alkoxycycloalkyl.
  • L 1 is selected from the group consisting of optionally substituted alkynediyl and alkylthiodiyl.
  • L 1 and R 2 are linked to form a bicyclic optionally substituted heterocyclyl. In some embodiments, L 1 and R 2 are linked to form an optionally substituted cycloalkylalkanediyl.
  • L 1 , R 1 , and R 2 are linked to form a bicyclic optionally substituted heterocyclyl.
  • the compounds represented by formula (SC-01 ) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 131-137, 143, 144, 183, 197, or 201, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 131, 133, 143, or 144, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC-02):
  • SC-02 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • Y is selected from the group consisting of CH 2 and NH;
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl;
  • Ar is selected from the group consisting of optionally substituted aryl and heteroaryl.
  • the compound of formula (SC-02) is the S-enantiomer.
  • Y is CH 2 . In some embodiments when Y is CH 2 , R 1 is an optionally substituted alkyl. In some embodiments when Y is CH 2 and R 1 is an optionally substituted alkyl, Ar is an optionally substituted aryl. In some
  • R 1 when Y is CH 2 , R 1 is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In some embodiments when Y is CH 2 , R 1 is an optionally substituted aminoalkyl and Ar is an optionally substituted aryl. In some embodiments when Y is CH 2 , R 1 is an optionally substituted aminoalkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-02) is the S-enantiomer.
  • Y is NH. In some embodiments when Y is NH, R 1 is hydrogen and Ar is an optionally substituted aryl. In some embodiments when Y is NH, R 1 is an optionally substituted alkyl and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-02) is the S-enantiomer.
  • Ar when Ar is an optionally substituted aryl, it is selected from phenyl, 4-bromophenyl, and 3-bromophenyl. In some embodiments, when Ar is an optionally substituted heteroaryl, it is selected from 2-thienyl and 3-thienyl.
  • the compounds represented by formula (SC-02) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 93, 96, 147, 148, 164, 165, 182, 221, or 222, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 96, 164, 165, or 222, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • Compounds of formula (SC-02) comprise a 1 ,3-diazepine-type core and compounds of formula (SC-05) comprise an imidazoline core.
  • the 1 ,3-diazepine-type core compounds appear to be more polar than the imidazoline core compounds, despite the addition of two carbon units to the ring.
  • the compounds of this disclosure are represented by general formula (SC-03):
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl and heteroalkyl
  • Ar is selected from the group consisting of optionally substituted aryl and heteroaryl.
  • the compound of formula (SC-03 1 ) is the S-enantiomer.
  • R 1 is hydrogen and Ar is an optionally substituted aryl.
  • the compound of formula (SC-03) is the S-enantiomer.
  • R 1 is hydrogen and Ar is an optionally substituted heteroaryl.
  • the compound of formula (SC-03) is the S-enantiomer.
  • R 1 is an optionally substituted alkyl and Ar is an optionally substituted aryl.
  • the compound of formula (SC-03) is the S-enantiomer.
  • R 1 is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl.
  • the compound of formula (SC-03) is the S-enantiomer.
  • R 1 is hydrogen and Ar is phenyl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer. In some embodiments, R 1 is an optionally substituted alkyl and Ar is phenyl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer.
  • the compound represented by formula (SC-03) is:
  • the compounds of this disclosure are represented by general formula (SC-04):
  • SC-04 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, alkoxy, aminoalkyl, arylalkyl, heteroarylalkyl, arylalkoxy, and heteroarylalkoxy;
  • Ar is selected from the group consisting of optionally substituted aryl and heteroaryl; wherein R 1 and R 2 can optionally form a monocyclic, bicyclic or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted heterocyclyl.
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 and R 2 are hydrogen and Ar is an optionally substituted aryl.
  • the compound of formula (SC-04) is the S- enantiomer.
  • R 1 and R 2 are hydrogen and Ar is an optionally substituted heteroaryl.
  • the compound of formula (SC-04) is the S- enantiomer.
  • R 1 is an optionally substituted alkyl
  • R 2 is hydrogen
  • Ar is an optionally substituted aryl
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted alkyl
  • R 2 is hydrogen
  • Ar is an optionally substituted heteroaryl
  • the compound of . formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted aminoalkyl
  • R 2 is an optionally substituted alkyl
  • Ar is an optionally substituted aryl.
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted aminoalkyl
  • R 2 is an optionally substituted alkyl
  • Ar is an optionally substituted heteroaryl
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted alkoxy
  • R 2 is hydrogen
  • Ar is an optionally substituted aryl.
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted alkoxy
  • R 2 is hydrogen
  • Ar is an optionally substituted heteroaryl
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted arylalkoxy
  • R 2 is hydrogen
  • Ar is an optionally substituted aryl.
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 is an optionally substituted arylalkoxy
  • R 2 is hydrogen
  • Ar is an optionally substituted heteroaryl.
  • the compound of formula (SC-04) is the S-enantiomer.
  • R 1 and R 2 form an optionally substituted cycloalkyi.
  • the compound of formula (SC-04) is the S-enantiomer.
  • Ar when Ar is an optionally substituted aryl, Ar is a substituted phenyl. In certain such embodiments, the phenyl group is substituted at the 3 or the 4 position with halogen, -SCF 3 , or optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer. In some embodiments, the compounds represented by formula (SC-04) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 112, 145, 157, 160, 161, 162, 163, 176, or 198, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 160, 161, 162, 163, or 176, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC-05):
  • SC-05 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 2 is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 3 is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • Ar is selected from the group consisting of optionally substituted aryl and heteroaryl.
  • the compound of formula (SC-05) is the S-enantiomer.
  • R 1 and R 3 are each hydrogen.
  • R 2 is an optionally substituted alkyl and Ar is an optionally substituted aryl.
  • R 1 and R 3 are each hydrogen, R 2 is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl.
  • R 1 and R 3 are each hydrogen, R 2 is an optionally substituted cycloalkyl and Ar is an optionally substituted aryl.
  • R 1 and R 3 are each hydrogen, R 2 is an optionally substituted cycloalkyl and Ar is an optionally substituted heteroaryl. In some embodiments when R 1 and R 3 are each hydrogen, R 2 is an optionally substituted aminoalkyl and Ar is an optionally substituted aryl. In some embodiments when R 1 and R 3 are each hydrogen, R 2 is an optionally substituted aminoalkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.
  • R 1 is an optionally substituted aminoalkyl and R 3 is hydrogen. In some embodiments when R 1 is an optionally substituted aminoalkyl and R 3 ,is hydrogen, R 2 is an optionally substituted alkyl and Ar is an optionally substituted aryl. In some embodiments when R 1 is an optionally substituted aminoalkyl and R 3 is hydrogen, R 2 is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-05) is the S- enantiomer. In some embodiments, R 1 is an optionally substituted hydroxyalkyl and R 3 is hydrogen.
  • R 1 when R 1 is an optionally substituted hydroxyalkyl and R is hydrogen, R is an optionally substituted alkyl and Ar is an optionally substituted aryl. In some embodiments when R 1 is an optionally substituted hydroxyalkyl and R 3 is hydrogen, R 2 is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.
  • R 1 is an optionally substituted alkyl.
  • the compound of formula (SC-05) is the S-enantiomer.
  • R 3 is an optionally substituted hydroxyalkyl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.
  • R 3 is an optionally substituted alkyl. In certain such embodiments,
  • the compound of formula (SC-05) is the S-enantiomer.
  • R 3 is an optionally substituted aminoalkyl.
  • the compound of formula (SC-05) is the S-enantiomer.
  • R 1 is hydrogen
  • R is an optionally substituted alkyl, Ar is not unsubstituted phenyl and R is not unsubstituted methyl.
  • the heteroaryl is selected from an optionally substituted thienyl-pyridyl, isothiazole, 2-thienyl, 3-thienyl, benzothiophenyl, benzisothiazolo, or 3-amino-4-pyridyl.
  • the compounds represented by formula (SC-05) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 3, 33, 102, 103, 108, 123-130, 146, 153, 155, 158, 168, 185, 193-196, 220, or 360-368, or a pharmaceutically acceptable salt, a free base form, a tautomer, enantiomer, disastereomer, or a solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 3, 33, 102, 103, 108, 123-130, 146, 153, 155, 158, 168, 185, 193-196, 220, or 360-368, or a pharmaceutically acceptable salt, a free base form, a tautomer, enantiomer, disastereomer, or a solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 102, 103, 108, 123-130, 146, 153, 155, 158, 168, 185, 193-196, 220, or 360- 368, or a pharmaceutically acceptable salt, a free base form, a tautomer, enantiomer, disastereomer, or a solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 123-129, 146, 153, 158, 185, 193, 195, 220, 361, 364-366, or 368, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC-06):
  • SC-06 or a pharmaceutically acceptable salt, diastereomer, enantiomer, tautomer, or solvate thereof, wherein as valence and stability permit: — represents a single or double bond;
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein R 1 and R 2 can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, cycloalkenyl, aryl, and heteroaryl.
  • — represents a single bond. In some embodiments,— represents a single bond and R is hydrogen. In some embodiments when— represents a single bond and R is hydrogen, R is an optionally substituted alkenyl.
  • R 2 represents a single bond and R 2 is hydrogen. In some embodiments when— represents a single bond and R 2 is hydrogen, R 1 is an optionally substituted alkenyl.
  • — represents a single bond and R 1 and R 2 form an optionally substituted cycloalkenyl.
  • R 1 and R 2 form an optionally substituted aryl. In some embodiments, R 1 is an optionally substituted alkyl.
  • the compounds represented by formula (SC-06) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 12 or 224-229, or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 224-228 or 229, or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 224-227 or 228, or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC-07):
  • Y is selected from the group consisting of NH and O;
  • R 1 , R 2 , R 3 , and R 6 are independently selected from the group consisting of hydrogen, halogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkynyloxy, alkylthio, -SCF 3 , and alkylamino; and R 4 and R 5 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkylthio, and alkylamino; wherein R 1 and R 4 or R 1 and R 5 can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl.
  • the compound of formula (SC-07) is the S-enantiomer.
  • Y is NH. In some embodiments when Y is NH, R 1 , R 2 , R 3 , R 5 and R 6 are each hydrogen. In some embodiments when Y is NH and R 1 , R 2 , R 3 , R 5 and R 6 are each hydrogen, R 4 is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer.
  • R 2 , R 3 , R 5 , and R 6 are each hydrogen. In some embodiments when Y is NH and R 2 , R 3 , R 5 , and R 6 are each hydrogen, R 4 is an optionally substituted alkyl. In some embodiments when Y is NH and R 2 , R 3 , R 5 , and R 6 are each hydrogen, R 1 is an optionally substituted alkylthio and R 4 is an optionally substituted alkyl. In some embodiments when Y is NH and R 2 , R 3 , R 5 , and R 6 are each hydrogen, R 1 is -SCF 3 , and R 4 is an optionally substituted alkyl.
  • R 1 is halogen and R 4 is an optionally substituted alkyl.
  • the compound of formula (SC-07) is the S-enantiomer.
  • Y is O. In some embodiments when Y is O, R 1 , R 2 , R 3 , R 5 and R 6 are each hydrogen. In some embodiments when Y is O and R 1 , R 2 , R 3 , R 5 and R 6 are each hydrogen, R 4 is an optionally substituted alkyl. In some embodiments when Y is O and R 1 , R 2 , R 3 , R 5 and R 6 are each hydrogen, R 4 is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC-07) is the S- enantiomer.
  • R 2 , R 3 , R 5 , and R 6 are each hydrogen. In some embodiments when Y is O and R 2 , R 3 , R 5 , and R 6 are each hydrogen, R 4 is an optionally substituted alkyl. In some embodiments when Y is O and R 2 , R 3 , R 5 , and R 6 are each hydrogen, R 1 is an optionally substituted alkynyloxy and R 4 is an optionally substituted alkyl. In some embodiments when Y is O and R 2 , R 3 , R 5 , and R 6 are each hydrogen, R 1 is an optionally substituted alkyloxy and R 4 is an optionally substituted alkyl.
  • R 4 is an optionally substituted alkynyl.
  • R 2 , R 3 , R 5 , and R 6 are each hydrogen, and R is an optionally substituted alkynyl, R is an optionally substituted alkyloxy.
  • the compound of formula (SC-07) is the S-enantiomer.
  • R 1 , R 2 , R 3 , and R 5 are each hydrogen.
  • R 1 , R 2 , R 3 , and R 5 are each hydrogen, R 6 is halogen.
  • R 4 is an optionally substituted alkynyl.
  • the compound of formula (SC-07) is the S-enantiomer.
  • R 3 , R 5 , and R 6 are each hydrogen.
  • R 1 and R 2 are each halogen.
  • R 4 is an optionally substituted alkyl.
  • R 1 is an optionally substituted alkyl.
  • the compound of formula (SC-07) is the S-enantiomer.
  • R 5 is an optionally substituted alkyl.
  • the compound of formula (SC-07) is the S-enantiomer.
  • R 3 is halogen.
  • the compound of formula (SC-07) is the S-enantiomer.
  • the compounds represented by formula (SC-07) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 1, 2, 5, 20, 25, 28, 37, 38, 47, 223, 230, 231, 232, 233, 234, or 369-373, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 223, 230-234, or 369-373, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 223, 231-233, or 372, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds of this disclosure are represented by general formula (SC-08):
  • R 1 and R 2 are independently selected from the group consisting of optionally
  • R 3 and R 4 are independently selected from the group consisting of hydrogen and
  • R 1 and R 2 can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • R 3 and R 4 are each hydrogen. In some embodiments when R 3 and R 4 are each hydrogen, R 1 is an optionally substituted alkyl. In some embodiments when R 3 and R 4 are each hydrogen and R 1 is an optionally substituted alkyl, R 2 is an optionally substituted alkenyl. In some embodiments when R 3 and R 4 are each hydrogen, R 1 is an optionally substituted alkenyl. In some embodiments when R 3 and R 4 are each hydrogen, R 1 is an optionally substituted alkenyl. In some embodiments when R 3 and R 4 are each hydrogen and is an optionally substituted alkenyl, R 2 is an optionally substituted alkenyl.
