WO2004029031A2 - Therapeutic piperazine compounds - Google Patents

Therapeutic piperazine compounds Download PDF

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Publication number
WO2004029031A2
WO2004029031A2 PCT/US2003/030185 US0330185W WO2004029031A2 WO 2004029031 A2 WO2004029031 A2 WO 2004029031A2 US 0330185 W US0330185 W US 0330185W WO 2004029031 A2 WO2004029031 A2 WO 2004029031A2
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WIPO (PCT)
Prior art keywords
compound
halo
phenyl
alkyl
substituted
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PCT/US2003/030185
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English (en)
French (fr)
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WO2004029031A3 (en
Inventor
Qun Sun
Xiaoming Zhou
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Euro-Celtque, S.A.
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Priority to CA2500113A priority Critical patent/CA2500113C/en
Priority to JP2004539882A priority patent/JP4560610B2/ja
Priority to DE60312544T priority patent/DE60312544T2/de
Priority to EP03754883A priority patent/EP1562936B1/en
Priority to SI200330815T priority patent/SI1562936T1/sl
Priority to NZ539205A priority patent/NZ539205A/en
Priority to MXPA05003302A priority patent/MXPA05003302A/es
Priority to BR0314699-5A priority patent/BR0314699A/pt
Application filed by Euro-Celtque, S.A. filed Critical Euro-Celtque, S.A.
Priority to DK03754883T priority patent/DK1562936T3/da
Priority to AU2003272685A priority patent/AU2003272685A1/en
Publication of WO2004029031A2 publication Critical patent/WO2004029031A2/en
Publication of WO2004029031A3 publication Critical patent/WO2004029031A3/en
Priority to HK06102046A priority patent/HK1083216A1/xx
Priority to CY20071100730T priority patent/CY1106634T1/el

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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to Hydroxyiminopiperazine Compounds, compositions comprising an effective amount of a Hydroxyiminopiperazine Compound and methods for treating or preventing a Condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Hydroxyiminopiperazine Compound.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K.M. Foley, Pain, in Cecil Textbook of Medicine 100-107 (J.C. Bennett and F. Plum eds., 20th ed. 1996)).
  • Urinary incontinence is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large.
  • UI afflicts 15- 30% of elderly people living at home, one-third of those living in acute-care settings, and at least one-half of those living in long-term care institutions (R.M. Resnick, Lancet 346:94 (1995)). Persons having UI are predisposed to also having urinary-tract infections, pressure ulcers, perineal rashes and urosepsis. Psychosocially, UI is associated with embarrassment, social stigmatization, depression and a risk of institutionalization (Herzo et al, Annu. Rev. Gerontol. Geriatr. 9:74 (1989)).
  • UI acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle.
  • Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity.
  • anticholinergics such as propantheline bromide and glycopyrrolate
  • smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic
  • Ulcers develop as a result of an imbalance between acid-secretory factors, also known as "aggressive factors,” such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosal-protective factors, such as secretion of bicarbonate, mucus, and prostaglandins.
  • acid-secretory factors also known as "aggressive factors”
  • gastrosin such as stomach acid, pepsin, and Helicobacter pylori infection
  • local mucosal-protective factors such as secretion of bicarbonate, mucus, and prostaglandins.
  • Antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.
  • H 2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine are also used to treat ulcers. H 2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H 2 agonists in the stomach and duodenum. H 2 antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.
  • H + , K + - ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers.
  • H + , K + - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid.
  • Side effects associated with FT, K - ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness- somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.
  • Sucraflate is also used to treat ulcers.
  • Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing.
  • Sucraflate can cause constipation, dry mouth, and interfere with the absorption of other drugs.
  • Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer. Often antibiotic therapy is coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate. The bismuth compounds are believed to enhance secretion of mucous and HCO " , inhibit pepsin activity, and act as an antibacterial against H. pylori. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi +3 and can interfere with the absorption of other drugs.
  • Prostaglandin analogues such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients.
  • Carbenoxolone a mineral corticoid
  • Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier.
  • Carbenoxolone can lead to Na + and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance.
  • Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers. Side effects of muscarinic cholinergic antagonists include dry mouth, blurred vision, and constipation.
  • the Merck Manual of Medical Information 496-500 (R. Berkow ed., 1997) and Goodman and Gilman 's The Pharmacological Basis of Therapeutics 901-915 (J. Hardman and L. Limbird eds., 9 th ed. 1996).
  • IBD Inflammatory-bowel disease
  • Crohn's disease which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract. Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss.
  • Crohn's disease Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses.
  • the risk of cancer of the large intestine is increased in people who have Crohn's disease.
  • Crohn's disease is associated with other disorders such as gallstones, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primary sclerosing cholangitis.
  • Crohn's disease There is no known cure for Crohn's disease.
  • antibiotics are often administered to treat the symptoms of Crohn's disease.
  • the antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus.
  • Long-term use of metronidazole can damage nerves, resulting in pins-and-needles sensations in the arms and legs.
  • Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flare-ups.
  • Corticosteroids such as prednisone, reduce fever and diarrhea and relieve abdominal pain and tenderness.
  • Ulcerative colitis is a chronic d sease n whic the large intestine becomes inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30, however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine.
  • IBS Irritable-bowel syndrome
  • IBS intracranial pressure
  • spastic-colon type is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen. The person suffering from spastic- colon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating.
  • the second type of IBS usually produces painless diarrhea or constipation. The diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening.
  • IBS IBS-patient's diet
  • an IBS patient avoid beans, cabbage, sorbitol, and fructose.
  • a low-fat, high-fiber diet can also help some IBS patients.
  • Regular physical activity can also help keep the gastrointestinal tract functioning properly.
  • Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS.
  • Antidiarrheal drugs such as diphenoxylate and loperamide, help with diarrhea. Tfie Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).
  • U.S. Patent No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms.
  • U.S. Patent No. 5,574,052 to Rose et al. discloses co- administration of an addictive substance with an antagonist to partially block the pharmacological effects of the substance.
  • U.S. Patent No. 5,075,341 to Mendelson et al sc oses t e use o a m xe op ate agon st antagonist to trea cocaine and opiate addiction.
  • U.S. Patents No. 5,039,680 and 5,198,459 to Imperato et al disclose using a serotonin antagonist to treat chemical addiction.
  • U.S. Patent No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual.
  • U.S. Patent. No. 5,762,925 to Sagan discloses implanting encapsulated adrenal medullary cells into an animal's central nervous system to inhibit the development of opioid intolerance.
  • Parkinson's disease is a clinical syndrome comprising bradykinesia (slowness and poverty of movement), muscular rigidity, resting tremor (which usually abates during voluntary movement), and an impairment of postural balance leading to disturbance of gait and falling.
  • Parkinson's disease a loss of pigmented, dopaminergic neurons of the substantia nigra pars compacta and the appearance of intracellular inclusions known as Lewy bodies (Goodman and Gillman 's The Pharmaceutical Basis of Therapeutics 506 (9 th ed. 1996)). Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride.
  • Anxiety is a fear, apprehension, or dread of impending danger often accompanied by restlessness, tension, tachycardia, and dyspnea.
  • benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety.
  • the azapirones such as buspirone, are also used to treat moderate anxiety.
  • Epilepsy is a disorder characterized by the tendency to have recurring seizures.
  • drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, 7-vinyl GABA, acetazolamide, and felbamate.
  • Anti-seizure drugs can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens- Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia.
  • a stroke or cerebro vascular accident is the death of brain tissue (cerebral infarction) resulting from the lack of blood flow and insufficient oxygen to the brain.
  • a stroke can be either ischemic or hemorrhagic.
  • drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids.
  • the Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997). Pruritus is an unpleasant sensation that prompts scratching.
  • Pruritus can be attributed to dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, and fiberglass dermatitis.
  • pruritus is treated by phototherapy with ultraviolet B or PUNA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.