  • R 1 and R 2 form an optionally substituted cycloalkyl.
  • the compounds represented by formula (SC-08) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 4, 21, 22, 50, 235, 236, or 237, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 235, 236, or 237, or a
  • the compounds are selected from a group of compounds having the formula 235 or 236, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC-09):
  • SC-09 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • Y is selected from the group consisting of N and O;
  • R 1 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl;
  • R 5 is selected from the group consisting of hydrogen and optionally substituted
  • R 6 is selected from the group consisting of absent, hydrogen, and optionally
  • R 2 and R 3 are each hydrogen, Y is O, and R 6 is absent. In some embodiments when R 2 and R 3 are each hydrogen, Y is O, and R 6 is absent, R 4 is hydrogen. In some embodiments when R 2 and R 3 are each hydrogen, Y is O, R 6 is absent, and R 4 is hydrogen, R 1 is an optionally substituted aryl and R 5 is hydrogen. In some embodiments, R 2 and R 3 are each hydrogen, Y is O, R 6 is absent, R 4 is hydrogen, R 1 is an optionally substituted aryl, and R 5 is an optionally substituted arylalkyl.
  • R 2 , R 3 , and R 6 are each hydrogen and Y is N. In some embodiments when R 2 , R 3 , and R 6 are each hydrogen and Y is N, R 4 is hydrogen. In some embodiments when R 2 , R 3 , R 4 , and R 6 are each hydrogen and Y is N, R 5 is hydrogen. In some embodiments when R 2 , R 3 , R 4 , R 5 , and R 6 are each hydrogen and Y is N, R 1 is an optionally substituted aryl.
  • R and R are each hydrogen and Y is N. In some embodiments, R and R are each hydrogen and Y is N. In some
  • R 2 and R 3 are each hydrogen ' and Y is N
  • R 4 is hydrogen.
  • R 5 is hydrogen.
  • R 1 is an optionally substituted aryl
  • R 6 is an optionally substituted arylalkyl.
  • R 1 is selected from the group consisting of optionally substituted alkyl and cycloalkyl.
  • R 3 is an optionally substituted alkyl.
  • the compounds represented by formula (SC-09) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 6, 11, 13, 15, 16, 24, or 238-246, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 238, 239, 240, 241, 242, 243, 244, 245, or 246, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 238, 239, 240, or 241, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC- 10):
  • SC-10 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • Y is selected from the group consisting of NH and CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylthio, -SCF 3 , and amino; and R 3 and R 4 are independently selected from the group consisting of hydrogen and halogen; wherein R 1 and R 2 can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted aryl and heteroaryl.
  • Y is CH 2 . In some embodiments, Y is CH 2 and R 4 is hydrogen. In some embodiments, Y is CH 2 and R 3 and R 4 are each hydrogen. In some embodiments when Y is CH 2 and R 3 and R 4 are each hydrogen, R 1 is an optionally substituted heteroaryl and R 2 is an optionally substituted alkylthio. In some embodiments when Y is CH 2 and R 3 and R 4 are each hydrogen, R 1 is an optionally substituted heteroaryl and R 2 is -SCF 3 . In some embodiments, Y is CH 2 and R 2 and R 4 are each hydrogen. In some embodiments when Y is CH 2 and R 2 and R 4 are each hydrogen, R 1 is an optionally substituted heteroaryl and R 3 is halogen.
  • Y is NH.
  • R 1 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, alkenyl, and amino.
  • R 2 is selected from the group consisting of optionally substituted alkyl, alkenyl, and amino.
  • R 4 is halogen. In some embodiments, R 1 and R 2 form an optionally substituted heteroaryl.
  • the compounds represented by formula (SC- 10) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 7, 17, 26, 34, 53, or 247-253, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 247, 248, 249, 250, 251, 252, or 253, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 247 or 248, or a
  • the compounds of this disclosure are represented by general formula (SC- 1 1 ):
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen and optionally substituted alky 1, alkenyl, alkynyl, heteroalkyi, hydroxyalkyl, aryl, and heteroaryl;
  • R and R can optionally form a ring, wherein the ring is a optionally substituted cycloalkyl.
  • the compound of formula (SC- 1 1 ) is the S-enantiomer.
  • — represents a single bond. In some embodiments,— represents a single bond, R 2 is an optionally substituted alkyl, and R 3 is hydrogen. In some embodiments,— represents a single bond, R 2 is an optionally substituted alkyl, R 3 is hydrogen, and R 1 is an optionally substituted hydroxyalkyl. In certain such embodiments, the compound of formula (SC-1 1 ) is the S-enantiomer.
  • — represents a single bond. In some embodiments,— represents a single bond, R 2 is hydrogen and R 1 is hydrogen. In some embodiments, — represents a single bond, R 2 is hydrogen, R 1 is hydrogen, and R 3 is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC- 1 1 ) is the S-enantiomer.
  • — represents a double bond.
  • the compound of formula (SC- 1 1 ) is the S-enantiomer.
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl.
  • the compound of formula (SC-1 1) is the S-enantiomer.
  • R is hydrogen.
  • the compound of formula (SC-1 1 ) is the S-enantiomer.
  • R 2 is an optionally substituted alkynyl.
  • the compound of formula (SC-1 1 ) is the S-enantiomer.
  • R 3 is an optionally substituted alkyl.
  • the compound of formula (SC-1 1) is the S-enantiomer.
  • the compounds represented by formula (SC-1 1 ) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 8, 10, 18, 23, 29, 30, 31, 36, 43, 254-256, or 374, or a pharmaceutically acceptable salt, tautomer, diastereomer, enantiomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 254, 255, 256, or 374, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compound is a compound having the formula 254, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate thereof.
  • the compounds of this disclosure are represented by general formula (SC- 12):
  • SC-12 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit: a and ⁇ ⁇ represent a single or double bond;
  • R 1 is selected from the group consisting of hydrogen, CH 2 , and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;
  • R 8 is selected from the group consisting of absent, hydrogen, hydroxyl, and optionally substituted alkyl and haloalkyl;
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;
  • R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen,
  • R 6 is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxyalkyl, and cycloalkylacyl;
  • R 7 is selected from the group consisting of hydrogen and optionally substituted alkyl
  • R 9 is selected from the group consisting of hydrogen and optionally substituted alkyl and haloalkyl
  • R 1 and R 2 , R 3 and R 4 , R 4 and R 5 , R 4 and R 7 , or R 8 and R 9 can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, and heterocyclyl;
  • R 1 and R 9 can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, heterocyclyl, and aryl; wherein when R 1 and R 9 form an optionally substituted aryl, R 8 is absent;
  • R 5 and R 6 can optionally form a monocyclic, bicyclic, or polycyclic ring, wherein the ring is selected from the group optionally substituted heterocyclyl and heteroaryl.
  • the compound of formula (SC-12) is the R-enantiomer.
  • At least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is other than hydrogen.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • R 8 when R 8 is absent, at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 is other than hydrogen.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • both a and ⁇ are single bonds.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a double bond
  • ⁇ is a single bond
  • R 8 is absent.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a single bond
  • ⁇ is a double bond
  • R 1 is CH 2
  • R 8 is absent.
  • the compound of formula (SC-12) is the R- enantiomer.
  • R 1 and R 2 are both an optionally substituted alkyl.
  • both a and ⁇ are single bonds, R 1
  • both an optionally substituted alkyl, and R is an optionally substituted alkyl.
  • both a and ⁇ are single bonds
  • R 1 , R 2 , and R 5 are each an optionally substituted alkyl
  • R 3 , R 4 , R 6 , and R 7 are each hydrogen
  • R 8 and R 9 form an optionally substituted cycloalkyl.
  • both a and ⁇ are single bonds
  • R' , R 2 , and R 5 are each an optionally substituted alkyl
  • R 3 , R 4 , R 6 , and R 7 are each hydrogen
  • R 8 and R 9 form an optionally substituted halocycloalkyl.
  • both a and ⁇ are single bonds
  • R 1 , R 2 , and R 5 are each an optionally substituted alkyl
  • R 3 , R 4 , R 6 , and R 7 are each hydrogen
  • R 8 and R 9 form a difluorocyclopropyl.
  • both a and ⁇ are single bonds
  • R 1 , R 2 , R 5 , and R 6 are each an optionally substituted alkyl
  • R 3 , R 4 , and R 7 are each hydrogen.
  • both a and ⁇ are single bonds, R 1 , R 2 , R 5 , and R 6 are each an optionally substituted alkyl, and R 3 , R 4 , and R 7 are each hydrogen, and R 8 and R 9 form an optionally substituted cycloalkyi.
  • both a and ⁇ are single bonds, R 1 , R 2 , R 5 , and R 6 are each an optionally substituted alkyl, and R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen.
  • both a and ⁇ are single bonds, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted cycloalkyi, and R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen.
  • both a and ⁇ are single bonds, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted alkenyl, and R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen.
  • both a and ⁇ are single bonds, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted alkynyl, and R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen. In some embodiments both a and ⁇ are single bonds, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted alkoxyalkyl, and R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen.
  • both a and ⁇ are single bonds
  • R 1 , R 2 , and R 5 are each an optionally substituted alkyl
  • R 3 , R 4 , R 6 , R 7 and R 9 are each hydrogen
  • R 8 is a hydroxyl.
  • both a and ⁇ are single bonds
  • R 1 , R 2 , and R 5 are each an optionally substituted alkyl
  • R 3 , R 4 , R 6 , R 7 and R 9 are each hydrogen
  • R 8 is hydrogen.
  • the compound of formula (SC-12) is the R-enantiomer.
  • R 5 is an optionally substituted alkyl. In some embodiments both a and ⁇ are single bonds, R 5 is an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen. In some embodiments both a and ⁇ are single bonds, R 5 , R 6 , and R 8 are each an optionally substituted alkyl, R 3 , R 4 , R 7 , and R 9 are each hydrogen, and R 1 and R 2 form an optionally substituted cycloalkyi.
  • both a and ⁇ are single bonds, R 5 , R 6 , and R 8 are each an optionally substituted alkyl, R 3 , R 4 , R 7 , and R 9 are each hydrogen, and R 1 and R 2 form an optionally substituted halocycloalkyl.
  • both a and ⁇ are single bonds, R 5 , R 6 , and R 8 are each an optionally substituted alkyl, R 3 , R 4 , R 7 , and R 9 are each hydrogen, and R 1 and R 2 form a difluorocyclopropyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • both a and ⁇ are single bonds
  • R 1 , R 5 , and R 7 are each an optionally substituted alkyl
  • R 2 is an optionally substituted alkylamino
  • R 6 is an optionally substituted cycloalkylacyl
  • R 3 , R 4 , R 8 , and R 9 are each hydrogen.
  • the compound of formula (SC-12) is the R-enantiomer.
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R are each an optionally substituted haloalkyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen, R 1 and R 2 are each trifluoromethyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each ' hydrogen
  • R 1 and R 2 are each an optionally substituted haloalkyl
  • R 6 is an optionally substituted haloalkyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each trifluoromethyl
  • R 6 is a trifluoromethyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each an optionally substituted haloalkyl
  • R 6 is an optionally substituted alkyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each trifluoromethyl
  • R 6 is an optionally substituted alkyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each an optionally substituted haloalkyl
  • R 6 is an optionally substituted alkynyl.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each trifluoromethyl
  • R 6 is an optionally substituted alkynyl.
  • R 5 when both a and ⁇ are single bonds, R 5 is an optionally substituted alkyl, R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen, and R and R are each an optionally substituted haloalkyi, R is hydrogen. In some embodiments when both a and ⁇ are single bonds, R 5 is an optionally substituted alkyl, R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen, and R 1 and R 2 are each trifluoromethyl, R 6 is hydrogen.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each an optionally substituted haloalkyi
  • R 6 is an optionally substituted cycloalkyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • R 5 is an optionally substituted alkyl
  • R 3 , R 4 , R 7 , R 8 , and R 9 are each hydrogen
  • R 1 and R 2 are each trifluoromethyl
  • R 6 is an optionally substituted cycloalkyl.
  • the compound of formula (SC-12) is the R-enantiomer.
  • R 1 and R 2 are both an optionally substituted haloalkyi and R 3 , R 8 , and R 9 are each hydrogen. In some embodiments when both a and ⁇ are single bonds, R 1 and R 2 are both trifluoromethyl and R 3 , R 8 , and R 9 are each hydrogen. In some embodiments when both a and ⁇ are single bonds, R 1 and R 2 are both an optionally substituted haloalkyi, and R 3 , R 8 , and R 9 are each hydrogen, R 4 and R 7 are each hydrogen and R 5 and R 6 form an optionally substituted heterocyclyl.
  • R 1 and R 2 are both trifluoromethyl, and R 3 , R 8 , and R 9 are each hydrogen, R 4 and R 7 are each hydrogen and R 5 and R 6 form an optionally substituted heterocyclyl.
  • R 1 and R 2 are both an optionally substituted haloalkyi, and R 3 , R 8 , and R 9 are each hydrogen, R 4 and R 7 form an optionally substituted heterocyclyl, R 5 is an optionally substituted alkyl, and R 6 is hydrogen.
  • R 1 and R 2 are both trifluoromethyl, and R 3 , R 8 , and R 9 are each hydrogen, R 4 and R 7 form an optionally substituted heterocyclyl, R 5 is an optionally substituted alkyl, and R 6 is hydrogen.
  • the compound of formula (SC-12) is the R- enantiomer.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, and R 1 and R 2 are both an optionally substituted alkyl.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both an optionally substituted alkyl, and R 7 and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both an optionally substituted alkyl, R 5 and R 6 form an optionally substituted heterocyclyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted cycloalkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted haloalkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is trifluoromethyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted alkenyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, R 6 is an optionally substituted alkynyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl, and R 3 , R 4 , R 6 , R 7 , and R 9 are each hydrogen.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a double bond, ⁇ is a single bond, R is absent, R , R , and R 6 are each an optionally substituted alkyl, and R 7 and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 6 are each an optionally substituted alkyl, and R 3 , R 7 , and R 9 are each hydrogen.
  • a is a double bond
  • ⁇ is a single bond
  • R 8 is absent
  • R 1 , R 2 , and R 6 are each an optionally substituted alkyl
  • R 4 and R 5 form an optionally substituted cycloalkyl
  • R 3 , R 7 , and R 9 are each hydrogen.
  • the compound of formula (SC-12) is the R-enantiomer.
  • a is a double bond
  • ⁇ is a single bond
  • R 8 is absent
  • R 1 and R 2 are both an optionally substituted alkyl
  • R 5 and R 6 form an optionally substituted heterocyclyl
  • R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • the compound of formula (SC-12) is the R-enantiomer.
  • a is a double bond
  • ⁇ is a single bond
  • R 8 is absent
  • R 1 and R 2 are both an optionally substituted alkyl
  • R 3 , R 6 , and R 9 are each hydrogen
  • R 5 is an optionally substituted alkyl
  • R 4 and R 7 form an optionally substituted heterocyclyl.
  • the compound of formula.(SC-12) is the R-enantiomer.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, and R 1 is an optionally substituted haloalkyl, R 2 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, and R 1 is trifluoromethyl, R 2 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 is an optionally substituted haloalkyl, R 2 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is hydrogen.
  • R 1 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 is trifluoromethyl, R 2 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is hydrogen.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 is an optionally substituted haloalkyl, R 2 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is an optionally substituted alkyl.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 is trifluoromethyl, R 2 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is an optionally substituted alkyl.
  • ⁇ is a single bond
  • R 8 is absent
  • R 1 is an optionally substituted haloalkyi
  • R 2 and R 5 are both an optionally substituted alkyl
  • R 3 , R 4 , R 7 , and R 9 are each hydrogen
  • R 6 is an optionally substituted haloalkyi
  • R 8 is absent
  • R 1 is trifluoromethyl
  • R 2 and R 5 are both an optionally substituted alkyl
  • R 3 , R 4 , R 7 , and R 9 are each hydrogen
  • R 6 is trifluoromethyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 2 is an optionally substituted haloalkyi, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 2 is trifluoromethyl, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 2 is an optionally substituted haloalkyi, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is hydrogen.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 2 is trifluoromethyl, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is hydrogen.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 2 is an optionally substituted haloalkyi, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is an optionally substituted alkyl.
  • R 8 when a is a double bond, ⁇ is a single bond, R 8 is absent, R 2 is trifluoromethyl, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is an optionally substituted alkyl.
  • ⁇ is a single bond
  • R 8 is absent
  • R 2 is an optionally substituted haloalkyi
  • R 1 and R 5 are both an optionally substituted alkyl
  • R 3 , R 4 , R 7 , and R 9 are each hydrogen
  • R 6 is an optionally substituted haloalkyl.
  • ⁇ when a is a double bond, ⁇ is a single bond, R is absent, R is trifluoromethyl, R 1 and R 5 are both an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen, R 6 is trifluoromethyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a double bond, ⁇ is a single bond, R is absent, and R and R 2 are both an optionally substituted haloalkyl.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, and R 1 and R 2 are both trifluoromethyl.
  • a is a double bond, ⁇ is a single bond; R 8 is absent, R 1 and R 2 are both an optionally substituted haloalkyl, and R 7 and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both trifluoromethyl, and R 7 and R 9 are each hydrogen.
  • a is a double bond
  • ⁇ is a single bond
  • R 8 is absent
  • R 1 and R 2 are both an optionally substituted haloalkyl
  • R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both trifluoromethyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both an optionally substituted haloalkyl, R 5 and R 6 form an optionally substituted heterocyclyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both trifluoromethyl, R 5 and R 6 form an optionally substituted heterocyclyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond,.R 8 is absent, R 1 and R 2 are each an optionally substituted haloalkyl, R 5 is an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each trifluoromethyl, R 5 is an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each an optionally substituted haloalkyl, R 5 is an optionally substituted alkyl, R 6 is an optionally substituted cycloalkyj, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each trifluoromethyl, R 5 is an optionally substituted alkyl, R 6 is an optionally substituted cycloalkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each an optionally substituted haloalkyl, R 5 is an optionally substituted alkyl, R 6 is an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each trifluoromethyl, R 5 is an optionally substituted alkyl, R 6 is an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each an optionally substituted haloalkyl, R 5 is an optionally substituted alkyl, R 6 is hydrogen, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each trifluoromethyl, R 5 is an optionally substituted alkyl, R 6 is hydrogen, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each an optionally substituted haloalkyl, R 5 is an optionally substituted alkyl, R 6 is an optionally substituted alkynyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are each trifluoromethyl, R 5 is an optionally substituted alkyl, R 6 is an optionally substituted alkynyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 and R 2 are both an optionally substituted haloalkyl, R 3 , R 6 , and R 9 are each hydrogen, R 5 is an optionally substituted alkyl, and R 4 and R 7 form an optionally substituted heterocyclyl.
  • a is a double bond
  • ⁇ is a single bond
  • R 8 is absent
  • R 1 and R 2 are both trifluoromethyl
  • R 3 , R 6 , and R 9 are each hydrogen
  • R 5 is an optionally substituted alkyl
  • R 4 and R 7 form an optionally substituted heterocyclyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , and R 5 are each an optionally substituted alkyl.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 1 , R 2 , R 5 , and R 6 are each an optionally substituted
  • a is a double bond
  • ⁇ is a single bond
  • R is absent
  • R , R 2 , R 5 , and R 6 are each an optionally substituted alkyl
  • R 3 and R 4 form an optionally substituted cycloalkyl
  • R 7 and R 9 are each hydrogen.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, and R 5 and R 6 are each an optionally substituted alkyl.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 5 and R 6 are each an optionally substituted alkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 5 and R 6 are each an optionally substituted alkyl, R 1 and R 2 are both an optionally substituted cycloalkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 5 and R 6 are each an optionally substituted alkyl, R 1 is an optionally substituted alkyl, R 2 is an optionally substituted cycloalkylalkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • a is a double bond, ⁇ is a single bond, R 8 is absent, R 5 and R 6 are each an optionally substituted alkyl, R 1 and R 2 form an optionally substituted cycloalkyl, and R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • the compound of formula (SC-12) is the R-enantiomer.
  • a is a single bond, ⁇ is a double bond, R 8 is absent, R 1 is CH 2 . In some embodiments, a is a single bond, ⁇ is a double bond, R 8 is absent, R 1 is CH 2 , and R 5 and R 6 are both an optionally substituted alkyl. In some embodiments, a is a single bond, ⁇ is a double bond, R 8 is absent, R 1 is CH 2 , and R 2 , R 5 , and R 6 are each an optionally substituted alkyl.
  • a is a single bond
  • ⁇ is a double bond
  • R 8 is absent
  • R 1 is CH 2 , R 2 , R 5 , and R 6 are each an optionally substituted alkyl
  • R 3 , R 4 , R 7 , and R 9 are each hydrogen.
  • compound of formula (SC- 12) is the R-enantiomer.
  • a is a single bond
  • ⁇ is a double bond
  • R 8 is absent
  • R 1 is CH 2
  • R 2 and R 5 are each an optionally substituted alkyl
  • R 3 , R 4 , R 6 , R 7 , and R 9 are each hydrogen.
  • the compound of formula (SC- 12) is the R- enantiomer.
  • R 1 and R 9 form an optionally substituted aryl and R 8 is absent. In some embodiments, R 1 and R 9 form an optionally substituted aryl, R 8 is absent, and R 5 and R 6 are both an optionally substituted alkyl. In some embodiments, R 1 and R 9 form an optionally substituted aryl, R 8 is absent, R 2 , R 5 , and R 6 are each optionally substituted alkyl, and R 3 , R 4 , and R 7 are each hydrogen. In some embodiments, R 1 and R 9 form an optionally substituted aryl, R 8 is absent, R 5 and R 6 are each an optionally substituted alkyl, and R 2 , R 3 , R 4 , and R 7 are each hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.
  • R 1 is hydrogen.
  • the compound of formula (SC-12) is the R-enantiomer.
  • R 3 is an optionally substituted alkyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • R 4 is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.
  • R 5 is hydrogen.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • R 6 is selected from the group consisting of optionally substituted heteroalkyi and alkoxyaikyl.
  • the compound of formula (SC-12) is the R-enantiomer.
  • R 9 is an optionally substituted alkyl.
  • the compound of formula (SC- 12) is the R-enantiomer.
  • the compounds represented by formula (SC- 12) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 9, 27, 44, 99, 110, 111, 113- 120, 138-142, 167, 188, 199, 203, 212-217, 219, 257-259, 315-359, or 430-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, or a solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 99, 110, 111 , 113-120, 138- 142, 167, 188, 199, 212-217, 219, 257-259, 318-354, 358-359, or 430-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, or a solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 111, 113-118, 140-142, 167, 188, 212-216, 217, 219, 258, 259, 323-325, 328-330, 336-349, 358-359, or 430-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, or a solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC- 13):
  • Y is selected from the group consisting of O and CH 2 ;
  • W is selected from the group consisting of CH 2 , CH, N, NH, C, and CHCH 3 ;
  • Z is selected from the group consisting of NR. 6 , C, CH, and CH 2 ;
  • R 1 is selected from the group consisting of hydrogen, halogen, and isothiocyanate
  • R 2 is selected from the group consisting of hydrogen and halogen
  • R 3 is selected from the group consisting of hydrogen and optionally substituted alkyl
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, and optionally
  • R 5 is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl;
  • R 6 is selected from the group consisting of absent, hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; wherein R 4 and R 5 can optionally form a ring, wherein the ring is an optionally
  • W and R 3 or Z and R 3 can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • represents a single bond
  • Z is NR 6
  • Y is CH 2
  • W is CH 2
  • R 4 and R 5 form an optionally substituted heterocyclyi
  • R 1 , R 2 , and R 3 are each hydrogen
  • R 6 is an optionally substituted alkyl.
  • Z is NR 6
  • Y is CH 2
  • W is CH 2
  • R 4 and R 5 form an optionally substituted heterocyclyi
  • R 1 , R 2 , and R 3 are each hydrogen
  • R 6 is an optionally substituted aminoalkyl.
  • represents a single bond
  • Z is NR 6
  • Y is CH 2
  • W is CHCH 3
  • R 4 and R 5 form an optionally substituted heterocyclyi
  • Z is NR 6
  • Y is CH 2
  • W is CHCH 3
  • R 4 and R 5 form an optionally substituted heterocyclyi
  • R 1 , R 2 , and R 3 are each hydrogen
  • R 6 is an optionally substituted alkyl.
  • Z is NR 6
  • Y is CH 2
  • W is CHCH 3
  • R 4 and R 5 form an optionally substituted heterocyclyi
  • R 1 , R 2 , and R 3 are each hydrogen
  • R 6 is an optionally substituted aminoalkyl.
  • R 3 is an optionally substituted alkyl.
  • R 4 is an optionally substituted alkyl.
  • R 5 is an optionally substituted alkyl.
  • R 6 is hydrogen
  • the compounds represented by formula (SC- 13) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 14, 45, 76, 97, or 177, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 76, 97, or 177, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compound is a compound having the formula 177, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate thereof.
  • the compounds of this disclosure are represented by general formula (SC- 14):
  • Y is selected from the group consisting of N and CH;
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, and aminoalkyl;
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen and
  • the compound of formula (SC-14) is the S-enantiomer.
  • Y is CH. In some embodiments when Y is CH, R 2 is an optionally substituted alkyl. In some embodiments when Y is CH and R 2 is an optionally substituted alkyl, R 1 is an optionally substituted arylalkyl. In some embodiments when Y is CH and R 2 is an optionally substituted alkyl, R 1 is an optionally substituted heteroarylalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.
  • R 3 and R 4 are each hydrogen.
  • R 3 and R 4 are each hydrogen.
  • the compound of formula (SC- 14) is the S-enantiomer.
  • R 3 and R 4 form an optionally substituted cycloalkyl.
  • R 3 and R 4 form an optionally substituted cycloalkyl.
  • the compound of formula (SC- 14) is the S-enantiomer.
  • R 2 when Y is CH, R 2 is hydrogen, R 1 is an optionally substituted arylalkyi, and R 3 and R 4 are each hydrogen. In some embodiments when Y is CH, R 2 is hydrogen, R 1 is an optionally substituted heteroarylalkyl, and R 3 and R 4 are each hydrogen. In certain such embodiments, the compound of formula (SC- 14) is the S- enantiomer.
  • R 2 when Y is CH, R 2 is hydrogen, R 1 is an optionally substituted arylalkyi, and R 3 and R 4 form an optionally substituted cycloalkyl. In some embodiments when Y is CH, R 2 is hydrogen, R 1 is an optionally substituted heteroarylalkyl, and R 3 and R 4 form an optionally substituted cycloalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.
  • Y is N. In some embodiments when Y is N, R 1 is an optionally substituted aminoalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.
  • R 1 is an optionally substituted alkyl.
  • the compound of formula (SC- 14) is the S-enantiomer.
  • R 3 is an optionally substituted alkyl.
  • the compound of formula (SC- 14) is the S-enantiomer.
  • R 4 is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.
  • the compounds represented by formula (SC-14) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 100, 101, 104-107, 109, 149-152, 154, 156, 159, 178, 180, 181, or 202, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 149, 150, 152, 178, or 202, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC- 15):
  • R ] , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkoxy, alkylthio, -SCF 3 , difluoromethoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxy, heteroaryloxy, aryloxyalkoxy, and heteroaryloxyalkoxy; and
  • R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxyalkyl, and heteroaryloxyalkyl; wherein R 5 and R 6 can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted heterocyclyl and optionally substituted aminoalkylheterocyclyl; wherein R 6 and R 7 can optionally form a ring, wherein the ring is an optionally
  • R 8 is hydrogen. In some embodiments when R 8 is hydrogen, R 7 is hydrogen. In some embodiments when R 7 and R 8 are both hydrogen, R 5 and R 6 7 8 form an optionally substituted heterocyclyl. in some embodiments when R and R
  • R 5 6 1 2 are both hydrogen and R and R form an optionally substituted heterocyclyl, R , R , R 3 , and R 4 are each hydrogen.
  • R 7 and R are both hydrogen
  • R 5 and R 6 form an optionally substituted aminoalkylheterocyclyl.