  • mGluR5 metabotropic glutamate receptor 5
  • the present invention encompasses compounds having the formula (I):
  • Ri is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 2 is independently:
  • R 4 is -H, -(C ⁇ -C 10 )alkyl, -C(O)R 9 , or -C(O)NHR 9 ;
  • each R 7 and R 8 is independently -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each Rio is independently -H, -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 - C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo) 3 , -CH(halo) 2 , -CH(halo) 3 , -CH(halo) 2 , or -CH 2 (
  • the present invention encompasses compounds having the formula (II):
  • Ri is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(haio) 3 , - H halo 2 , or -CH 2 (halo); each R is independently:
  • R A is -H, -(C ⁇ -C ⁇ 0 )alkyl, -C(O)R 9 , or -C(O)NHR 9 ;
  • R 5 is -H or -(C 1 -C ⁇ o)alkyl;
  • Re is:
  • each halo is independently -F, -CI, -Br, or -I; p is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
  • the present invention also encompasses compounds having the formula (III):
  • R ! is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 2 is independently:
  • R4 is -H, -(C ⁇ -C ⁇ o)alkyl, -C(O)R 9 , or -C(O)NHR 9 ;
  • R 5 is -H or -(d-C 10 )alkyl;
  • R_ is:
  • the present invention also encompasses compounds having the formula (IN):
  • Ri is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 2 is independently:
  • H A is -H, -(C ⁇ -C ⁇ o)alkyl, -C(O)R 9 , or -C(O)NHR 9 ;
  • R 5 is -H or -(C ⁇ -C ⁇ o)alkyl;
  • R 6 is: (a) -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 - C 10 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 8 -Ci 4 )tricycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl,-(C 8 - C ⁇ 4 )bicycloalkenyl, -(C 8 -C ⁇ )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10- membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7 groups; or
  • the present invention also encompasses compounds having the formula (V):
  • Ri is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 3 is independently:
  • R4 is -H, -(C ⁇ -C 10 )alkyl, -C(O)R 9 , or -C(O)NHR 9 ;
  • R 5 is -H or -(C ⁇ -C ⁇ o)alkyl; Re is:
  • each R 7 and R 8 is independently -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each R 9 is -H, -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -
  • Ri is -H, -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 2 is independently: (a) -halo, -CN, -OH, NO 2 , -O(C ⁇ -C 6 )alkyl, or -NH 2 ;
  • R 4 is -H, -(d-C 10 )alkyl, -C(O)R 9 , or -C(O)NHR 9 ;
  • R 5 is -H or -(C 1 -C ⁇ o)alkyl; each R and R 8 is independently -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each R 9 is -H, -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -
  • each Rio is independently -H, -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -
  • each Rn and R ⁇ 2 is independently -(C ⁇ -C 6 )a ⁇ kyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each R 13 is independently -(C ⁇ -Ce)alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C - C )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo) 3 , - CH(halo) 2 , CH 2 (halo), or -halo; each halo is independently -F, ⁇ C1, -Br, or -I; s is an integer ranging from 0 to 4; o is an integer ranging from 0 to 4; q is an integer ranging from 0 to 6; r is an integer ranging from 0 to 5; t is an
  • Ri is -H, -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 2 is independently: (a) -halo, -CN, -OH, NO 2 , -O(C ⁇ -C 6 )alkyl, or -NH 2 ;
  • a compound of formula (I)-(VII) or a pnarmaceutically acceptable salt thereof is useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression (each being a "Condition") in an animal.
  • the invention also relates to compositions comprising an effective amount of a Hydroxyiminopiperazine Compound and a pharmaceutically acceptable carrier or excipient.
  • the compositions are useful for treating or preventing a Condition in an animal.
  • the invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Hydroxyiminopiperazine Compound.
  • the invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Hydroxyiminopiperazine Compound.
  • the mvention still further relates to methods for inhibiting Nanilloi Receptor 1 ("NRi") function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a Hydroxyiminopiperazine Compound.
  • the invention still further relates to methods for inhibiting n ⁇ G ⁇ uR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Hydroxyiminopiperazine Compound.
  • the invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 ("mGluRl") function in a cell, comprising contacting a cell capable of expressing mGluRl with an effective amount of a Hydroxyiminopiperazine Compound.
  • mGluRl metabotropic glutamate receptor 1
  • the invention still further relates to a method for preparing a composition, comprising the step of admixing a Hydroxyiminopiperazine Compound and a pharmaceutically acceptable carrier or excipient.
  • the invention still further relates to a kit comprising a container containing an effective amount of a Hydroxyiminopiperazine Compound.
  • n is 0. In another embodiment n is i.
  • n is 2.
  • n 3.
  • n is an integer ranging from 0 to 3.
  • n is 0. In another embodiment, m is 1.
  • n 2
  • Ri is -halo. hi another embodiment, Ri is -CI.
  • Ri is -Br. In another embodiment, Rj is -I.
  • i is -F.
  • Rj is -CH 3 .
  • Ri is -NO 2 .
  • i is -OH. In another embodiment, Ri is -OCH 3 .
  • Ri is -NH 2 .
  • Ri is -C(halo) 3 .
  • Ri is -CH(halo) 2 .
  • Ri is -CH 2 (halo).
  • n is 1 and R 2 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - C 6 )alkyl, or -NH 2 .
  • n is 1 and R 2 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - C 6 )alkyl, or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -
  • m is 1 and R 3 is a -(C ⁇ -C ⁇ o)alkyl.
  • m is 1
  • R 3 is a -(C ⁇ -C ⁇ o)alkyl
  • the carbon to which the R group is attached is in the (R)-configuration.
  • m is 1, R 3 is a and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • n is 1 and R 3 is methyl.
  • m is 1, R 3 is methyl, and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1, R 3 is methyl, and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • 1 ⁇ is -H.
  • R 4 is -(C ⁇ -C ⁇ o)alkyl.
  • I t is -C(O)R 9 .
  • R4 is -C(O)NHR 9 .
  • R5 is -H.
  • R 5 is -(C ⁇ -C ⁇ o)alkyl.
  • R 6 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -
  • Re is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(5- to 10- membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • Re is -phenyl
  • n and m are 0, Ri is -CH 3; R 4 is -H, R 5 is -H, and Re is -phenyl.
  • the Re-phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re •phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a /-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is an iso-propyl group substituted at the para-position of the R 6 -phenyl.
  • n and m are 0, Ri is -CF )
  • R 4 is -H
  • R 5 is -H
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is an t_O-propyl group substituted at the para-position of the Re -phenyl.
  • n and m are 0, Ri is -CI, R is -H, R 5 is -H, and R 6 is -phenyl.
  • the Rg -phenyl is substituted with a -(Ci-C ⁇ ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is an t-O-propyl group substituted at the para-position of the R 6 -phenyl.
  • n and m are 0, R] is -CH 3 , R 4 is -CH 3 , R 5 is -H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an t_*_>-propyl group substituted at the para-position of the R 6 -phenyl.
  • n and m are 0, Ri is -CF 3 , is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is an wro-propyl group substituted at the para-position of the Re -phenyl.
  • n and m are 0, Ri is -CI, R t is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(Ci-C ⁇ ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl. In another embodiment, the -(C ⁇ -C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the R -phenyl.
  • n 0, m is 1 , Ri is -CH 3 , R 3 is -CH 3j Rj is -H, R 5 is : -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(Ci-Ce) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para- position of the R -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the R 6 - ⁇ henyl.
  • the -(Ci- C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the R -phenyl.
  • n 0, m is 1, Ri is -CF , R is -CH 3 , R 4 is -H, R 5 is - H, and R is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C) -C 6 ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the e -phenyl.
  • the -(Ci- C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • n 0, m is 1, Ri is -CI, R 3 is -CH 3) R4 is -H, R 5 is - H, and Re is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the R -phenyl.
  • the -(Ci- C 6 ) alkyl group is an z_O-propyl group substituted at the para-position of the Re -phenyl.
  • n is 0, m is 1, i is -CH 3 , R 3 is -CH 3 , Rt is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(d- C 6 ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the Re -phenyl.
  • n 0, m is 1, i is -CF , R 3 is -CH 3> t is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(Ci- C 6 ) alkyl group.
  • the -(d-C 6 ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(d-C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(d- C 6 ) alkyl group is an zso-propyl group substituted at the para-position of the Re -phenyl.
  • n is 0, m is 1, i is -CI, R 3 is -CH 3 , t is -CH 3 , R_ is -H, and Re is -phenyl.
  • the R 6 -phenyl is substituted with a -(Ci-C ⁇ ) alkyl group.
  • the -(C]-C 6 ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R -phenyl.
  • the -(Ci- C 6 ) aikyl group is an z_*_>-propyl group substituted at the para-position of the Re -phenyl.
  • n and m are 0, Ri is -CH 3 , t is -H, R 5 is -H, and R is -phenyl substituted at its para-position with a -CF 3 .
  • n and m are 0, Ri is -CF 3 , 4 is -H, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • n and m are 0, Ri is -CI. t is -H, R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 . In another embodiment, n and m are 0, Ri is -CH 3 , t is -CH 3 , R 5 is -H, and
  • R 5 is -phenyl substituted at its para-position with a -CF 3 .
  • n and m are 0, Ri is -CF 3 , R 4 is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF .
  • n and m are 0, R is -CI, Rt is -CH 3 , R 5 is -H, and Ro is -phenyl substituted at its para-position with a -CF .
  • n 0, m is 1, i is -CH 3 , R 3 is -CH 3 , Rt is -H, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • n 0, m is 1, R t is -CF 3 , R 3 is -CH 3 , R 4 is -H, R 5 is - H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • n is 0, m is 1, Ri is -CI, R 3 is -CH 3 , R4 is -H, R 5 is - H, and R is -phenyl substituted at its para-position with a -CF 3 .
  • n 0, m is 1, Ri is -CH 3 , R 3 is -CH 3 , R t is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • n 0, m is 1, Ri is -CF 3 , R 3 is -CH 3 , R t is -CH 3 , R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • n is 0, m is 1, i is -CI, R 3 is -CH 3 , R t is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • the present invention also encompasses compounds of formula (II):
  • p is 0.
  • p is 1.
  • p is 2.
  • n is 0. In another embodiment, m is 1. i another embodiment, m is 2.
  • Ri is -halo
  • Ri is -CI.
  • Ri is -Br. In another embodiment, Ri is -I.
  • Ri is -F.
  • Ri is -CH 3 . In another embodiment, Ri is -NO .
  • Ri is -OH.
  • Ri is -OCH 3 .
  • Ri is -NH 2 . In another embodiment, Ri is -C(halo) 3 .