  • R 7 and R 8 are both hydrogen and R 5 and R 6 form an optionally substituted aminoalkylheterocyclyl
  • R 1 , R 2 , R 3 , and R 4 are each hydrogen.
  • R 4 and R 6 are both hydrogen and R 5 is an optionally substituted alkyl.
  • R 4 , R 6 , R 7 , and R 8 are each hydrogen and R 5 is an optionally substituted alkyl
  • R 1 and R 2 are each hydrogen and R 3 is an optionally substituted aryloxyalkoxy.
  • R 4 , R 6 , R 7 , and R 8 are each hydrogen and R 5 is an optionally substituted alkyl
  • R 2 and R 3 are each hydrogen and R 1 is an optionally substituted aryloxyalkoxy.
  • R 8 when R 8 is hydrogen, R 5 is hydrogen, R 6 is an optionally substituted alkyl, and R 7 is an optionally substituted alkyl. In some embodiments when both R 5 and R 8 are hydrogen, R 6 is an optionally substituted alkyl, and R 7 is an optionally substituted alkyl, R 1 , R 3 , and R 4 are hydrogen and R 2 is an optionally substituted alkylthio. In some embodiments when both R 5 and R 8 are hydrogen, R 6 is an optionally substituted alkyl, and R 7 is an optionally substituted alkyl, R 1 , R 3 , and R 4 are hydrogen and R 2 is -SCF 3 .
  • R 1 is selected from the group consisting of optionally substituted alkyl, aminoalkyl, alkylthio, -SCF 3 , difluoromethoxy, aryl, aryloxy, and aryloxyalkoxy.
  • R 2 is selected from the group consisting of optionally substituted alkyl, aminoalkyl, alkoxy, -SCF 3 , difluoromethoxy, aryl, arylalkoxy, aryloxy, and aryloxyalkoxy.
  • R 3 is selected from the group consisting of optionally substituted alkyl, aminoalkyl, alkoxy, alkylthio, -SCF 3 , difluoromethoxy, aryl, arylalkoxy, and aryloxy.
  • R 4 is selected from the group consisting of halogen and optionally substituted aryloxyalkoxy.
  • R 5 is selected from the group consisting of optionally substituted aminoalkyl, aryl, arylalkyl, and aryloxyalkyl.
  • R 6 is selected from the group consisting of optionally substituted aminoalkyl, aryl, arylalkyl, and aryloxyalkyl.
  • R 7 is selected from the group consisting of optionally substituted arylalkyl and aryloxyalkyl.
  • R 8 is selected from the group consisting of optionally substituted alkyl, aminoalkyl, and arylalkyl.
  • R 6 and R 7 form an optionally substituted heterocyclyl.
  • the compounds represented by formula (SC-15) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 68-71, 98, 169-171, 173, 174, 179, 190-192, 200, 218, or 265-291, or a pharmaceutically acceptable salt, a free base form, aJmitomer, or a solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 169-171, 173, 174, 179, 190-192, 200, or 265-291, or a pharmaceutically acceptable salt, tautomer, enantiomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 169, 170, 284, 286, or 289, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC- 16):
  • SC-16 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkylaminoalkyl, arylalkyl, heteroarylalkyl, and carbamoylaminoalkyl; wherein R 1 and R 2 can optionally form a ring, wherein the ring is selected from the group optionally substituted heterocyclyl and optionally substituted
  • R 2 and R 3 can optionally form a ring, wherein the ring is an optionally
  • R 1 is hydrogen
  • R 2 is an optionally substituted alkylaminoalkyl
  • R 3 is an optionally substituted alkyl
  • R 3 is hydrogen and R 1 and R 2 form an optionally substituted aminoalkylheterocyclyl.
  • R 1 is selected from the group consisting of optionally substituted alkyl, aminoalkyl, arylalkyl, and carbamoylaminoalkyl.
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl, aminoalkyl, and arylalkyl.
  • R 3 is selected from the group consisting of optionally substituted aminoalkyl, alkylaminoalkyl, and arylalkyl. In some embodiments, R 1 and R 2 form an optionally substituted heterocyclyl.
  • R and R form an optionally substituted heterocyclyl.
  • R 1 , R 2 , and R 3 are not all hydrogen.
  • the compounds represented by formula (SC- 16) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 19, 40, 54, 91, 184, 189, 206, 209, 260-264, 292, 375, or 377, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 54, 91, 184, 189, 206, 209, 260-264, 292, or 375, or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 184, 189, 260-264, or 292, or a
  • the compound is a compound having the formula 189, or a pharmaceutically acceptable salt, tautomer or solvate thereof.
  • the compounds of this disclosure are represented by general formula (SC- 17):
  • Y is selected from the group NH and O;
  • R 1 is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, amino, cycloalkyl, heterocyclyl, cycloalkylalkylamino, heterocyclylalkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylamino, heteroarylamino, and aminoalkylaryloxyalkoxyaryl; and
  • R 2 and R 3 are independently selected from the group consisting of hydrogen and
  • R 2 and R 3 can optionally form a ring, wherein the ring is an optionally
  • Y is NH. In some embodiments when Y is NH, R 2 is hydrogen. In some embodiments, Y is NH, R 2 is hydrogen, R 1 is an optionally substituted aryl, and R 3 is hydrogen. In some embodiments, Y is NH, R 2 is hydrogen, R 1 is an optionally substituted arylalkyl, and R 3 is an optionally substituted aminoalkyl. .
  • Y is O.
  • R is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, amino, cycloalkylalkylamino, heteroaryl, heteroaryl alkyl, arylamino, heteroarylamino, and aminoalkylaryloxyalkoxyaryl.
  • R 1 is selected from optionally substituted isoquinolinyl, indazol-l -ylamino, phenylalkyl, pyrimidin-5-ylamino, cycloalkylmethylamino, (aminoalkylphenoxy)alkoxyphenyl, benzothiophenylamino, or indolylalkyl.
  • R 2 is selected from the group consisting of optionally substituted alkyl, heteroalkyl, and aminoalkyl.
  • R is selected from the group consisting of optionally substituted alkyl and heteroalkyl.
  • R 2 and R 3 form an optionally substituted heterocyclyl.
  • the compounds represented by formula (SC- 17) are selected from a group of compounds having the formula;
  • the compounds are selected from a group of compounds having the formula 35, 41, 42, 51, 94, 121, 122, 172, 293, 294, or 376, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 121, 122, 172, 293, 294, or 376, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compound is compound 172, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate thereof.
  • the compound is a compound having the formula 376, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compounds of this disclosure are represented by general formula (SC- 18):
  • L 1 is a 4 to 12 carbon atom linker selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl,
  • heterocyclylalkanediyl alkenediyl, alkynediyl, arylalkanediyl,
  • R' and R 2 are independently selected from the group consisting of hydrogen and
  • R 3 and R 4 are independently selected from the group consisting of hydrogen and
  • R 1 and R 2 can optionally form a ring, wherein the ring is an optionally
  • R 1 and R 2 are each hydrogen and R 3 and R 4 are each an optionally substituted alkyl. In some embodiments when R 1 and R 2 are each hydrogen and R 3 and R 4 are each an optionally substituted alkyl, L 1 is an optionally substituted alkylaryloxydiyl. In some embodiments when R 1 and R 2 are each hydrogen and R 3 and R 4 are each an optionally substituted alkyl, L 1 is an optionally substituted aminoalkylaminodiyl. In some embodiments, L 1 is selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, arylalkanediyl, and aminoalkanediyl.
  • R 1 is an optionally substituted alkyl.
  • R 2 is an optionally substituted alkyl. In some embodiments, R 1 and R 2 form an optionally substituted heterocyclyl.
  • the compounds represented by formula (SC-18) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 186, 187, 295, or 296, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 187 or 296, a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC- 19):
  • R 1 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl;
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, and alkynyl.
  • the compound of formula (SC-19) is the R-enantiomer.
  • R 1 is an optionally substituted alkenyl and R 2 is an optionally substituted alkynyl.
  • the compound of formula (SC- 19) is the R-enantiomer.
  • R 1 is selected from the group consisting of optionally substituted alkyl and arylalkyl.
  • the compound of formula (SC- 19) is the R-enantiomer.
  • R 2 is selected from the group consisting of hydrogen and optionally substituted alkyl and alkenyl.
  • the compound of formula (SC- 19) is the R-enantiomer.
  • the compounds represented by formula (SC- 19) are selected from a group of compounds having the formula: or a pharmaceutically acce ⁇ ptable salt, enantiomer, diastereomer, or solvate of any the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 175, 297, 298, 299, or 300, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvate of any of the foregoing compounds.
  • the compound is a compound having the formula 298, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvate thereof.
  • the compounds of this disclosure are represented by general formula (SC-20):
  • R 1 is selected from the group consisting of hydrogen and optionally substituted alk l and aminoalkyl; and R 2 is selected from hydrogen and optionally substituted alkyl, aminoalkyl, and cycloalkylaminoalkyl.
  • R 1 and R 2 are each an optionally substituted aminoalkyl.
  • R is hydrogen and R is an optionally substituted
  • R 1 is an optionally substituted alkyl.
  • R 2 is selected from the group hydrogen and an optionally substituted alkyl.
  • the compounds represented by formula (SC-20) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 39, 301, 302, 303, or 304, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 301, 302, 303, or 304, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 303 or 304, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compounds of this disclosure are represented by general formula (SC-21 ): '
  • V is selected from the group consisting of C, CH, and N
  • W is selected from the group consisting of C, CH, and N
  • Y is selected from the group consisting of CH 2 and NH;
  • R 1 is selected from the group consisting of optionally substituted alkyl and amino; and R 2 is selected from the group consisting of absent and hydrogen;
  • Y is CH 2 . In some embodiments when Y is CH 2 , a is a single bond, ⁇ is a double bond, and R 2 is absent. In some embodiments when Y is CH 2 , a is a single bond, ⁇ is a double bond, and R 2 is absent, W is CH, V is N, and R 1 is an optionally substituted amino.
  • a is a double bond
  • V is C
  • W is C
  • ⁇ is a single bond
  • R 2 is hydrogen
  • a is a single bond and V is CH.
  • a is a single bond and W is N.
  • Y is NH.
  • R 1 is an optionally substituted alkyl.
  • the compounds represented by formula (SC-21 ) are selected from a group of compounds having the formula:
  • the compounds are selected from a group of compounds having the formula 46, 305, 306, or 307, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compounds are selected from a group of compounds having the formula 305, 306, or 307, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.
  • the compound is a compound having the formula 306, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compounds of this disclosure are represented by general formula (SC-22):
  • SC-22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:
  • L 1 is a 4 to 12 carbon linker selected from the group consisting of optionally
  • alkanediyl substituted alkanediyl, heteroalkanediyl, alkenediyl, heteroalkenediyl, oxyalkoxydiyl, alkylcycloalkylalkanediyl,
  • Ar 1 is selected from the group consisting of optionally substituted aryl and heteroaryl.
  • Ar 1 is an optionally substituted aryl. In some embodiments, when Ar 1 is an optionally substituted aryl, L 1 is an optionally substituted
  • L 1 is an optionally substituted alkylheterocyclylalkanediyl. In some embodiments, Ar 1 is an ' optionally substituted heteroaryl. In some embodiments, when Ar 1 is an optionally substituted heteroaryl, L 1 is an optionally substituted alkylheterocyclylalkanediyl.
  • Ar 1 when Ar 1 is an optionally substituted aryl or heteroaryl, Ar 1 is phenyl, thiophene, or benzothiophene optionally substituted with alkyl or halogen.
  • L 1 is selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, and alkylcycloalkylalkanediyl.
  • the compounds represented by formula (SC-22) are selected from a group of compounds having the formula:
  • the compounds of this disclosure are represented by general formula (SC-23):
  • R 1 is selected from the group consisting of halogen and optionally substituted C
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen and optionally substituted Cj-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 2 -C 5 heterocycloalkyl, Ci-C alkoxy, Ci -C 6 alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Q-Q alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 - C 6 cycloalkenyl, C 2 -C 5 heterocycloalkyl, Ci-C 6 alkylthio, and CpC 6 alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH 3 , OCH 2 CH 3 , CH 3 , C 2 H 5 ,
  • R 2 and R 3 can optionally form a ring, wherein the ring is an optionally
  • R 3 and R 4 can optionally form a ring, wherein the ring is an optionally
  • R 1 is halogen, SCF 3 , OCF 3 , CF 3 , or unsubstituted SCHF 2 ,
  • R 1 when R 1 is halogen, it is F, CI, Br, or I. In some embodiments when R 1 is halogen, R 2 is halogen, and R 3 and R 4 are hydrogen. In some embodiments when R 1 is halogen, R 2 is optionally substituted Ci-C 6 alkoxy, and R 3 and R 4 are hydrogen. In some embodiments when R 1 is halogen, R 2 is optionally substituted Ci-C 6 alkyl, and R 3 and R 4 are hydrogen. In some embodiments when R 1 is halogen, R 3 is halogen, and R 2 and R 4 are hydrogen. In some embodiments when R 1 is halogen, R 4 is halogen, and R 2 and R 3 are hydrogen.
  • the compounds represented by formula (SC-23) are selected from a group of compounds having the formula:
  • a p armaceut ca y accepta e sa t, tautomer, or so vate o any o t e orego ng compounds.
  • the compounds of this disclosure are represented by general formula (SC-24):
  • R 1 , R 2 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halogen, and optionally substituted C1-C3 alkyl, C1 -C3 alkoxy, C1 -C3 alkylthio, dimethylamino, methylamino, and amino;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C 2 -C 5 heterocycloalkyl, Ci-C 6 alkoxy, Ci-C 6 alkylthio, phenyl, and monocyclic heteroaryl; and R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 2 -C5 heterocycloalkyl, Ci-C 6 alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6
  • R 4 and R 5 can optionally form a ring, wherein the ring is an optionally
  • R 5 and R 6 can optionally form a ring, wherein the ring is an optionally
  • R 1 and R 3 can optionally form a ring, wherein the ring is an optionally
  • R 6 and R 7 can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R and R can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R and R can optionally form a ring, wherein the ring is an optionally
  • R 1 is halogen or hydrogen.