  • R ⁇ is -CH(halo) 2 .
  • Ri is -CH 2 (halo).
  • p is 1 and R 2 is -halo, -CN, -OH, NO 2 , -O(d- C 6 )alkyl, or -NH 2 .
  • p is 1 and R 2 is -(d-C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -
  • R 2 is -phenyl, -naphthyl, -(Ci 4 )aryl. or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - C 6 )aUcyl, or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C 1 o)alkenyl, -
  • m is 1 and R 3 is a -(C ⁇ -C ⁇ o)alkyl.
  • m is 1, R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1, R is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • m is 1 and R 3 is -CH 3 . In another embodiment, m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • Rt is -H.
  • Rt is -(C ⁇ -C ⁇ o)alkyl.
  • Rt is -C(O)R 9 .
  • R is -C(O)NHR 9 .
  • R 5 is -H. In another embodiment, R 5 is -(C ⁇ -C ⁇ o)alkyl.
  • R 6 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 - C ⁇ o)alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 8 -C ⁇ )tricycloalkyl, -(C 5 - C ⁇ o)cycloalkenyl,-(Cs-C ⁇ 4 )bicycloalkenyl, -(C 8 -C ⁇ )tricycloaIkenyl, -(3- to 7- membered)heterocycle, or -(7- to l-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7 groups.
  • Re is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(5- to 10- membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 3 ⁇ ...- groups.
  • R 6 is -phenyl.
  • p and m are 0, Ri is -CH 3 , R t is -H, R 5 is -H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R_ -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an z_O-propyl group substituted at the para-position of the Re -phenyl.
  • Ri is -CF 3
  • t is -H
  • R 5 is -H
  • R 6 is -phenyl.
  • the R 6 -phenyl is substituted with a -(Ci-Ce) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an tsopropyl group substituted at the para-position of the Re -phenyl.
  • Ri is -CI
  • R 4 is -H
  • R 5 is -H
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(Ci-C ⁇ ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • R ! is -CH 3
  • R 5 is -H
  • R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is an zso-propyl group substituted at the para-position of the Re -phenyl.
  • p and m are 0, Ri is -CF 3 , R t is -CH 3 , R 5 is -H, and
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an iso-propy! group substituted at the para-position of the Re -phenyl.
  • Ri is -CI
  • R is -CH 3
  • R 5 is -H
  • Re is -phenyl
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is an wo-propyl group substituted at the para-position of the R 6 -phenyl.
  • R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an zso-propyl group substituted at the para-position of the R 6 -phenyl.
  • p is 0, m is 1, Ri is -CF 3 , R 3 is -CH ) R is -H, R 5 is - H, and Re is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C ⁇ ) alkyl group is an zsopropyl group substituted at the para-position of the R b -phenyl.
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3 , Rt is -H, R_ is - H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an ts ⁇ -propyl group substituted at the para-position of the R 6 -phenyl.
  • p is 0, m is 1, Ri is -CH 3 , R 3 is -CH 3) R 4 is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(Cj- C 6 ) alkyl group.
  • the -(Cj-C_) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci- C 6 ) alkyl group is an t_*o-propyl group substituted at the para-position of the R 6 -phenyl.
  • R 6 -phenyl is substituted with a -(Ci- C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para- . position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(d- C 6 ) alkyl group is an z_*o-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3; t is -CH , R 5 is -H, and R 6 is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • p and m are 0, Ri is -CH 3 , R t is -H, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • p and m are 0, Ri is -CF 3
  • R t is -H
  • R 5 is -H
  • R is -phenyl substituted at its para-position with a -CF 3 .
  • p and m are 0, Ri is -CI, R is -H, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CH 3
  • R 4 is -CH
  • R 5 is -H
  • R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CF 3
  • R t is -CH 3
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3
  • p and m are 0, Ri is -CI
  • R4 is -CH 3
  • R5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CH 3 , R 3 is -CH 3 , is -H, R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CF 3 , R 3 is -CH , R 4 is -H, R 5 is -
  • R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3 , R t is -H, R 5 is - H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CH 3 , R 3 is -CH 3 , t is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, R ⁇ is -CF 3 , R 3 is -CH 3 , R 4 is -CH 3 , R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3 , R t is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • the present invention also encompasses compounds of formula (III):
  • p is 0. In another embodiment p is 1. In another embodiment, p is 2. In another embodiment, m is 0.
  • n is 1. In another embodiment, m is 2. In another embodiment, Ri is -halo.
  • R is -CI. In another embodiment, R is -Br. In another embodiment, R is -I. In another embodiment, R is-F. In another embodiment, R is -CH 3 . In another embodiment, R is -NO 2 . In another embodiment, R is -OH. In another embodiment, R is -OCH 3 . In another embodiment, R is -NH 2 . hi another embodiment, R is -C(halo). In another embodiment, is -CH(halo) 2 . In another embodiment, R is -CH 2 (halo).
  • p s 1 and R 2 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - C 6 )alkyl, or -NH 2 .
  • R 2 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, - (C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 8 -C ⁇ 4 )tricycloalkyl, -(C 5 - C ⁇ o)cycloalkenyl, -(C 8 -C ⁇ 4 )bicycloalkenyl, -(C 8 -C ⁇ )tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R groups.
  • R 2 is -phenyl, -naphthyl, -(C ⁇ )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - Ce)alkyl, or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, - (C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ )bicycloalkyl, -(C 5 - C ⁇ o)cycloalkenyl, -(C 8 -C ⁇ 4 )bicycloalkenyl, -(C 8 -Ci 4 )tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R groups.
  • m is 1 and R 3 is -phenyl, -naphthyl, -(C ⁇ )aryl, or - (5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is a -(C ⁇ -C ⁇ o)alkyl. In another embodiment, m is 1, R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1, R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (S)-configuration. In another embodiment, m is 1 and R is -CH 3 .
  • m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • t is -H.
  • t is -(C ⁇ -C ⁇ o)alkyl.
  • R t is -C(O)R 9 .
  • 4 is -C(O)NHR .
  • R 5 is -H. In another embodiment, R 5 is -(CrC ⁇ o)alkyl.
  • R 6 is -(C ⁇ -C 1 o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 - C ⁇ o)alkynyl,.-(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ )bicycloalkyl, -(C 8 -C) )tricycloalkyl, -(C 5 - .
  • Re is -phenyl
  • Re is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(5- to 10- membered)heteroaryl, each of which is unsubstituted or substituted with one or more Rs groups.
  • p and m are 0, R t is -CH 3 , R t is -H, R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is an tso-propyl group substituted at the para-position of the R 6 -phenyl.
  • p and m are 0, Ri is -CF 3 , Rt is -H, R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(d-C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an w ⁇ -propyl group substituted at the para-position of the R 6 -phenyl.
  • Ri is -CI
  • R 4 is -H
  • R 5 is -H
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(d-Ce) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(d-C 6 ) alkyl group is an zsO-propyl group substituted at the para-position of the Re -phenyl.
  • Ri is -CH 3
  • R t is -CH 3
  • R 5 is -H
  • R 6 is -phenyl.
  • the Re-phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the Re -phenyl.
  • p and m are 0, Ri is -CF 3 , R is -CH , R 5 is -H, and
  • R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(Ci-Ce) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the e -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is an wo-propyl group substituted at the para-position of the R 6 -phenyl.
  • p and m are 0, Ri is -CI, R t is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, Ri is -CH 3 , R 3 is -CH 3) t is -H, R 5 is -H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(d-C ⁇ ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, Ri is -CF 3 , R 3 is -CH 3; R t is -H, R 5 is - H, and R 6 is -phenyl.
  • the -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(d- Ce) alkyl group is an ts ⁇ -propyl group substituted at the para-position of the R 6 -phenyl.
  • p is 0, m is 1, i is -CI, R 3 is -CH 3> R t is -H, R 5 is -
  • Re is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the R -phenyl.
  • the -(Ci- C 6 ) alkyl group is an zsO-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, i is -CH 3 , R 3 is -CH 3j Rt is -CH 3 , R5 is -H, and Re is -phenyl.
  • the e -phenyl is substituted with a -(Ci- C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an iso-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, i is -CF 3 , R 3 is -CH 3 , Rj is -CH 3 , R_ is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(d- C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an tj- ⁇ -propyl group substituted at the para-position of the R 6 -phenyl.
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3> t is -CH 3 , R 5 is -H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(Ci-Ce) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci- C 6 ) alkyl group is an t-O-propyl group substituted at the para-position of the Re -phenyl.
  • p and m are 0, Ri is -CH 3 , R 4 is -H, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF3.
  • Ri is -CF 3
  • t is -H
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF .
  • Ri is -CI
  • R t is -H
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3
  • p and m are 0, Ri is -CH 3
  • t is -CH 3
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CF 3
  • Rt is -CH 3
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3
  • p and m are 0, Ri is -CI, is -CH 3
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CH 3 , R 3 is -CH 3 , R t is -H, R is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CF 3 , R 3 is -CH 3 , R t is -H, R 5 is - H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, i is -CI, R 3 is -CH 3 , R 4 is -H, R 5 is - H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CH j R is -CH 3 , R 4 is -CH 3 , R is -H, and Re is -phenyl substituted at its para-position with a -CF .
  • p is 0, m is 1, Ri is -CF 3 , R 3 is -CH 3 , R 4 is -CH 3 , R 5 is -H, and R_ is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -Ci, R 3 is -CH 3 , R 4 is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • the present invention also encompasses compounds of formula (IV):
  • n 0.
  • n is 1. hi another embodiment, m is 2. In another embodiment, Rj is -halo.
  • Ri is -CI.
  • R] is -Br.
  • Ri is -I.
  • Ri is -F. In another embodiment, Ri is -CH 3 .
  • Ri is -NO 2 .
  • Ri is -OH.
  • Ri is -OCH .
  • Ri is -NH 2 . In another embodiment, Ri is -C(halo) .
  • Ri is -CH(halo) 2 .
  • Ri is -CH 2 (halo).
  • p is 1 and R 2 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - C 6 )alkyl, or -NH 2 .
  • p is 1 and R 2 is -(C ⁇ -C ⁇ 0 )alkyl, -(C 2 -C ⁇ o)alkenyl, -
  • R 2 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, NO 2 , -O(C ⁇ - C 6 )alk.yl, or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyl, -(C -C ⁇ o)alkenyl, -
  • m is 1 and R 3 is -phenyl, -naphthyl, -(C 1 )aryl, or - (5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is a -(C ⁇ -C ⁇ o)alkyl. In another embodiment, m is 1, R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1
  • R is a -(C ⁇ -C ⁇ o)alkyl
  • the carbon to which the R group is attached is in the (S)-configuration.
  • m is 1 and R 3 is -CH 3 . In another embodiment, m is 1 , R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • R 4 is -H.
  • R t is -(C ⁇ -C ⁇ o)alkyl.
  • t is -C(O)R .
  • R 4 is -C(O)NHR 9 .
  • R 5 is -H.
  • R 5 is -(C ⁇ -C ⁇ o)alkyl.
  • Re is -(C ⁇ -do)alkyl, -(C 2 -C ⁇ o)alke ⁇ yl, -(C 2 -
  • Re is -phenyl, -naphthyl, -(C ⁇ )aryl, or -(5- to 10- membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • R 6 is -phenyl
  • Ri is -CH 3
  • Rt is -H
  • R 5 is -H
  • R 6 is - phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-Ce) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the R 6 -phenyl.
  • p and m are 0, Ri is -CF 3 , R t is -H, R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl. In another embodiment, the -(C ⁇ -C 6 ) alkyl group is an zs ⁇ -propyl group substituted at the para-position of the R 6 -phenyl.
  • Ri is -CI
  • R is -H
  • R 5 is -H
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is an wo-propyl group substituted at the para-position of the R -phenyl.
  • Ri is -CH 3
  • t is -CH 3
  • R 5 is -H
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(d-C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an ir ⁇ -propyl group substituted at the para-position of the R b -phenyl.
  • Ri is -CF 3
  • R t is -CH 3
  • R 5 is -H
  • Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C b ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the R -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the R -phenyl.
  • p and m are 0, Ri is -CI, t is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(d-C ⁇ ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1 , Ri is -CH 3 , R 3 is -CH 3 , R 4 is -H, R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, R ⁇ is -CF 3 , R 3 is -CH 3) R is -H, R 5 is - H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(d-C 6 ) alkyl group, hi another embodiment, the -(Cj-Ce) alkyl group is substituted at the para- position of the Re-phenyl.
  • the -(d-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3; R 4 is -H, R 5 is - H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(Cj-C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- Ce alkyl group is an wo-propyl group substituted at the para-position of the R 6 -phenyl.
  • p is 0, m is 1, Ri is -CH 3 , R 3 is -CH 3; R 4 is -CH 3 , R5 is -FI, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(Ci- ,., Ce) alkyl group.
  • the -(d-C 6 ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl .1 group substituted at the para-position of the Re -phenyl.
  • the -(d- Ce) alkyl group is an iso-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, Ri is -CF 3 , R is -CH 3j t is -CH 3 , R5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(Ci- Ce) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ Ce) alkyl group is an iro-propyl group substituted at the para-position of the Re -phenyl.
  • p is 0, m is 1, Ri is -CI, R is -CH 3; R 4 is -CH3, R 5 is -H, and R 6 is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group, hi another embodiment, the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- Ce) alkyl group is an wo-propyl group substituted at the para-position of the Re -phenyl.
  • Ri is -CH 3
  • R 4 is -H
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3
  • p and m are 0, Ri is -CF 3
  • R4 is -H
  • R 5 is -H
  • R is -phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CI
  • R4 is -H
  • R 5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • p and m are 0, Ri is -CH 3
  • R_ > is -CH 3
  • R5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CF 3
  • t is -CH 3
  • R5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CI
  • R4 is -CH 3
  • R5 is -H
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CH 3 , R3 is -CH3, Rj is -H, R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, R ⁇ is -CF 3 , R 3 is -CH3, R4 is -H, R 5 is - H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CI, R 3 is -CH3, R4 is -H, R_ is -
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, is 1, Ri is -CH , R 3 is -CH 3 , Ri is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CF 3 , R 3 is -CH 3 , t is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • p is 0, m is 1, Ri is -CI, R 3 is -CH 3 , is -CH_, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • m is 0.
  • n 1
  • n is 2. In another embodiment, Ri is -halo.
  • Ri is -CI.
  • Ri is -Br.
  • Ri is -I.
  • Ri is -F. In another embodiment, Ri is -CH 3 .
  • Ri is - ⁇ O 2 .
  • i is -OH.
  • Ri is -OCH 3
  • R t is -NH 2 .
  • Ri is -C(halo) 3 .
  • Ri is -CH(hak>) 2 .
  • Ri is -CH 2 (halo).
  • m is 1 and R 3 is -halo, -CN, -OH, NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(d-C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, - (C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 - C ⁇ o)cycloalkenyl, -(C 8 -C ⁇ 4 )bicycloalkenyl, -(C 8 -C ⁇ 4 )tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or - (5 - to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • m is 1 and R 3 is a -(C ⁇ -C 10 )alkyl.
  • m is 1, R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (Reconfiguration. In another embodiment, m is 1. R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • m is 1 and R 3 is -CH 3 .
  • m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (Reconfiguration. In another embodiment, m is 1, R 3 is -CH 3 , and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • R 4 s -(C ⁇ -C ⁇ o)alkyl.
  • Rt s -C(O)R 9 .
  • R t s -C(O)NHR 9 .
  • R 5 s -H is another embodiment
  • R 5 s -(C ⁇ -C ⁇ o)alkyl.
  • Re is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(5- to 10- m.embered)heteroaryl, each of which is unsubstituted or substituted with one or more R 8 groups.
  • R_ is -phenyl
  • m is 0, Ri is -CH 3 , R 4 is -H, R 5 is -H, and Re is - phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R -phenyl.
  • the -(C ⁇ -C_) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is an. w ⁇ -propyl group substituted at the para-position of the R 6 -phenyl.
  • m is 0, i is -CF 3 , R t is -H, R 5 is -H, and Re is - phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group, hi another embodiment, the -(d-C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(d-C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an tio-propyl group substituted at the para-position of the Re -phenyl.
  • m is 0, Rj is -CI, R t is -H, R 5 is -H, and R 6 is - phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-Ce) alky] group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl. In another embodiment, the -(C ⁇ -C 6 ) alkyl group is an z_O-propyl group substituted at the para-position of the Re -phenyl.
  • m is 0, Ri is -CH 3 , t is -CH 3 , R 5 is -H, and Re is - phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-C ⁇ ) alkyl group is an z_O-propyl group substituted at the para-position of the R 6 -phenyl.
  • m is 0, Ri is -CF 3 , R t is -CH 3 , R 5 is -H, and Re is - phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an is ⁇ -propyl group substituted at the para-position of the Re -phenyl.
  • m is 0, Ri is -CI, R 4 is -CH 3 , R5 is -H, and Re is - phenyl.
  • the R -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(Ci-d) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the Re -phenyl.
  • m is ⁇ , i is -CH 3 , R 3 is -CH 3 , R t is -H, R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the R 6 -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • m is 1, Ri is -CF 3 , R 3 is -CH 3 , is -H, R 5 is -H, and R 6 is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-d) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the R 6 -phenyl.
  • m is 1, Ri is -CI , R 3 is -CH 3 , R t is -H, R 5 is -H, and R 6 is -phenyl.
  • the R 6 -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para-position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the R 6 -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is an z_O-propyl group substituted at the para-position of the Re -phenyl.
  • m is 1, Ri is -CH 3 , R 3 is -CH 3 , R t is -CH 3 , R 5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(Ci-C ⁇ ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(Ci- Ce) alkyl group is an tso-propyl group substituted at the para-position of the Re -phenyl.
  • Rj is -CF 3
  • R 3 is -CH3
  • R 4 is -CH3
  • R 5 is -H
  • Re is -phenyl.
  • the R 6 -phenyl is substituted with a -(Ci-Ce) alkyl group.
  • the -(d ⁇ Ce) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(C ⁇ -C 6 ) alkyl group is a t-butyl group substituted at the para-position of the e -phenyl.
  • the -(d- C 6 ) alkyl group is an wo-propyl group substituted at the para-position of the R 6 -phenyl.