  • R 7 is halogen or hydrogen.
  • R 2 is hydrogen, halogen, or optionally substituted C 1 -C3 alkyl.
  • R 8 is hydrogen, halogen, or optionally substituted C 1 -C3 alkyl.
  • R 3 is hydrogen, halogen, SCF3, OCF 3 , CF3, or unsubstituted SCHF 2 , OCHF 2 , or CF 2 H.
  • R 4 is hydrogen, halogen, or optionally substituted C i-C 6 alkyl or C i-C 6 alkoxy.
  • R 5 is hydrogen, halogen, or optionally substituted C
  • R 6 is hydrogen, halogen, or optionally substituted C i-C 6 alkyl.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen. In some embodiments when R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, R 3 is halogen. In some embodiments when R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, R 3 is hydrogen. In some embodiments when R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, R 3 is SCF 3 .
  • R 3 is unsubstituted SCHF 2 . In some embodiments when R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, R 3 is optionally substituted Ci-C 6 alkoxy. In some embodiments when R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, R 3 is unsubstituted OCHF 2 .
  • R 8 is optionally substituted C1-C3 alkyl. In some embodiments when R 8 is optionally substituted C1-C3 alkyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments when R 8 is optionally substituted C1 -C3 alkyl, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen, and R 3 is halogen. In some embodiments when R 8 is optionally substituted C1 -C3 alkyl, R 1 , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen, and R 4 is halogen.
  • R 8 when R 8 is optionally substituted C 1 -C3 alkyl, R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 are hydrogen, and R 5 is halogen. In some embodiments when R 8 is optionally substituted C1-C3 alkyl, R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are hydrogen, and R 6 is halogen.
  • R 8 is halogen. In some embodiments when R 8 is halogen, R 1 , R 2 , R ⁇ R 4 , R S , R 6 , and R 7 are hydrogen. In some embodiments, when R 8 is halogen, R 7 is halogen. In some embodiments when R 7 and R 8 are halogen, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen. In some embodiments when R 7 and R 8 are halogen, R 1 , R 2 , R 4 , R 5 , and R 6 are hydrogen and R 3 is optionally substituted Ci-C 6 alkoxy.
  • R 1 and R 2 are halogen. In some embodiments when R 1 and R 2 are halogen, R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen and R 3 is optionally substituted Ci- C 6 alkoxy.
  • R 3 is halogen. In some embodiments when R 3 is halogen, R 1 , R 2 , R 7 , and R 8 are hydrogen. In some embodiments when R 3 is halogen and R 1 , R 2 , R 7 , and R 8 are hydrogen, R 4 is halogen. In some embodiments when R 3 is halogen and R 1 , R 2 , R 7 , and R 8 are hydrogen, R 3 is halogen. In some embodiments when R 3 is halogen and R 1 , R 2 , R 7 , and R 8 are hydrogen, R 6 is halogen.
  • R 1 , R 2 , R 7 , and R 8 are hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 2 is halogen. In some embodiments, R 1 and R 2 are halogen. In some embodiments, R 4 is halogen. In some embodiments when R 4 is halogen, R 1 , R 2 , R 7 , and R 8 are hydrogen. In some embodiments, R 4 is optionally substituted Ci-C 6 alkoxy. In some embodiments when R 4 is optionally substituted C
  • the compounds represented by formula (SC-24) are selected from a group of compounds having the formula:
  • the compounds of this disclosure are represented by general formula (SC-25):
  • R' , R 2 , and R 3 are independently selected from the group consisting of hydrogen, and unsubstituted C 1 -C3 alkyl, C 3 -C 5 cycloalkyl, C 2 -C alkenyl, methoxyethyl, ethoxyethyl, and ethynyl; and
  • R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 2 -C 5 heterocycloalkyl, Ci-C 6 alkoxy, C
  • R 1 and R 3 can optionally form a ring, wherein the ring is an optionally
  • R 1 and R 7 can optionally form a ring, wherein the ring is an optionally
  • R 4 and R 5 can optionally form a ring, wherein the ring is an optionally
  • R 5 and R 6 can optionally form a ring, wherein the ring is an optionally
  • R and R can optionally form a ring, wherein the ring is an optionally
  • R 1 is hydrogen. In some embodiments, R 2 is hydrogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 1 , R 2 , and R 3 are hydrogen. In some embodiments, R 1 and R 2 are hydrogen and R 3 is unsubstituted Ci- C 3 alkyl. In some embodiments, R 1 and R 2 are hydrogen and R 3 is unsubstituted methyl.
  • R 4 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl, Ci-C 6 alkoxy, or difluoromethoxy.
  • R 4 when R 4 is hydrogen, halogen, or optionally substituted C]-C 6 alkyl or C
  • R 4 when R 4 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is C
  • R 4 when R 4 is hydrogen, halogen, or optionally substituted C]-C 6 alkyl or C
  • R 1 and R 2 are hydrogen and R 3 is methyl.
  • R 4 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or C
  • R 1 , R 2 , R 5 , and R 6 are hydrogen and R 3 is unsubstituted methyl.
  • R 4 is hydrogen, fluorine, or
  • R 4 when R 4 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , and R 3 are hydrogen. In some embodiments when R 4 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted Ci-C 3 alkyl.
  • R 4 when R 4 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , R 5 , and R 6 are hydrogen and R 3 is unsubstituted Ci-C 3 alkyl. In some embodiments when R 4 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted methyl.
  • R 4 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy
  • R 1 , R 2 , R 5 , and R 6 are hydrogen and R 3 is unsubstituted methyl.
  • R 5 is hydrogen, halogen, or optionally substituted Ci -C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy.
  • R , R , and R are hydrogen.
  • R 1 and R 2 are hydrogen and R 3 is unsubstituted C
  • R 5 when R 5 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or C i-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 , R 2 , R 4 , and R 6 are hydrogen and R 3 is unsubstituted Ci-C 3 alkyl. In some embodiments when R 5 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted methyl.
  • R 5 when R 5 is hydrogen, halogen, or optionally substituted C i-C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 , R 2 , R 4 , and R 6 are hydrogen and R 3 is unsubstituted methyl. In some embodiments, R 5 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy. In some
  • R 5 when R 5 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , and R 3 are hydrogen. In some embodiments when R 5 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted C
  • R 5 when R 5 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted methyl. In some embodiments when R 5 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , R 4 , and R 6 are hydrogen and R 3 is unsubstituted methyl. In some embodiments, R 6 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or C]-C 6 alkoxy, or unsubstituted difluoromethoxy.
  • R 6 when R 6 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 , R 2 , and R 3 are hydrogen. In some embodiments when R 6 is hydrogen, halogen, or optionally substituted C i-C 6 alkyl or Ci-C alkoxy, or unsubstituted difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted C i - C 3 alkyl.
  • R 6 when R 6 is hydrogen, halogen, or optionally substituted Ci-C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 , R 2 , R 4 , and R 5 are hydrogen and R 3 is unsubstituted Ci-C 3 alkyl. In some embodiments when R 6 is hydrogen, halogen, or optionally substituted C j-C 6 alkyl or Ci-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted methyl.
  • R 6 when R 6 is hydrogen, halogen, or optionally substituted C i-C 6 alkyl or C i-C 6 alkoxy, or unsubstituted difluoromethoxy, R 1 , R 2 , R 4 , and R 5 are hydrogen and R 3 is unsubstituted methyl. In some embodiments, R 6 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy. In some
  • R 6 when R 6 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , and R 3 are hydrogen. In some embodiments when R 6 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted Ci-C 3 alkyl. In some embodiments when R 6 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , R 4 , and R 5 are hydrogen and R 3 is unsubstituted C
  • R 6 when R 6 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 and R 2 are hydrogen and R 3 is unsubstituted methyl. In some embodiments when R 6 is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R 1 , R 2 , R 4 , and R 5 are hydrogen and R 3 is unsubstituted methyl.
  • the compounds represented by formula (SC-25) are selected from a group of compounds having the formula:
  • the compound of this disclosure is selected from a group of compounds having the formula:
  • the compound of this disclosure is selected from the group of compounds having the formula 1-432, or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compound of this disclosure is selected from the group of compounds having the formula 1, 54-93, 95-376, or 378-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds.
  • the compound of this disclosure is selected from the group of compounds having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a pharmaceutically acceptable salt, enantiomer, disastereomer, a free base form, tautomer or solvate of any of the foregoing compounds.
  • the compound of this disclosure is selected from the group of compounds having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315, 316, 317, 355, 356, 357, or 375, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds.
  • the compound of this disclosure is selected from the group of compounds having the formula 93, 96, 99-202, 212-217, 219-314, 318-354, 358-374, 376, or 378-432, or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.
  • the compound of this disclosure is selected from the group of compounds having the formula 96, 111, 113-118, 123-129, 131, 133, 140-144, 146, 149, 150, 152, 153, 158, 160-167, 169, 170, 172, 176-178, 185, 187-
  • heteroaryloxyalkoxy cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclylalkenyl, alkoxycycloalkyl, cycloalkylalkyl, cycloalkylacyl, cycloalkylalkylamino,
  • cycloalkylaminoalkyl heterocyclylalkyl, heterocyclylalkylamino, acylaminoalkyl, carbamoylaminoalkyl, alkanediyl, heteroalkanediyl, cycloalkanediyl,
  • heterocyclylheteroalkanediyl alkenediyl, heteroalkenediyl, alkynediyl, alkylthiodiyl, arylalkanediyl, alkylaryloxydiyl, aminoalkanediyl, aminoalkylaminodiyl,
  • alkylcycloalkylalkanediyl alkylcycloalkylalkanediyl, heteroalkylcycloalkylheteroalkanediyl, alkylcycloalkenylalkanediyl, heteroalkylcycloalkenylheteroalkanediyl,
  • alkylheterocyclylalkanediyl, heteroalkylheterocyclylheteroalkanediyl, and 1 , 1 - dialkylcycloalkanediyl are substituted, they are substituted, valency and stability permitting, with one or more substituents selected from substituted or unsubstituted alkyl (such as perfluoroalkyl (e.g., trifiuoromethyl and difluoromethyl)), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, aryloxyalkoxy, hydroxyl, halo, alkoxy (such as perfluoroalkoxy (e.g., trifluoromethoxy and difluoromethoxy)), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl
  • esters for example pharmaceutically acceptable esters.
  • a carboxylic acid group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester.
  • an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, propionate, or other ester.
  • the disclosure of this application includes prodrugs of the compounds selected from the group of compounds having the formulae (SC-01 ), (SC- 02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC- 1 1 ), (SC- 12), (SC-13), (SC- 14), (SC-15), (SC- 16), (SC- 17), (SC- 18), (SC- 19), (SC- 20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the disclosure of this application (e.g., any one of a compound selected from the group of compounds having formula (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC-1 1 ), (SC- 12), (SC-13), (SC-14), (SC- 15), (SC- 16), (SC-17), (SC-18), (SC-19), (SC-20), (SC-21), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds).
  • a common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to yield the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • a prodrug with a nitro group on an aromatic ring can be reduced by an endogenous reductase to generate the desired amino group of the corresponding active compound in vivo.
  • functional groups such as a hydroxyl, carbonate, or carboxylic acid in the parent compound are presented as an ester, which can be cleaved by esterases.
  • amine groups in the parent compounds are presented in, but not limited to, carbamate, N-alkylated or N-acylated forms (Simplicio, et al, "Prodrugs for Amines,” Molecules, (2008), 13:5 19-547).
  • Some embodiments of this disclosure include metabolites of the compounds selected from the group of compounds having the formulae (SC-01 ), (SC-02), (SC-03), (SC- 04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC-1 1), (SC-12), (SC- 13), (SC-14), (SC-15), (SC-16), (SC- 17), (SC- 18), (SC-19), (SC-20), (SC-21 ), (SC- 22), (SC-23), (SC-24), (SC-25), or formula 1-8, 10-26, or 28-432, or a
  • metabolite is intended to encompass compounds that are produced by metabolism/biochemical modification of the parent compound under physiological conditions, e.g. through certain enzymatic pathways.
  • an oxidative metabolite is formed by oxidation of the parent compound during metabolism, such as the oxidation of a pyridine ring to pyridine-N-oxide.
  • an oxidative metabolite is formed by demethylation of a methoxy group to result in a hydroxyl group.
  • a variety of compounds of the embodiments of disclosure may exist in particular geometric or stereoisomeric forms.
  • This disclosure includes all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this disclosure. All tautomeric forms are encompassed in this disclosure. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure, unless the stereochemistry or isomeric form is specifically indicated.
  • optically active or racemic forms Compounds described herein containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents.
  • the therapeutic preparations of the disclosure may be enriched to provide predominantly one enantiomer of a compound described herein (e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC- 1 1 ), (SC- 12), (SC- 13), (SC- 14), (SC- 15), (SC- 16), (SC-17), (SC- 18), (SC- 19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base, enantiomer, disastereomer, tautomer, solvate, or prodrug of any of the foregoing compounds).
  • a compound described herein e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5 or even 100 mol percent.
  • the compound described herein enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1 % as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound disclosed herein (e.g., any of the compounds of formulae (SC-01), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC- 07), (SC-08), (SC-09), (SC-10), (SC- 1 1 ), (SC- 12), (SC-13), (SC-14), (SC-15), (SC- 16), (SC-17), (SC-1 8), (SC- 19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC- 25), or formula 1-432, or a pharmaceutically acceptable salt, free base, tautomer, enantiomer, disastereomer, solvate or prodrug of any of the foregoing compounds).
  • a compound disclosed herein e.g., any of the compounds of formulae (SC-01), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, 96, 97, 98, 99, or even 100 mol percent.
  • the compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds (e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC- 1 1 ), (SC-12), (SC- 13), (SC- 14), (SC- 15), (SC-16), (SC-17), (SC- 18), (SC- 19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula .1-432, or a pharmaceutically acceptable salt, prodrug, tautomer, enantiomer, disastereomer, or solvate, or free
  • An “isotopically” or “radio-labeled” compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Certain isotopically labeled compounds e.g., any of the compounds of formulae (SC- 01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC- 1 1 j, (SC- 12), (SC-13), (SC-14), (SC- 15), (SC- 16), (SC- 17), (SC- 1 8), (SC- 19), (SC-20), (SC-21), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, prodrug, tautomer, enantiomer, disastereomer, solvate, or free base form of any of the foregoing compounds) in this disclosure, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, i.e. 3 H, and carbon 14, i.e., 1 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain ⁇
  • the isotopically labeled compound is a substituted mucate salt of compound 9, such as (R)-isometheptene-N-CD 3 mucate (compound 357), 6,7-D 6 -(R)-isometheptene mucate (compound 358), or 6,7-D 6 -(R)- isometheptene-N-CD 3 mucate (compound 359).
  • Isotopically labeled compounds e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC- 1 1 ), (SC-12), (SC-13), (SC- 14), (SC- 15), (SC-16), (SC- 17), (SC-18), (SC- 19), (SC-20), (SC-21), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or free base form of any of the foregoing compounds) or their corresponding prodrugs described herein are prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Suitable isotopes that may be incorporated in compounds of this disclosure include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), n C, 13 C, ,4 C, 13 N, 15 N, 15 0, , 7 0, , 8 0, 18 F, 35 S, 36 C1 , 82 Br, 75 Br, 76 Br, 77 Br, 123 I, l24 I, l 25 I, and l 3 , I.
  • compositions of this disclosure include pharmaceutically acceptable salts of compounds of this disclosure.
  • pharmaceutically acceptable salts includes salts of the compounds described herein which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic, acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
  • the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a sulfate acid salt.
  • the pharmaceutically acceptable salt is a phosphate salt. In some embodiments, the pharmaceutically acceptable salt is a mucate salt. In some embodiments, the pharmaceutically acceptable salt is an oxalate salt. In some embodiments, the pharmaceutically acceptable salt is a tartrate salt. In some embodiments, the pharmaceutically acceptable salt is a malate salt. In some embodiments, the pharmaceutically acceptable salt is a maleate salt. In some embodiments,
  • contemplated salts of the compounds include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of compounds include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl)morpholine, piperazine, potassium, l -(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of compounds include, but are not limited to, Li, Na, Ca, , Mg, Zn or other metal salts. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, et ah, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1 -19). Certain specific compounds of this disclosure may contain both basic and acidic functionalities, as such, these compounds can be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid, as is appropriate, and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.
  • the compounds of this disclosure can also exist as various solvates, such as with water (also known as hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • the compounds of this disclosure, including their pharmaceutically acceptable salts and prodrugs can also exist as various polymorphs, pseudopolymorphs, or in amorphous state.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo- polymorphs, such as hydrates, solvates, or salts of the same compound.
  • pseudo- polymorphs such as hydrates, solvates, or salts of the same compound.
  • Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as X-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents.
  • crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry
  • this disclosure relates to use of one or more compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1), formula (SC- 12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC-17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds, as an analgesic.
  • this disclosure relates to any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC- 05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), or formula (SC-25), or formula 1-432, or mixtures thereof, or a
  • this disclosure relates to the use of any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, in the manufacture of a medicament for the treatment of pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disorder, or
  • epilepsy a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;
  • TMJ temporomandibular joint syndrome
  • TMJ lower back pain
  • interstitial cystitis Gulf War syndrome
  • visceral pain kidney stones
  • gout gout
  • neuropathic pain post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;
  • osteoarthritis rheumatoid arthritis
  • Lyme disease Parkinson's disease
  • pain associated with cancer opioid-induced constipation
  • opioid withdrawal symptom or pain associated with post-traumatic stress disorder (PTSD), or a combination of any of the foregoing conditions.
  • PTSD post-traumatic stress disorder
  • this disclosure relates to a method of treating or preventing pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension- type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness;
  • this disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of any one of a compound having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, in association with at least one pharmaceutically acceptable excipient
  • this disclosure relates to use of a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC-1 8), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, as an analgesic.
  • composition comprising any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC- 15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, in the manufacture of a medicament for the treatment of pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder
  • this disclosure relates to a method of treating or preventing pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension- type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness;
  • a pharmaceutical composition comprising any one of a compound of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC- 04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1), formula (SC- 12), formula (SC-13), formula (SC- 14), formula (SC- 15), formula (SC-16), formula (SC- 17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a
  • this disclosure relates to a method of modulating an imidazoline- 1 (I
  • the compounds of this disclosure, or mixtures thereof modulate the 11 receptor. In some embodiments, the compounds of this disclosure, or mixtures thereof, modulate the I i receptor to reduce pain. Without wishing to be bound by theory, in some embodiments, the compounds of this disclosure, or mixtures thereof, activate the I) receptor to reduce pain. In some embodiments, the compounds of this disclosure, or mixtures thereof, may reduce pain through a pathway that is independent of the Ii receptor (the Imidazoline- 1 Receptor- Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).
  • this disclosure relates to a method of modulating an imidazoline-1 (I
  • the compounds of this disclosure, or mixtures thereof modulate the Ii receptor to reduce pain in a patient in need thereof.
  • the compounds of this disclosure, or mixtures thereof activate the 1
  • the compounds of this disclosure, or mixtures thereof may reduce pain in a patient in need thereof through a pathway that is independent of the I i receptor (the Imidazoline- 1 Receptor-Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).
  • a pathway that is independent of the I i receptor the Imidazoline- 1 Receptor-Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway.
  • the I i receptor is selected from the group consisting of: a) an I
  • an I) receptor comprising the amino acid sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91 %, 90%, 85%, 80%, or 75% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; c) an 11 receptor comprising the amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; d) an Ii receptor comprising the amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; e) an I i receptor comprising the amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: l or a counterpart amino acid sequence of another species; f) an I i receptor comprising the amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 1 or a
  • this disclosure relates to a method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of any one of a compound having the formula (SC-01 ), formula (SC- 02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SCr22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable
  • an immunosuppressive agent an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.
  • an inflammatory disease or disorder In the treatment of pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate
  • one of more of the compounds and compositions of this disclosure may be used alone or together or conjointly administered with another type of therapeutic agent.
  • the phrase "conjoint administration” refers to any form of administration of two or more different therapeutic compounds or compositions such that the second compound or composition is administered while the previously administered therapeutic compound or composition is still effective in the body.
  • the different therapeutic compounds or compositions can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment.
  • the different therapeutic compounds or compositions are administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds or compositions.
  • conjoint administration of compounds or compositions described herein with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of this disclosure (e.g., any one of a compound of formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC- 08), formula (SC-09), formula (SC- 10), formula (SC-1 1), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC- 22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug of any of the foregoing compounds) or the one or more additional therapeutic agent(s) or the one
  • the compounds or compositions described herein are used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal anti- inflammatory drug (NSA1D), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin- norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.
  • NSA1D non-steroidal anti- inflammatory drug
  • ibuprofen ibuprofen
  • naprosyn a cyclooxygenase-2 inhibitor
  • aspirin caffeine, dichloralphenazone, a triptan
  • an antidepressant a serotonin- norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.
  • SNRI serotonin-
  • the compound is used with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.
  • the compound is used with one or more opiates.
  • compositions disclosed herein, and mixtures thereof, may also be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Methods of Treatment and Use
  • the compounds and compositions of this disclosure, or mixtures thereof, are useful as analgesics or to treat pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate
  • the compounds of this disclosure are ligands of the
  • the compounds and compositions of this disclosure modulate the I ] receptor. In some embodiments, the compounds and compositions of this disclosure modulate the l i receptor to reduce pain. Without wishing to be bound by theory, in some embodiments, the compounds and
  • compositions of this disclosure activate the I i receptor to reduce pain.
  • the compounds and compositions of this disclosure may reduce pain through a pathway that is independent of the I i receptor (the Imidazoline- 1 Receptor- Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).
  • the compounds and compositions of this disclosure, or mixtures thereof, simultaneously, separately, or sequentially in combination with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti- asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an NSAID nonsteroidal anti-inflammatory drug
  • ibuprofen ibuprofen
  • naprosyn a cyclooxygenase-2 inhibitor
  • aspirin caffeine, dichloralphenazone, a triptan
  • immunomodulatory agent a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a ⁇ TNF-alpha inhibitor, or one or more opiates are useful for inhibiting nitric oxidase in a patient in need thereof.
  • An analgesic is a member of the group of drugs used to achieve analgesia or relief from pain Pain
  • Pain is an unpleasant feeling triggered by the nervous system. It is often classified by the region of the body involved, the system whose dysfunction may be causing the pain, the duration and pattern of occurrence, the intensity and time since onset, and the etiology. Many types of pain exist, including, but not limited to, nociceptive pain, neuropathic pain, psychogenic pain, visceral pain, and chronic pain.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of diseases of inflammation and allergy as manifested in cells required to mount an inflammatory response, such as neutrophils, macrophages, mast cells, T- cells, B-cells, plasma cells, dendritic cells, basophils, and eosinophils.
  • the pain and tension associated with inflammatory diseases or conditions which are treatable by the compounds and compositions of this disclosure include, but are not limited to, autoimmune diseases and common arthritis types, including rheumatoid arthritis, osteoarthritis, ankyolsing spondylitis, psoriatic arthritis; psoriasis, systemic lupus erythematosus, glomerulonephritis, scleroderma, general renal failure, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, multiple sclerosis; inflammation due to hyper-responsiveness to cytokine production, chronic obstructive pulmonary, airway or lung disease (COPD, COAD, or COLD), acute respiratory distress syndrome (ARDS) and occupation-related diseases such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Additionally,
  • the compounds and compositions of this disclosure are useful for the treatment or prevention of diseases and conditions related to immediate-type hypersensitivity, also referred to as allergic responses, conditions and diseases.
  • diseases and conditions include, but are not limited to, asthma (extrinsic or intrinsic), asthma related sequelae including small and large airway hyperactivity, bronanaphylaxis, aspirin induced asthma, allergic airway inflammation, urticaria, Steven-Johnson syndrome, atopic dermatitis, bolus pemphigoid and the like.
  • Metabolic diseases include, but are not limited to, asthma (extrinsic or intrinsic), asthma related sequelae including small and large airway hyperactivity, bronanaphylaxis, aspirin induced asthma, allergic airway inflammation, urticaria, Steven-Johnson syndrome, atopic dermatitis, bolus pemphigoid and the like.
  • Metabolic diseases include, but are not limited to, asthma (extrinsic or intrinsic), asthma related sequelae including small and large air
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of discomfort and pain due to inflammation associated with metabolic diseases, such as diabetes and obesity.
  • Cardiovascular diseases or disorders Cardiovascular diseases, acute heart failure, enlargement of the heart, and
  • Atherosclerosis are also diseases that are suitable for ameliorating the treatment ' or prevention using the compounds and compositions of this disclosure.
  • cardiovascular diseases also include pulmonary hypertension, deep venous thrombosis, stroke, myocardial infarction, myocardial contractility diseases or disorders, ischemia, thromboembolism, pulmonary embolism, acute arterial ischemia, peripheral thrombotic occlusions, coronary artery disease and acute coronary syndrome (ACS).
  • the cardiovascular disease treated or prevented by compounds and compositions of this disclosure is atherosclerosis.
  • the neurovascular effect on cardiovascular disease treated or prevented by compounds and compositions of this disclosure is a myocardial contractility disease or disorder or an acute coronary syndrome. Neurogenic vascular diseases or painful conditions associated therewith
  • compounds and compositions of this disclosure are useful in the treatment or prevention of pain caused by neurogenic vascular diseases.
  • Symptoms are caused by the compression of the spinal cord or nerve roots in the lower region of the spine or by narrowing of the arteries in the legs, and include leg pain, leg weakness, tingling, fatigue, a sensation of heaviness, and weakness.
  • compounds and compositions of this disclosure are useful in the treatment or prevention of pain caused by headaches and episodic tension-type headaches.
  • a headache is pain in any region of the head, and may occur on one or both sides of the head, be isolated to a certain location, radiate across the head from one point, or have a vise-like quality. Headaches can cause sharp pain, a throbbing sensation, or a dull ache.
  • Primary headaches can be caused by problems with or overactivity of pain-sensitive structures in the head, and secondary headaches can be caused by diseases, such as brain cancer, glaucoma, and trigeminal neuralgia, which activate the pain-sensitive nerves in the head.
  • a tension-type headache is classified into subtypes based on how often it occurs: infrequent episodic tension-type headache (ETTH) ( ⁇ 1 day /month on average), frequent ETTH ( 1 - 14 days/month on average), or chronic TTH, or CTTH, ( ⁇ 15 days/month on average).
  • ETTH episodic tension-type headache
  • An ETTH may be described as a mild to moderate constant band-like pain, tightness, or pressure around the forehead or back of the head and neck. ETTH may last from 30 minutes to several days. ETTH usually begins gradually, and often occurs in the middle of the day. The severity of a tension headache generally increases significantly with its frequency. Because the symptoms of ETTH overlap with other primary headache types, diagnosis is generally made, not only by inclusion, but also of exclusion of certain symptoms such as nausea, exacerbation by physical exercise and occurrence of both photophobia and
  • compounds and compositions of this disclosure are useful in the treatment or prevention of migraines; tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; or tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.
  • Migraine is described as a paroxysmal disorder or a recurrent, incapacitating, neurovascular disorder characterized by unilateral and throbbing headaches associated characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia.
  • Migraine affects people of all races and both sexes with women accounting for 79% (61 % between 20 and 49 years of age) of physician visits for migraines and
  • migraine headache involves a) the cranial blood vessels, b) the trigeminal innervation of these vessels, and c) the reflex connection of the trigeminovascular system in the cranial parasympathetic outflow.
  • Migraine pathophysiology is believed by genetic predisposition to involve leakage of ion channels in the brain stem such that the decreased blood flow in the brain leads to neuropeptide release from trigeminal nerves inducing dilatation of cranial
  • Phantom pain is pain coming from a body part that's no longer there. This pain originates in the spinal cord and brain and may be described as shooting, stabbing, boring, squeezing, throbbing or burning. Cramps or cramping
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of cramps or cramping.