  • m is 1, Rj is -CI, R 3 is -CH 3 , R4 is -CH3, R5 is -H, and Re is -phenyl.
  • the Re -phenyl is substituted with a -(C ⁇ -C 6 ) alkyl group.
  • the -(C ⁇ -C 6 ) alkyl group is substituted at the para- position of the Re -phenyl.
  • the -(Ci-Ce) alkyl group is a t-butyl group substituted at the para-position of the Re -phenyl.
  • the -(d- C ⁇ s) alkyl group is an wo-propyl group substituted at the para-position of the R 6 -phenyl.
  • m is 0, Ri is -CH3, R 4 is -H, R 5 is -H, and ⁇ is - phenyl substituted at its para-position with a -CF 3 .
  • m is 0, Ri is -CF 3 , Rt is -H, R 5 is -H, and Re is - phenyl substituted at its para-position with a -CF 3 .
  • m is 0, Ri is -CI, Rt is -H, R 5 is -H, and Re is - phenyl substituted at its para-position with a -CF 3 .
  • Ri is -CH3, R4 is -CH3, R 5 is -H, and Re is - phenyl substituted at its para-position with a -CF 3 .
  • m is 0, Ri is -CF 3 , R4 is -CH 3 , R 5 is -H, and R 6 is - phenyl substituted at its para-position with a -CF 3 .
  • m is 0, Ri is -CI, Rt is -CH 3 , R ⁇ is -H, and R 6 is - phenyl substituted at its para-position with a -CF 3 .
  • m is 1, Ri is -CH 3 , R 3 is -CH 3 , Rt is -H, R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • m is 1, Ri is -CF 3 , R 3 is -CH 3 , R4 is -H, R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • m is 1, Ri is -CI, R 3 is -CH 3 , R4 is -H, R 5 is -H, and
  • Re is -phenyl substituted at its para-position with a -CF 3 .
  • m is 1, Ri is -CH 3 , R 3 is -CH 3 , Rt is -CH 3 , R 5 is -H, and R 6 is -phenyl substituted at its para-position with a -CF 3 .
  • m is 1, Ri is -CF 3 , R 3 is -CH 3 , t is -CH 3 , R 5 is -H, and R is -phenyl substituted at its para-position with a -CF 3 .
  • m is 1, R ⁇ is -CI, R 3 is -CH 3 , R4 is -CH 3 , R 5 is -H, and Re is -phenyl substituted at its para-position with a -CF 3 .
  • Ari is a pyridyl group.
  • Ari is a pyrimidinyl group.
  • Ari is a pyridazinyl group.
  • Ari is a pyrazinyl group.
  • ri is a thiadiazolyl group.
  • Ar 2 is a benzothiazolyl group.
  • Ar 2 is a benzoimidazolyl group.
  • Ar 2 is a benzooxazolyl group.
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n is 0. In another embodiment, ,mis ' . hi another embodiment ,.mis_ __ In another embodiment ,.nis 0 In another embodiment ,.nis 1 In another embodiment ,.nis2 In another embodiment ,nis 3 In another embodiment. ,pis0 In another embodiment. ,pis 1 In another embodiment ,pis2 In another embodiment. , t is 0. In another embodiment, , t is 1. hi another embodiment ,, t is 2. h another embodiment ,, s is 0. hi another embodiment. , s is 1. In another embodiment, s is 2.
  • s is 3.
  • s is 4.
  • o is 0. In another embodiment, o is 1.
  • o is 2.
  • o 3.
  • o is 4.
  • q is 0. In another embodiment, q is 1.
  • q is 2.
  • q is 3.
  • q is 4.
  • q is 5. In another embodiment, q is 6.
  • r is 0.
  • r is 1.
  • r is 2. hi another embodiment, r is 3. In another embodiment, r is 4.
  • r is 5.
  • n or p is 1 and R is -halo, -CN, -OH, -NO 2 , or - NH 2 .
  • n or p is 1 and R 2 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C_-C ⁇ o)alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloaIkyl, -(C 8 -Ci 4 )tricycloalkyl, -(C 5 - C ⁇ o)cycloalkenyl, -(C 8 -C ⁇ )bicycloalkenyl, -(C 8 -Ci 4 )tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • n or p is 1 and R 2 is -phenyl, -naphthyl, -(C ⁇ )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -do)alkenyl, - (C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 8 -C ⁇ 4 )tricycloalkyl, -(C 5 - C ⁇ o)cycloalkenyl, -(C 8 -C ⁇ 4 )bicycloalkenyl, -(C 8 -Ci 4 )tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • m is 1 and R 3 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more Re groups.
  • m is 1 and R 3 is a -(C ⁇ -C ⁇ o)alkyl.
  • m is 1, R 3 is a -(C ⁇ -C ⁇ o)alkyl, and the carbon to which the R group is attached is in the (R)-configuration. In another embodiment, m is 1, R 3 is a -(d-C ⁇ o)alkyl, and the carbon to which the R 3 group is attached is in the (S)-configuration.
  • m is 1 and R 3 is -CH 3 .
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the R 3 is attached is in the (Reconfiguration. In another embodiment, m is 1, R 3 is -CH 3 , and the carbon atom to which the
  • R 3 is attached is in the (S)-configuration.
  • the present invention also encompasses compounds of formula (Nil):
  • Ari, Ar 2 , R 3 -R 5 , R13, m and t are defined above for the Hydroxyiminopiperazine Compounds of formula (VII).
  • Ari is apyridyl group.
  • Ari is a pyrimidinyl group
  • Ari is a pyridazinyl group.
  • Ari is a pyrazinyl group.
  • Ari is a thiadiazolyl group.
  • Ar 2 is a benzothiazolyl group.
  • Ar 2 is a benzoimidazolyl group.
  • Ar is a benzooxazolyl group.
  • Ar 2 is
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is
  • Ar 2 is
  • R is -H.
  • Rj is -halo
  • Ri is -CI.
  • Ri is -Br.
  • Ri is -I.
  • Ri is -F.
  • Ri is -CH 3 .
  • Ri is -NO 2 .
  • Ri is -CN.
  • Rj is -OH.
  • Ri is -OCH 3 .
  • R t is -NH 2 .
  • Ri is -C(halo) 3 .
  • Ri is -CH(halo) 2 .
  • Ri is -CH 2 (halo). hi another embodiment, m is 0. hi another embodiment, m is 1.
  • n 2
  • n 0.
  • n 1
  • n is 2.
  • n 3.
  • p is 0.
  • p is 1. In another embodiment, p is 2.
  • t is 0.
  • t is 1.
  • t is 2.
  • s is 0.
  • s is 1.
  • s is 2.
  • s is 3.
  • s is 4. In another embodiment, o is 0. h another embodiment, o is 1.
  • o is 2.
  • o 3.
  • o is 4. In another embodiment, q is 0.
  • q is 1.
  • q is 2.
  • q is 3.
  • q is 4. In another embodiment, q is 5.
  • q is 6.
  • r is 0.
  • r is 1.
  • r is 2. i another embodiment, r is 3.
  • r is 4.
  • r is 5.
  • n or p is 1 and R 2 is -halo, -CN, -OH, -NO 2 , or - NH 2 .
  • n or p is 1 and R 2 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl,
  • n or p is 1 and R 2 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -
  • m is 1 and R 3 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more Re groups.
  • m is 1 and R 3 is a -(C ⁇ -C o)alkyl.
  • m is 1
  • R 3 is a -(C ⁇ -C ⁇ o)alkyl
  • the carbon to which the R 3 group is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is a -(C ⁇ -C ⁇ o)alkyl
  • the carbon to which the R 3 group is attached is in the (S)-configuration.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH
  • the carbon atom to which the R 3 is attached is in the (Reconfiguration.
  • m is 1, R 3 is -CH3, and the carbon atom to which the R 3 is attached is in the (S)-configuration.
  • each R 3 can be on any carbon of the piperazine ring.
  • the Hydroxyiminopiperazine Compounds have only one R 3 group, and that 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group.
  • two R 3 groups are on the same carbon atom of the piperazine ring.
  • the Hydroxyiminopiperazine Compound has two R 3 groups, each being attached to a different carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group.
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups
  • the carbon atom to which an R 3 group is attached has the (R) configuration.
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups
  • the carbon atom to which the R 3 group is attached has the (S) configuration.
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups, and at least one of the carbon atoms to which an R 3 group is attached has the (R) configuration.
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups, and at least one of the carbon atoms to which an R 3 group is attached has the (S) configuration.
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; and the carbon to which the 3 group is attached is in the (R) configuration, hi another embodiment, the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -CH 3 .
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R group is attached is in the (R) configuration; and R 3 is -CF 3 .
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -CH 2 CH 3 .
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; and the carbon to which the R 3 group is attached is in the (S) configuration.
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R3 is -(d-C )alkyl unsubstituted or substituted with one or more halo groups, hi another embodiment, the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R 3 is -CH 3 .
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R 3 is -CF 3 .
  • the Hydroxyiminopiperazine Compound has one or two R 3 groups; an R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R 3 is -CH2CH3.
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; and the carbon to which the R 3 group is attached is in the (R) configuration.
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -CH 3 .
  • the Hydroxyiminopiperazine Compound has only one R group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group * is attached ' is in the (R) configuration; and R 3 is -CF 3 .