  • Cramps are unpleasant, sometimes painful sensations caused by involuntary muscle contraction or muscle over-shortening. Cramps can be symptoms of muscle spasm and can be separated into smooth muscle cramps and skeletal muscle cramps.
  • Cramps related to internal (or visceral) organs are related to spasm of smooth muscle or skeletal muscle or distension of organs by functional or pathological disorders, and can be associated with visceral pain.
  • Smooth muscle cramps are commonly associated with menstruation or visceral disorders including gastrointestinal and urinary disorders. In the female, smooth muscle cramps that are associated with menstruation are called menstrual cramps and may also occur before and during a female menstrual cycle.
  • Severe or persistent smooth muscle cramps may also be symptomatic of endometriosis or other health problems.
  • smooth muscle cramps can be associated with gastrointestinal disorders, including infectious or autoimmune gastroenteritis and functional disorders such as irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • Skeletal muscle cramps are associated with muscle fatigue, low sodium, low potassium and certain drugs, including statins. Skeletal muscle cramps also include nocturnal leg cramps which are involuntary muscle contractions that occur during the night or (less commonly) while resting. Nocturnal leg cramps are common in the elderly, teenagers or in women during the late stages of pregnancy, and can vary in intensity from mild to extremely painful.
  • Menopause is an event that typically occurs in women that can be defined as the permanent cessation of the primary functions of the ovaries and is functionally evident when there is a termination of periodic shedding of the uterine lining (known as menses).
  • Hot flashes also known as night sweats if they happen at night
  • Hot flashes are a symptom which may have several other causes, but which is often caused by the changing hormone levels that are characteristic of menopause.
  • Cognitive disorders are a category of mental health disorders that primarily affect learning, memory, perception, and problem solving, and include amnesia, dementia, and delirium. Causes vary between the different types of disorders but most include damage to the memory portions of the brain.
  • Mild cognitive impairment also known as incipient dementia, or isolated memory impairment
  • MCI can be a transitional stage between normal aging and dementia.
  • Alzheimer's disease is the most common form of dementia.
  • AD Alzheimer's disease
  • TBI Traumatic brain injury
  • TBI traumatic brain injury
  • TBI is also known as intracranial injury, occurs when an external force traumatically injures the brain.
  • TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area).
  • Head injury usually refers to TBI, but is a broader category because it can involve damage to structures other than the brain, such as the scalp and skull.
  • Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue.
  • Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, certain drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, ' and some naturally occurring substances.
  • Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems, and sexual dysfunction.
  • depression clinical depression, major depression, unipolar depression, unipolar disorder, or recurrent depression in the case of repeated episodes is a psychiatric diagnosis for a mood disorder characterized by episodes of all encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities (anhedonia) and disturbed sleep (typically early morning awakening).
  • depression is ambiguous and can be used to describe manic-depressive disorder, but is also used to describe other mood disorders or to lower mood states lacking clinical significance.
  • endogenous depression or the depressed phases of bipolar disorder can be associated with widespread pain or regional pain disorders.
  • Pain experienced during depression can include, but is not limited to, psychogenic pain, psychiatric pain, psychic pain, and psychological pain.
  • Psychogenic pain is pain that results from psychological mechanisms including traumatic experiences, empathic reactions or somatization. For example, loss of a loved friend or relative by death or other separation can result in widespread pain, regional pain, and other symptoms including reactive depression.
  • Psychiatric pain is pain that results from conditions that are believed to have biological causes. Psychic pain and psychological pain are caused by a non-physical origin and can lead to emotional suffering and mental agony.
  • Schizophrenia is a psychiatric diagnosis for a thought disorder characterized by a breakdown of thought processes and by a deficit of typical emotional responses.
  • Anxiety disorder is a blanket term covering several different forms of a type of common psychiatric disorder characterized by excessive rumination, worrying, uneasiness, apprehension, and fear about future uncertainties either based on real or imagined events, which may affect both physical and psychological health.
  • the compounds and compositions of this disclosure are useful in the treatment and prevention of the symptoms of anxiety.
  • the anxiety is associated with white coat syndrome. Patients with white coat syndrome feel anxiety in a medical environment, which can lead to elevated blood pressure.
  • the compounds or compositions of this disclosure are useful in the treatment of anxiety and tension associated with dementias such as Alzheimer's disease.
  • Epilepsy The compounds and compositions of this disclosure are useful in the treatment and prevention of epilepsy.
  • Epilepsy is a common and diverse set of chronic neurological disorders characterized by seizures. In many cases a cause cannot be identified;
  • Stress disorders are an increasingly recognized group of conditions relating to the body's reaction to stressful circumstances and in some cases to decompensated reactions.
  • the compounds and compositions of this disclosure are useful in the treatment and prevention of stress disorders. Excess sweating
  • Hyperhidrosis or excess sweating
  • Hands, feet, armpits, and the groin area are among the most active regions of perspiration due to the relatively high concentration of sweat glands.
  • Generalized or secondary hyperhidrosis usually involves the body as a whole and is the result of an underlying condition.
  • Hyperhidrosis can also be classified depending by onset, either congenital or acquired. Primary or focal hyperhidrosis must be distinguished from secondary hyperhidrosis, which can start at any point in life. The later form may be due to a disorder of the thyroid or pituitary glands, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. Hyperhidrosis may also be divided into palmoplanar (symptomatic sweating of primarily the hands or feet), gustatory and generalized hyperhidrosis.
  • compositions of this disclosure are useful in the treatment and prevention of symptoms of drug withdrawal.
  • Opioid analgesics are a class of analgesic agents with morphine-like actions.
  • Synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; and benzomorphans. These compounds have pharmacologically diverse activities. Some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g. codeine); still others exhibit mixed agonist-antagonist activity (e.g. nalbuphine); and yet others are partial agonists (e.g. nalorphine). While opioids are inexpensive and effective, serious and potentially life-threatening side effects occur with their use, most notably respiratory depression and muscle rigidity. In addition, the doses of opioids which can be administered are limited by nausea, emesis, constipation, pruritis and urinary retention, often resulting in patients electing to receive suboptimal pain control rather than suffer these distressing side-effects.
  • the compounds and compositions of this disclosure are useful in the treatment and prevention of side effects associated with opioid administration or treatment. Headaches from mild to moderate hypertension and mild to moderate essential hypertension
  • High blood pressure is a common condition in which the force of the blood against the artery walls is high enough that it may eventually cause health problems, such as heart disease.
  • Hypertension puts strain on the heart, possibly leading to hypertensive heart disease and coronary artery disease, and it is a major risk factor for stroke, aneurysms of the arteries, peripheral arterial disease, and chronic kidney disease. Symptoms of hypertension include dull headaches and dizzy spells.
  • the compounds and compositions of this disclosure are useful in treatment to help prevent the immune system from rejecting a new organ after an organ transplant.
  • Allodynia The compounds and compositions of this disclosure are useful in the treatment or prevention of allodynia. Allodynia, or pain due to a stimulus that does not usually provoke pain, is a prominent symptom in patients with neuropathic pain. Allodynia is seen in various peripheral neuropathies and central pain disorders, and affects 15— 50% of patients with neuropathic pain. Allodynia is classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation.
  • the sensory modality touch, pressure, pinprick, cold, and heat
  • Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Research indicates that fibromyalgia amplifies painful sensations by affecting the way the brain processes pain signals. Symptoms of fibromyalgia sometimes begin after a physical trauma, surgery, infection, or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event. Symptoms include: widespread pain on both sides of the body and above and below the waist, fatigue, cognitive difficulties, depression, headaches, and pain or cramping in the lower abdomen. The compounds and compositions of this disclosure are useful in the treatment or prevention of fibromyalgia.
  • Fibromyalgia-ness is the tendency to respond to illness and psychosocial stress with fatigue and widespread pain.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of fibromyalgia-ness.
  • Central or chronic sensitization is a condition of the nervous system that is associated with the development and maintenance of chronic pain.
  • the nervous system goes through a process called "wind-up" and gets regulated in a persistent state of high reactivity. This persistent, or regulated, state of reactivity subsequently comes to maintain pain even after the initial injury might be healed.
  • Allodynia occurs when a person experiences pain with things that are normally not painful. Hyperalgesia occurs when an actual painful stimulus is perceived as more painful than it should. With allodynia and hyperalgesia, the sensation of pain travels through the nervous system, which is in a persistent state of high reactivity, and the pain is registered in the brain as a heightened level of pain. Centralization
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of centralization.
  • the pathogenesis of fibromyalgia is believed to involve sensitization of the central nervous system (CNS) to perceiving painful stimuli, which is termed “central sensitization” or “centralization”.
  • Centralization leads to the perception of widespread pain. Pain of this type is termed, “central neuropathic pain” or “central pain”.
  • Centralization also leads and to other symptoms, including visceral pain such as irritable bowel, tension-type headache, and migraine.
  • Regional pain syndrome The compounds and compositions of this disclosure are useful in the treatment or prevention of regional pain syndrome.
  • Regional pain syndrome or complex regional pain syndrome (CRPS) is a chronic pain condition most often affecting one of the limbs (arms, legs, hands, or feet), usually after an injury or trauma to that limb.
  • CRPS is believed to be caused by damage to, or malfunction of, the peripheral and central nervous systems.
  • CRPS is characterized by prolonged or excessive pain and mild or dramatic changes in skin color, temperature, and/or swelling in the affected area.
  • TJ Temporomandibular joint syndrome
  • TMJ disorders can cause pain in the jaw joint and in the muscles that control jaw movement. Signs and symptoms of TMJ disorders may include: pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing. Lower back pain
  • Lower back pain may be dull or sharp pain in the lower back.
  • the pain may be in one small area or over a broad area and may include muscle spasms.
  • Lower back pain may be caused by overuse, strain, or injury; aging; a herniated disc; arthritis;
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of lower back pain.
  • Interstitial cystitis is a chronic condition in which one experiences bladder pressure, bladder pain, and sometimes pelvic pain, ranging from mild discomfort to severe pain.
  • Interstitial cystitis signs and symptoms include: pain in the pelvis or between the vagina and anus in women or between the scrotum and anus in men (perineum);
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of interstitial cystitis.
  • a prominent condition affecting Gulf War Veterans is a cluster of medically unexplained chronic symptoms that can include fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of Gulf War syndrome.
  • Visceral pain The compounds and compositions of this disclosure are useful in the treatment or prevention of visceral pain.
  • Visceral pain is caused by the activation of pain receptors in the chest, abdomen, or pelvic areas.
  • Visceral pain is caused by problems with internal organs, such as the stomach, kidney, gallbladder, urinary bladder, and intestines. These problems include distension, perforation, inflammation, and impaction or constipation, which can cause associated symptoms, such as nausea, fever, malaise, and pain.
  • Visceral pain is also caused by problems with abdominal muscles and the abdominal wall, such as spasm. Visceral pain is vague and not well localized and is usually described as pressure-like, deep squeezing, dull, or diffuse.
  • Kidney stones form in the kidney and as they travel through the tubes of the urinary tract their movement may cause: sudden, severe pain that gets worse in waves; intense pain in the back, side, abdomen, groin, or genitals; nausea and vomiting; blood in the urine (hematuria); and frequent and painful urination.
  • the compounds and compositions of this disclosure are useful in the treatment of kidney stones.
  • Gout The compounds and compositions of this disclosure are useful in the treatment of gout. Gout occurs when urate crystals accumulate in joints, causing inflammation and intense pain. The signs and symptoms of gout almost always occur suddenly and include: intense joint pain, inflammation and redness, and decreased joint mobility.
  • Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured, and these damaged nerve fibers send incorrect signals to other pain centers. The impact of a nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury.
  • the compounds and compositions of this disclosure are useful to treat or prevent neuropathic pain.
  • Post-herpetic neuralgia is a complication of shingles, which is caused by the chickenpox (herpes zoster) virus.
  • Post-herpetic neuralgia affects the nerve fibers and skin, and the burning pain associated with postherpetic neuralgia can be severe enough to interfere with sleep and appetite.
  • the signs and symptoms of post-herpetic neuralgia are generally limited to the area of the skin where the shingles outbreak first occurred, and may include: pain, sensitivity to light touch, itching and numbness, and weakness or paralysis. Diabetic neuropathy
  • Diabetic neuropathy is a type of nerve damage that can occur with diabetes. Diabetic neuropathy most often damages nerves in the legs and feet. Symptoms of diabetic neuropathy can range from pain and numbness in the extremities, extreme sensitivity to touch, muscle weakness and difficulty walking, and serious foot problems to problems with the digestive system, urinary tract, blood vessels, and heart. The compounds and compositions of this disclosure are useful in the treatment or prevention of diabetic neuropathy.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of sickle cell pain.
  • Sickle cell disease causes red blood cells to form into a crescent shape, like a sickle.
  • the sickle-shaped red blood cells break apart easily, causing anemia, and the damaged sickle red blood cells clump together and stick to the walls of blood vessels, blocking blood flow. This can cause severe pain and permanent damage to the brain, heart, lungs, kidneys, liver, bones, and spleen.
  • Priapism is a prolonged erection of the penis.
  • the unwanted, persistent erection is not caused by sexual stimulation or arousal, and priapism is usually painful.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of priapism.
  • Nociceptive pain is caused when special nerve endings— called nociceptors— are irritated.
  • Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. The pain is typically well localized, constant, and often with an aching or throbbing quality.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of nociceptive pain.
  • Post-operative pain is pain that occurs after an operation.
  • the compounds and compositions of this disclosure are useful in the treatment or prevention of postoperative pain.
  • Orthopedic injuries are conditions involving the musculoskeletal system, and can include musculoskeletal trauma, sports injuries, degenerative diseases, or infections. Pain caused by orthopedic injury may be treated or prevented by the compounds and compositions of this disclosure.
  • a bunion is an enlargement of the joint at the base of the big toe, and is comprised of bone and soft tissue.
  • the pain of a bunion can make walking and other activities extremely difficult, leading to the need for bunionectomy, a surgical procedure to excise a bunion.
  • the compounds and compositions of this disclosure are useful in the treatment before, during, or after bunionectomy.
  • Dental extraction A dental extraction means having a tooth removed, usually because of disease, trauma, or crowding.