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -CH CH 3 .
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; and the carbon to which the R 3 group is attached is in the (S) configuration.
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R 3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R 3 is -CH 3 .
  • the Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R3 is -CF3.
  • the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R 3 group is attached is in the (S) configuration; and R3 is -CF3.
  • Hydroxyiminopiperazine Compound has only one R 3 group; the R 3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group; the carbon to which the R group is attached is in the (S) configuration; and R 3 is -CH 2 CH 3 .
  • phenpropyl group the carbon to which the R 3 group is attached is in the (R) configuration; and R 3 is -CH 2 CH 3 .
  • 'a means R3 is -H.
  • 'b means R 3 is -CH 3 and the Hydroxyiminopiperazine Compound is racemic.
  • 'c means R 3 is -CH 3 and the carbon atom to which R 3 is attached is in the (R) configuration,
  • 'd means R 3 is -CH 3 and the carbon atom to which R3 is attached is in the (S) configuration.
  • 'b means R 3 is -CH 3 and the Hydroxyiminopiperazine Compound is racemic.
  • 'c means R 3 is -CH 3 and the carbon atom to which R 3 is attached is in the (R) configuration.
  • 'd means R 3 is -CH 3 and the carbon atom to which R 3 is attached is in the (S) configuration.
  • a means that the Hydroxyiminopiperazine Compound is racemic.
  • TD means that the carbon atom to which -CH(CH 3 ) 2 is attached is in the (R) configuration
  • a" means R 3 is -H.
  • b" means R 3 is -CH3 and the Hydroxyiminopiperazine Compound is racemic.
  • c_ means R 3 is -CH 3 and the carbon atom to which R 3 is attached is in the (R) configuration
  • d means R3 is -CH3 and the carbon atom to which R 3 is attached is in the (S) configuration.
  • 'a means R 3 is -H.
  • TD means R is -CH 3 and the Hydroxyiminopiperazine Compound is racemic.
  • c means R 3 is -CH 3 and the carbon atom to which R 3 is attached is in the (R) configuration
  • 'd means R is -CH 3 and the carbon atom to which R 3 is attached is in the (S) configuration.
  • -(C ⁇ -C ⁇ o)alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative straight chain -(C ⁇ -C ⁇ o)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and - n-decyl.
  • Representative branched -(C ⁇ -C ⁇ o)alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
  • Representative straight chain -(Ci -C 6 )alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl.
  • Representative branched -(Ci- C 6 )alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.
  • -(C 2 -C ⁇ o)alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • Representative straight chain and branched (C 2 -do)alkenyls include -vinyl, - ally!, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3 -methyl- 1-butenyl, - 2-meti ⁇ yl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1- heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1
  • -(C 2 -C 6 )alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond.
  • Representative straight chain and branched (C 2 -Ce)alkenyls include -vinyl, - ally I, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3 -methyl- 1-butenyl, - 2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl and the like.
  • "-(C 2 -C ⁇ o)alkynyl” means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched -(C 2 -C ⁇ o)alkynyls include - acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-l- butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6- heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1- decynyl, -2-decynyl, -9-dec
  • -(C -Ce)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched (C 2 -Ce)alkynyls include - acetylenyl, -propynyl, -I -butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-l- butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like.
  • -(C 3 -C ⁇ o)cycloalkyl means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms.
  • Representative (C 3 -C ⁇ o)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyciohexyl, -cycloheptyl, -cyclooctyi, -cyclononyl, and -cyclodecyl.
  • -(C 3 -C 8 )cycloalkyl means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms.
  • Representative (C 3 -C 8 )cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyciohexyl, -cycloheptyl, and -cyclooctyi.
  • -(C 8 -C ⁇ 4 )bicycloalkyl means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.
  • Representative -(C 8 - C ⁇ )bicycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8- tetrahydronaphthyl, -perhydronaphthyl and the like.
  • -(C 8 -C ⁇ )tricycloalky_ means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic ring.
  • Representative -(C 8 - C ⁇ 4 )tricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceanthreneyl, - 1 ,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl and the like.
  • -(C 5 -C ⁇ o)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms.
  • Representative (C 5 -C ⁇ 0 )cycloalkenyls include -cyclopentenyl, -cyclopentadienyl,
  • -(C 5 -C 8 )cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms.
  • Representative (C 5 -C 8 )cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.
  • -(C 8 -C ⁇ )bicycloalkenyl means abi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms.
  • Representative -(Cs-C ⁇ )bicycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like.
  • "-(C 8 -C ⁇ )tricycloalkenyl” means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms.
  • Representative -(C 8 -C ⁇ )tricycloalkenyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, .w-indacenyl, s-indacenyl and the like.
  • -(3- to 7-membered)heterocycle or "-(3- to 7-membered)heterocyclo” means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3-membered -(3- to 7-membered)heterocycle can contain up to 3 heteroatoms, and a 4- to 7-membered -(3- to 7-membered)heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and su ⁇ fone.
  • the -(3- to 7-membered)heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(3- to 7-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tefrahydrothiopyranyl and the
  • “-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo” means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3-membered -(3- to 5-membered)heterocycle can contain up to 3 heteroatoms, and a 4- to 5-membered -(3- to 5-membered)heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 5-membered)heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(3- to 5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, tnazmyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofiiranyl, tetrahydrothiophenyl and the like.
  • -(7- to 10-membered)bicycloheterocycle or "-(7- to 10- membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a -(7- to 10- membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(7- to 10-membered)bicycloheterocycles include - quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, - benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinoly], - quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, -jS-carbolinyl and the like.
  • -(C ⁇ )aryl means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.
  • -(5- to 10-membered)heteroary ⁇ means an aromatic heterocycle ring of 5 to 10 members, including both mono- and bicyclic ring systems, wherein at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • One or both of the -(5- to 10-membered)heteroaryPs rings contain at least one carbon atom.
  • Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
  • -CH 2 (halo) means a methyl group wherein one of the hydrogens of the methyl group has been replaced with a halogen.
  • Representative -CH 2 (halo) groups include - CH 2 F, -CH 2 C1, -CH 2 Br, and -CH 2 I.
  • -CH(halo) 2 means a methyl group wherein two of the hydrogens of the methyl group have been replaced with a halogen.
  • Representative -CH(halo) 2 groups include -CHF 2 , -CHC1 2 , -CHBr 2 , CHBrCl, CHC1I, and -CHI 2 .
  • -C(halo) 3 means a methyl group wherein each of the hydrogens of the methyl group has been replaced with a halogen.
  • Representative -C(halo) 3 groups include - CF 3 , -CCl 3 , -CBr 3 , and -C_3.
  • w ere n ⁇ an s are e ne a ove or t e y roxyiminopiperazine compounds or formula (NI) or (Nil).
  • phenethyl group means an ethylene group attached to a terminal Ar 2 group, wherein one or each of two hydrogens of the ethylene group can be optionally substituted with an R ⁇ 3 group.
  • a phenethyl group is depicted below:
  • phenpropyl group means an n-propylene group attached to a terminal Ar 2 group, wherein one or each of two hydrogens of the n-propylene group can be optionally substituted with an R 13 group.
  • a phenpropyl group is depicted below:
  • animal includes, but is not limited to, a cow, monkey, chimpanzee., baboon, horse, sheep, pig, chicken, tutkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, and human.
  • phannaceutically acceptable salt is a salt formed from tm acid and a basic functional group, such as a nitrogen group, of one of the Hydroxyiminopiperazine Compounds.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, and pamoale (I.
  • pharmaceutically acceptable salt also refers to a salt formed from a Hydroxyiminopiperazine Compound having an acidic functional group, such as a carboxylic acid functional group, and an inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N,-dimethyl-N-(2-hydroxye
  • phrases "effective amount,” when used in connection with a Hydroxyiminopiperazine Compound means an amount effective for treating or preventing a Condition.
  • phrases "effective amount,” when used in connection with another therapeutic agent means an amount for providing the therapeutic effect of the therapeutic agent.
  • a first group is "substituted with one or more" second groups, each of one or more of the first group's hydrogen atoms is replaced with a second group.
  • each carbon atom of a first group is independently substituted with one or two second groups.
  • each carbon atom of a first group is independently substituted with only one second group.
  • UI means urinary incontinence.
  • IBD means inflammatory-bowel disease
  • IBS irritable-bowel syndrome
  • ALS means amyotrophic lateral sclerosis.
  • treatment of includes the amelioration or cessation of a Condition, or a symptom thereof.
  • prevention of include the avoidance of the onset of a Condition, or a symptom thereof.
  • the Hydroxyiminopiperazine Compounds can be made using conventional organic synthesis including the following illustrative methods shown in the schemes below.
  • the Hydroxyiminopiperazine Compounds wherein R t is -H can be obtained by the following illustrative method shown below in Scheme A:
  • a compound of formula A (about 0.3 mmol) is reacted with hydroxy.amine (50 weight, percent in water, about. 5.8 mmol) in about 1.5 mL of ethanol with stirring at a temperature of about 80°C for about 2 h.
  • the mixture is then concentrated under reduced pressure to provide the Hydroximinopiperazine Compound, which can then be purified.
  • the Hydroximinopiperazine Compound is purified using column chromatography or recrystallization.