  • the compounds and compositions of this disclosure are useful in the treatment before, during, or after dental extraction.
  • the co npounds and compositions of this disclosure are useful in the treatment to alleviate pain associated with spinal cord injury.
  • Osteoarthritis is the most common form of arthritis, affecting millions of people worldwide. It occurs when the protective cartilage on the ends of the bones wears down over time. Symptoms include: pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone spurs.
  • the compounds and compositions of this disclosure are useful in the treatment of osteoarthritis.
  • Rheumatoid arthritis is a chronic inflammatory disorder that typically affects the small joints in the hands and feet. Rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity.
  • An autoimmune disorder, rheumatoid arthritis occurs when the immune system mistakenly attacks the body's own tissues. In addition to causing joint problems, rheumatoid arthritis sometimes can affect other organs of the body—such as the skin, eyes, lungs, and blood vessels. Signs and symptoms of rheumatoid arthritis may include: tender, warm, swollen joints; morning stiffness; rheumatoid nodules; and fatigue, fever, and weight loss.
  • Lyme disease is the most common tick-borne illness in North America and Europe. Lyme disease is caused by the bacterium Borrelia burgdorferi, and deer ticks, which feed on the blood of animals and humans, can harbor the bacteria and spread it when feeding. Signs and symptoms of Lyme disease include: joint pain and neurological problems.
  • the compounds and compositions of this disclosure are useful in the treatment of Lyme disease. Parkinson 's disease
  • Parkinson's disease is a neurodegenerative disorder of the central nervous system caused by the death of dopaminergic neurons in the substania nigra. Symptoms of Parkinson's disease may include tremor, bradykinesia, rigid muscles, impaired posture and balance, speech changes, and loss of automatic movements.
  • Cancer pain can result from the cancer itself as the cancer grows into or destroys nearby tissues. As a tumor grows, it may put pressure on nerves, bones or organs, causing pain. Cancer pain may also not just be from the physical effect of the cancer on a region of the body, but also due to chemicals that the cancer may release in the region of the tumor.
  • Cancer treatments such as chemotherapy, radiation and surgery, are another potential source of cancer pain.
  • Surgery can be painful, radiation may leave behind a burning sensation or painful scars, and chemotherapy can cause many potentially painful side effects, including mouth sores, diarrhea and nerve damage.
  • PTSD post-traumatic stress disorder
  • PTSD is a mental health condition that's triggered by a cosmic event— either experiencing it or witnessing it. Symptoms may include chronic pain, flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.
  • treatment generally mean obtaining a desired pharmacologic and/or physiologic effect.
  • Treating a condition or disease refers to curing as well as ameliorating at least one symptom of the condition or disease, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject in need relative to a subject which does not receive the composition.
  • Treatment may also be use of any of the compounds and compositions described herein as an analgesic.
  • “treatment” may be use of the compounds and compositions described herein to modulate an imidazoline-1 (Ii) receptor in a patient in need thereof.
  • treatment may be use of the compounds and compositions of this disclosure to modulate the I
  • treatment may be use of the compounds and compositions of this disclosure to activate the I
  • treatment may be use of the compounds and compositions of this disclosure to reduce pain through a pathway that is independent of the I
  • ibuprofen ibuprofen
  • naprosyn a cyclooxygenase-2 inhibitor
  • aspirin caffeine, dichloralphenazone, a triptan
  • a chemotherapeutic drug an antidepressant
  • SNR1 serotonin-norepinephrine reuptake inhibitor
  • an antiproliferative agent an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood , disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates to inhibit nitric oxidase in a patient in need thereof.
  • treatment of a migraine headache may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with migraine headache (or combination thereof): pain on one side or both sides of the head, sensitivity to light and sounds, nausea and vomiting, blurred vision, allodynia, and lightheadness.
  • Treatment of pain may include, but is not limited to, a reduction in the pain experienced by the patient.
  • Treatment of fibromyalgia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with fibromyalgia (or combination thereof): widespread pain, fatigue, and cognitive difficulties (e.g., impaired ability to focus).
  • Treatment of an inflammatory disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with an inflammatory disease or disorder (or combination thereof): pain, tension, redness, soreness, and irritation.
  • Treatment of an allergic disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with an allergic disease or disorder (or combination thereof): asthma (extrinsic or intrinsic), asthma related sequelae including small and large airway hyperactivity, bronanaphylaxis, aspirin induced asthma, allergic airway inflammation, urticaria, and atopic dermatitis.
  • “Treatment” of a metabolic disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a metabolic disease or disorder (or combination thereof): discomfort, pain, and inflammation.
  • “Treatment” of a cardiovascular disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a cardiovascular disease or disorder (or combination thereof): chest pain; shortness of breath; pain, numbness, weakness, or coldness in the arms or legs; and pain in the neck, jaw, throat, upper abdomen, or back.
  • “Treatment" of a neurogenic vascular disease or a painful condition associated therewith may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a neurogenic vascular disease or a painful condition associated therewith (or combination thereof): leg pain, leg weakness, tingling, fatigue, a sensation of heaviness, and weakness.
  • “Treatment” of a headache or an episodic tension-type headache may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a headache or an episodic tension- type headache (or combination thereof): sharp pain, throbbing sensation, dull ache, and nausea.
  • “Treatment” of phantom limb pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with phantom limb pain (or combination thereof): shooting, stabbing, or squeezing pain coming from the body part that is no longer there.
  • “Treatment” of cramping may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with cramping (or combination thereof): skeletal muscle cramps, smooth muscle cramps, and muscle spasms.
  • “Treatment” of a headache from mild to moderate hypertension and mild to moderate essential hypertension may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a headache from mild to moderate hypertension and mild to moderate essential hypertension (or combination thereof): high blood pressure, dull headaches, and dizzy spells.
  • “Treatment” of a cognitive disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a cognitive disorder (or combination thereof): amnesia, dementia, delirium, confusion, irritability and aggression, mood swings, trouble with language, anxiety and tension, and long-term memory loss.
  • “Treatment” of organ transplant rejection may include, but is not limited to, an improvement in the body's acceptance of the organ.
  • Treatment of hot and cold flashes may include, but is not limited to, an
  • TBI traumatic brain injury
  • neurotoxicity may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with neurotoxicity (or combination thereof): limb weakness or numbness; loss of memory, vision, and/or intellect; uncontrollable obsessive and/or compulsive behaviors; delusions; headache; cognitive and behavioral problems; and sexual dysfunction.
  • depression may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with depression (or combination thereof):
  • Treatment of psychic or psychological pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with psychic or psychological pain (or combination thereof): emotional suffering and mental agony.
  • Treatment of psychiatric pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with psychiatric pain (or combination thereof): widespread pain and regional pain.
  • “Treatment” of schizophrenia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with schizophrenia (or combination thereof): hallucinations, delusions, depression, and social withdrawal.
  • “Treatment” of anxiety may include, but is not limited to, an improvement in any of the following. symptoms or conditions associated with anxiety (or combination thereof): heart palpitations or chest pain, trouble breathing, hot flashes or chills, and surge of overwhelming panic.
  • “Treatment” of epilepsy may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with epilepsy (or combination thereof): seizures, violent shaking, tingling, and loss of alertness.
  • “Treatment” of a stress disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a stress disorder (or combination thereof)'- depression, anxiety, headaches, pain, and nausea.
  • “Treatment” of excess sweating may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with excess sweating (or combination thereof): sweating and wetness.
  • “Treatment” of a symptom related to drug withdrawal may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to drug withdrawal (or combination thereof): anxiety, sweating, vomiting, diarrhea, irritability, fatigue, shaking, sweating, nausea, insomnia, headache, and difficulty concentrating.
  • Treatment of allodynia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to allodynia (or combination thereof): pain due to a stimulus that does not usually provoke pain.
  • Treatment of fibromyalgia-ness may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to fibromyalgia-ness (or combination thereof): fatigue and widespread pain.
  • Treatment of central sensitization may include, but is not limited to, an
  • Treatment of centralization may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a . symptom related to centralization (or combination thereof): irritable bowel, tension- type headache, and migraine.
  • Treatment of regional pain syndrome may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to regional pain syndrome (or combination thereof): swelling and pain in the arms, legs, hands, or feet.
  • TMJ temporomandibular joint syndrome
  • TMJ temporomandibular joint syndrome
  • “Treatment” of temporomandibular joint syndrome” may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to TMJ (or combination thereof): pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing.
  • “Treatment” of lower back pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to lower back pain (or combination thereof): pain in the lower back and muscles spasms in the lower back.
  • Treatment of interstitial cystitis may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to interstitial cystitis (or combination thereof): chronic pelvic pain; a persistent, urgent need to urinate; frequent urination, often of small amounts, throughout the day and night; pain or discomfort while the bladder fills and relief after urinating; and pain during sexual intercourse.
  • Treatment of Gulf War syndrome may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to interstitial cystitis (or combination thereof): chronic pelvic pain; a persistent, urgent need to urinate; frequent urination, often of small amounts, throughout the day and night; pain or discomfort while the bladder fills and relief after urinating; and pain during sexual intercourse.
  • “Treatment” of Gulf War syndrome may include, but is not limited to, an
  • “Treatment” of visceral pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to visceral pain (or combination thereof): pressure-like, deep squeezing, dull, or diffuse pain in the chest, abdomen, or pelvic areas.
  • “Treatment” of kidney stones may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to kidney stones (or combination thereof): intense pain in the back, side, abdomen, groin, or genitals, and nausea and vomiting.
  • Treatment of gout may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to gout (or combination thereof): intense joint pain, inflammation, and redness, and decreased joint mobility.
  • Treatment of neuropathic pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to neuropathic pain (or combination thereof): shooting and burning pain, tingling, and numbness.
  • “Treatment” of postherpetic neuralgia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to post-herpetic neuralgia (or combination thereof): pain, sensitivity to light touch, itching and numbness, and weakness or paralysis.
  • “Treatment” of diabetic neuropathy may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to diabetic neuropathy (or combination thereof): pain and numbness in the extremities, extreme sensitivity to touch, muscle weakness, and difficulty walking.
  • “Treatment” of sickle cell pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to sickle cell pain (or combination thereof): pain in the chest, abdomen, joints, and bones.
  • “Treatment” of priapism may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to priapism (or combination thereof): unwanted, persistent and painful erection.
  • “Treatment” of nociceptive pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to nociceptive pain (or combination thereof): aching or throbbing pain.
  • Treatment of post-operative pain may include, but is not - limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to post-operative pain (or combination thereof): pain, swelling, and irritation after an operation.
  • Treatment of orthopedic injury pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to orthopedic injury pain (or combination thereof): pain, swelling, and irritation after an orthopedic injury.
  • “Treatment” of bunionectomy may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to bunionectomy (or combination thereof): pain, swelling, and irritation after a bunionectomy.
  • “Treatment” of dental extraction may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to dental extraction (or combination thereof): pain, swelling, and irritation after a dental extraction.
  • “Treatment” of pain after severed spinal cord injury may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to pain after severed spinal cord injury (or combination thereof): pain and irritation after severed spinal cord injury.
  • “Treatment” of osteoarthritis may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to osteoarthritis (or combination thereof): pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone spurs.
  • “Treatment” of rheumatoid arthritis may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to rheumatoid arthritis (or combination thereof): tender, warm, swollen joints; morning “stiffness; rheumatoid nodules; and fatigue, fever and weight loss.
  • “Treatment” of Lyme disease may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to Lyme disease (or combination thereof): joint pain and neurological problems.
  • “Treatment” of Parkinson's disease may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to Parkinson's disease (or combination thereof): tremor and muscle rigidity.
  • “Treatment” of pain associated with cancer may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with cancer (or combination thereof): chronic pain, pain from nerve damage, and burning sensation.
  • “Treatment” of pain associated with post-traumatic stress disorder (PTSD) may include, but is not limited to, an PTSD.
  • PTSD post-traumatic stress disorder
  • Symptoms are not limited to those listed herein and other symptoms may also be monitored in order to determine the effectiveness of treatment.
  • the population of subjects treated by the method of this disclosure includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease.
  • administering any of the compounds and compositions described herein may have any one or more of the following effects: analgesia; alleviation of widespread pain; decrease in pain from headaches, tension-type headaches, and migraines; reduction in depression, seizures, convulsions, and fatigue; decrease in inflammation, pain, tension, redness, soreness, and irritation; relief from asthma, atopic dermatitis, chest pain, shortness of breath, and numbness; lowered blood pressure; decreased cramping; reduction of leg pain, leg weakness, tingling, fatigue, and weakness; improvement in amnesia, dementia, delirium, confusion, irritability and aggression, mood swings, trouble with language, and long-term memory loss; reductions in hot and cold flashes and excessive sweating; reduced muscle rigidity associated with Parkinson's disease; and relief of pain associated with cancer, PTSD, rheumatoid arthritis, allodynia, kidney stones, gout, fibromyalgia, and fibromyal
  • preventing is art-recognized and includes stopping a disease, disorder, or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.
  • a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • the subject is a human.
  • a patient refers to a subject afflicted with a disease or disorder.
  • therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If treatment is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof)-
  • therapeutic agent drug
  • immediate release drug drug
  • bioactive substance include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or
  • agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.
  • terapéuticaally effective dose refers to a dose that produces the desired effect for which it is administered.
  • the exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical
  • any of the compounds and compositions of this disclosure are useful in combination with other therapeutics.
  • any of the compounds and compositions of this disclosure, or mixtures of them are useful as analgesics.
  • the compounds and compositions of this disclosure can be used in combination with other therapeutics to treat pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated therewith; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate

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Abstract

La présente invention concerne des composés et des compositions à utiliser en tant qu'analgésiques et pour le traitement de divers états pathologiques, tels que la douleur, les maux de tête, l'allodynie, et la fibromyalgie. L'invention concerne également des composés qui sont des ligands, et dans certains modes de réalisation, des modulateurs (par exemple, des agonistes), pour le récepteur aux imidazolines de type 1.
PCT/US2015/000153 2014-12-22 2015-12-22 Ligands du récepteur aux imidazolines de type 1 à utiliser en tant qu'agents thérapeutiques WO2016105448A1 (fr)

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