  • a solution of a compound of formula C (about 1 mmol) and isothiocyanate, R 6 NCS, (about 1 mmol) in 1.5 mL of dichloromethane is stirred at room temperature for about 5 h.
  • the resulting mixture is then concentrated under reduced pressure to provide the compound of formula B, which can then be purified.
  • the compound of formula B is purified using column chromatography or recrystallization.
  • the compound of formula B (about 0.6 mmol) is then reacted with iodomethane (about 0.9 mmol) in about 3 mL of tetrahydrofuran with stirring at room temperature for about 12 h. Excess iodomethane is removed from the mixture using reduced pressure.
  • a solution of triethylamine (about 1.74 mmol) in about 2.5 mL of ethyl acetate is then added to the mixture and the mixture is allowed to stir for about 2 h.
  • the mixture is then concentrated under reduced pressure to provide the compound of formula A, which can then be purified.
  • the compound of formula A is purified using column chromatography or recrystallization.
  • Suitable protecting groups for hydroxyl group include, but are not limited to, methyl ether, methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxyn ⁇ ethyl ether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, 1-ethoxyethyl ether, 1 -methyl- 1-methoxyethyl ether, 2-(phenylselenyl ether), t-butyl ether, allyl ether, benzyl ether, ⁇ -nitrobenzyl ether, triphenylmethyl ether, o-napthyldiphenylmethyl ether, jt?
  • Suitable protecting groups for an amino group include, but are not limited to, l,l-dimethyl-2,2,2-trichloroethyl carbamate, 1 -methyl- l-(4-biphenylyl)ethyl carbamate, 2-trimethylsilylethyl carbamate, 9-fluorenylmethyl carbamate, and tert-butyl carbamate (T.W. Greene et al., Protective Groups in Organic Synthesis, 309-405 (2d ed. 1991)).
  • Ri, R 2 , R 3 , m, n, and p are defined above for the Hydroxyiminopiperazine Compounds of formula (1) - (VII) and X is a halogen.
  • X is bromide, chloride, or iodide.
  • a compound of formula D1-D5 (about 20 mmol) is reacted with a compound of formula E (about 27.5 mmol) in about 15 mL of dimethyl sulfoxide in the presence of triethylamine (about 30 mmol), optionally with heating, for about 24 h to provide a compound of formula C.
  • the compound of formula C can be isolated from the reaction mixture and purified. In one embodiment, the compound of formula C is purified using column chromatography or recrystallization. If the compound of formula E is substituted with a hydroxyl or amino group, the hydroxyl or amino group can be protected using a suitable protecting group, using methods well known to those skilled in the art, before being reacted with a compound of formula D1-D5.
  • Suitable protecting groups include, but are not limited to, those described above.
  • the Hydroxyiminopiperazine Compounds wherein R t is -(d-C ⁇ o)alkyl can be obtained by reacting a Hydroxyiminopiperazine Compound wherein t is -H (about 0.2 mmol), that can be prepared as described above, dissolved in dimethylformamide (about 1.5 mL) with NaH (60 weight percent, about 0.21 mmol) with stirring for about 0.5 h.
  • the resulting mixture is then quenched with water, extracted with ethyl ether, the organic layer dried, and the solvent removed under reduced pressure to provide the Hydroxyiminopiperazine Compounds wherein t is -(C ⁇ -C ⁇ o)alkyl.
  • the Hydroxyiminopiperazine Compounds wherein R t is -(Ci- C ⁇ o)alkyl can then be purified.
  • the Hydroxyiminopiperazine Compounds wherein Rt is -(C ⁇ -C ⁇ o)alkyl is purified using column chromatography or recrystallization.
  • Suitable protecting groups include, but are not limited to, those described above.
  • the Hydroxyiminopiperazine Compounds wherein is -C(O)R 9 can be obtained by reacting a Hydroxyiminopiperaxine Compound wherein Rt is -H with an acid halide of formula X-C(O)R 9 , wherein X and R 9 are defined above, to provide the Hydroxyiminopiperaxine Compound wherein Rt is -C(O)R 9 as shown below in Scheme D.
  • X is -Cl, -Br, -I, or -F and Ar, R , R ⁇ ,, R 9 , and m are defined above.
  • Ar Ar group of the Hydroxyiminopiperazine Compound wherein t is -H is substituted with a hydroxyl or amino group or -R 3 is a hydroxyl or amino group, the hydroxyl or amino group is protected using a suitable protecting group, using methods well known to those skilled in the art, before being reacted with the acid halide of formula X-C(O)R 9 .
  • suitable protecting groups include, but are not limited to, those described above.
  • acid halides can be prepared by reacting the carboxylic acid with thionyl chloride, bromide, or iodide.
  • An acid chloride can also be prepared by reacting a carboxylic acid with phosphorous trichloride or tribromide.
  • An acid chloride can also be prepared by reacting the carboxylic acid with PI1 3 P in carbon tetrachloride.
  • An acid fluoride can be obtained by reacting a carboxylic acid with cyanuric fluoride.
  • suitable protecting groups include, but are not limited to, those described above.
  • an amine, R 9 -NH 2 can be reacted with triphosgene in dichloromethane as depicted below in Scheme F.
  • a Hydroxyiminopiperazine Compound wherein R t is -H and R 5 is -H is reacted with di-tert-butyldicarbonate in the presence of dimethylaminopyridine in methylene chloride according to well known techniques to provide a compound of formula F.
  • the compound of formula F is then reacted with sodium hydride in tetrahydrofuran followed by an alkyl halide, R 5 -X, wherein R 5 is -(C ⁇ -C ⁇ o)alkyl and X is -Cl, -Br, -I, or -F, to provide a compound of formula G.
  • the compound of formula G is then reacted with trifluoroacetic acid in methylene chloride according to well known techniques to provide the Hydroxyiminopiperazine Compound wherein R 5 is -(C ⁇ -C ⁇ o)alkyl.
  • Hydroxyiminopiperazine Compounds of formula NI and Nil can be obtained by methods analogous to those described above in Scheme A-G wherein R 6 of the isothiocyanate, Re ⁇ CS, in Scheme B is a phenethyl group or a phenpropyl group.
  • Hydroxyiminopiperazine Compounds can have one or more asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
  • a Hydroxyiminopiperazine Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses Hydroxyiminopiperazine Compounds and their uses as described herein in the form of their optical isomers, diasteriomers, and mixtures thereof, including a racemic mixture.
  • one or more hydrogen, carbon or other atoms of a Hydroxyiminopiperazine Compound can be replaced by an isotope of the hydrogen, carbon or other atoms.
  • Such compounds which are encompassed by the present invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
  • Hydroxyiminopiperazine Compounds hi accordance with the invention, the Hydroxyiminopiperazine Compounds are administered to an animal in need of treatment or prevention of a Condition.
  • an effective amount of a Hydroxyiminopiperazine Compound can be used to treat or prevent any condition treatable or preventable by inhibiting VR1.
  • conditions that are treatable or preventable by inhibiting NR1 include, but are not limited to, pain, UI, an ulcer, IBD, and IBS.
  • Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR5.
  • conditions that are treatable or preventable by inhibiting mGluR5 include, but are not limited to, pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, and psychosis.
  • an effective amount of a Hydroxyiminopiperazine in another embodiment, an effective amount of a Hydroxyiminopiperazine
  • Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluRl .
  • conditions that are treatable or preventable by inhibiting mGluRl include, but are not limited to, pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, and depression.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent acute or chronic pain.
  • Examples of pain treatable or preventable using the Hydroxyiminopiperazine Compounds include, but are not limited to, cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, arthritic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.
  • the pain to be treated or prevented may be associated with inflammation associated with an inflammatory disease, which can arise where there is an inflammation of the body tissue, and which can be a local inflammatory response and/or a systemic inflammation.
  • an inflammatory disease which can arise where there is an inflammation of the body tissue, and which can be a local inflammatory response and/or a systemic inflammation.
  • the Phenylene Compounds can be used to treat, or prevent pain associated with inflammatory disease including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al. , J. Mol, Cell Cardiol.
  • inflammatory diseases of the joints including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett ' s syndrome, and Crohn's disease; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chrome obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disease of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory disease of the skin, including sclerodermatitis, psoriasis and
  • the Phenylene Compounds can also be used for inhibiting, treating, or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • inflammatory disease can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent UI.
  • UI treatable or preventable using the Hydroxyiminopiperazine Compounds include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent an ulcer.
  • ulcers treatable or preventable using the Hydroxyiminopiperazine Compounds include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, and a stress ulcer.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent IBS.
  • IBS treatable or preventable using the Hydroxyiminopiperazine Compounds include, but are not limited to, spastic-colon-type IBS and constipation- predominant IBS.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent an addictive disorder, including but not limited to, an eating disorder, an impulse-control disorder, an alcohol-related disorder, a nicotine-related disorder, an amphetamine-related disorder, a cannabis-related disorder, a cocaine-related disorder, an hallucinogen-related disorder, an inhalant-related disorders, and an opioid-related disorder, all of which are further sub-classified as listed below.
  • Eating disorders include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and Eating Disorder not otherwise specified (NOS).
  • Impulse control disorders include, but are not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, and Impulse Control Disorder not otherwise specified (NOS).
  • Alcohol-related disorders include, but are not limited to, Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse, Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol Dependence, Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced sexual Dysfunction, Alcohol-Induced Sleep Disorder, Alcohol-Related Disorder not otherwise specified (NOS), Alcohol Intoxication, and Alcohol Withdrawal.
  • Nicotine-related disorders include, but are not limited to, Nicotine
  • Amphetamine-related disorders include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced sexual Dysfunction, Amphetamine-Induced Sleep Disorder, Amphetamine Related Disorder not otherwise specified (NOS), Amphetamine Intoxication, and Amphetamine Withdrawal.
  • Amphetamine Dependence Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine
  • Cannabis-related disorders include, but are not limited to, Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, Cannabis Intoxication Delirium, Cannabis-Induced Psychotic Disorder with delusions, Cannabis-Induced Psychotic Disorder with hallucinations, Cannabis-Induced Anxiety Disorder, Cannabis Related Disorder not otherwise specified (NOS), and Cannabis Intoxication.
  • Cocaine-related disorders include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder with delusions, Cocaine-Induced Psychotic Disorders with hallucinations, Cocaine-Induced Mood Disorder, Cocaine-fhduced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, Cocaine Related Disorder not otherwise specified (NOS), Cocaine Intoxication, and Cocaine Withdrawal.
  • Hallucinogen-related disorders include, but are not limited to, Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder with delusions, Hallucinogen-Induced Psychotic Disorders with hallucinations, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced sexual Dysfunction, Hallucinogen-Induced Sleep Disorder, Hallucinogen Related Disorder not otherwise specified (NOS), Hallucinogen Intoxication, and Hallucinogen Persisting Perception Disorder (Flashbacks).
  • Inhalant-related disorders include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, Inhalant-Induced Psychotic Disorder with hallucinations, Inhalant-Induced Anxiety Disorder, Inhalant Related Disorder not otherwise specified (NOS), and Inhalant Intoxication.
  • Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, Opioid Related Disorder not otherwise specified (NOS), Opioid Intoxication, and Opioid Withdrawal.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent Parkinson's disease and parkinsonism and the symptoms associated with Parkinson's disease and parkinsonism, including but not limited to, bradykinesia, muscular rigidity, resting tremor, and impairment of postural balance.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent generalized anxiety or severe anxiety and the symptoms associated with anxiety, including but not limited to, restlessness; tension; tachycardia; dyspnea; depression, including chronic "neurotic" depression; panic disorder; agoraphobia and other specific phobias; eating disorders; and personality disorders.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent epilepsy, including but not limited to, partial epilepsy, generalized epilepsy, and the symptoms associated with epilepsy, including but not limited to, simple partial seizures, jacksonian seizures, complex partial (psychomotor) seizures, convulsive seizures (grand mal or tonic-clonic seizures), petit mal (absence) seizures, and status epilepticus.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent strokes, including but not limited to, ischemic strokes and hemorrhagic strokes.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent a pruritic condition, including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, or fiberglass dermatitis.
  • a pruritic condition including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent psychosis, including but not limited to, schizophrenia, including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtyp . schizophrenia, and non-deficit schizophrenia; a delusional disorder, including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, ashamed subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder; and brief psychosis.
  • schizophrenia including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtyp .
  • schizophrenia and non-deficit schizophrenia
  • a delusional disorder including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, ashamed subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delus
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent a cognitive disorder, including but not limited to, delirium and dementia such as multi-infarct dementia, dementia pugilistica, dimentia caused by AIDS, and dementia caused by Alzheimer's disease.
  • a cognitive disorder including but not limited to, delirium and dementia such as multi-infarct dementia, dementia pugilistica, dimentia caused by AIDS, and dementia caused by Alzheimer's disease.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ transplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent Huntington's chorea.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent ALS.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent retinopathy, including but not limited to, arteriosclerotic retinopathy, diabetic arteriosclerotic retinopathy, hypertensive retinopathy, non-proliferative retinopathy, and proliferative retinopathy.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent a muscle spasm.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent a migraine including, but not limited to, migraine without aura ("common migraine”), migraine with aura (“classic migraine”), migraine without headache, basilar migraine, familial hemiplegic migraine, migrainous infarction, and migraine with prolonged aura.
  • the Hydroxyiminopiperazine Compounds can be used to treat or vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.
  • the Hydroxyiminopiperazine Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder.
  • the Hydroxyiminopiperazine Compounds are antagonists for VRl .
  • the invention also relates to methods for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an amount of a Hydroxyiminopiperazine Compound effective to inhibit VRl function in the cell.
  • This method can be used in vitro, for example, as an assay to select cells that express VRl and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an ulcer, IBD, or IBS.
  • the method is also useful for inhibiting VRl function in a cell in vivo, in an animal (e.g., a human), by contacting a cell in an animal with an effective amount of a Hydroxyiminopiperazine Compound.
  • the method is useful for treating or preventing pain in an animal in need thereof.
  • the method is useful for treating or preventing UI in an animal in need thereof.
  • the method is useful for treating or preventing an ulcer in an animal in need thereof.
  • the method is useful for treating or preventing IBD in an animal in need thereof.
  • the method is useful for treating or preventing IBS in an animal in need thereof.
  • tissue comprising cells capable of expressing VRl include, but are not limited to, neuronal, brain, kidney, urothelium, and bladder tissue. Methods for assaying cells that express VRl are well known in the art.
  • Hydroxyiminopiperazine Compounds are antagonists for mGluR5.
  • the invention further relates to methods for inhibiting ⁇ GluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an amount of a Hydroxyiminopiperazine Compound effective to inhibit mGluR5 function in the cell.
  • This method can be used in vitro, for example, as an assay to select cells that express mGluR5 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, or psychosis.
  • the method is also useful for inhibiting n ⁇ GluR5 function in a cell in vivo, in an animal (e.g., a human), by contacting a cell in an animal with an amount of a Hydroxyiminopiperazine Compound effective to inhibit mGluR5 function in the cell.
  • the method is useful for treating or preventing pain in an animal in need thereof.
  • the method is useful for treating or preventing an addictive disorder in an animal in need thereof.
  • the method is useful for treating or preventing Parkinson's disease in an animal in need thereof.
  • the method is useful for treating or preventing parkinsonism in an animal in need thereof.
  • the method is useful for treating or preventing anxiety in an animal in need thereof.
  • the method is useful for treating or preventing a pruritic condition in an animal in need thereof, hi another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof.
  • Examples of cells capable of expressing mGluR5 are neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are well known in the art.
  • the Hydroxyiminopiperazine Compounds are antagonists for mGluRl .
  • the invention further relates to methods for inhibiting mGluRl function in a cell, comprising contacting a cell capable of expressing mGluRl with an amount of a Hydroxyiminopiperazine Compound effective to inhibit mGluRl function in the cell.
  • This method can be used in vitro, for example, as an assay to select cells that express mGluRl and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.
  • the method is also useful for inhibiting mGluRl function in a cell in vivo, in an animal (e.g., a human), by contacting a cell in an animal with an amount of a Hydroxyiminopiperazine Compound effective to inhibit mGluRl function in the cell.
  • the method is useful for treating or preventing pain in an animal in need thereof.
  • the method is useful for freating or preventing UI in an animal in need thereof.
  • the method is useful for treating or preventing an addictive disorder in an animal in need thereof.
  • the method is useful for treating or preventing Parkinson's disease in an animal in need thereof.
  • the method is useful for freating or preventing parkinsonism in an animal in need thereof.
  • the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing epilepsy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing stroke - in an animal in need thereof. In another embodiment, the method is useful for freating or preventing a seizure in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another / embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof.
  • the method is useful for treating or preventing a cognitive disorder in an animal in need thereof, hi another embodiment, the method is useful for freating or preventmg a memory deficit in an animal in need thereof. In another embodiment, the method is useful for treating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Htmtington's chorea in an animal in need thereof. In another embodiment, the method is useful for treating or preventing ALS in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dementia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing retinopathy in an animal in need thereof.
  • the method is useful for treating or preventing a muscle spasm in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a migraine in an animal in need thereof. In another embodiment, the method is useful for treating, preventing, or inhibiting vomiting in an animal in need thereof, fn another embodiment, the method is useful for treating or preventing dyskinesia in an animal in need thereof, hi another embodiment, the method is useful for treating or preventing depression in an animal in need thereof.
  • Examples of cells capable of expressing mGluRl include, but are not limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells.
  • cerebellar Purkinje neuron cells Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells.
  • Methods for assaying cells that express MGluRl are well known in the art.
  • the Hydroxyiminopiperazine Compounds are advantageously useful in veterinary and human medicine. As described above, the Hydroxyiminopiperazine Compounds are useful for treating or preventing a Condition in an animal in need thereof. When administered to an animal, the Hydroxyiminopiperazine Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient.
  • the present compositions, which comprise a Hydroxyiminopiperazine Compound can be administered orally.
  • the Hydroxyiminopiperazine Compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be, administered together with another biologically active agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the Hydroxyiminopiperazine Compound.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the Hydroxyiminopiperazine Compounds into the bloodstream.
  • Hydroxyiminopiperazine Compounds into the central nervous system or gastrointestinal tract by any suitable route including intraventricular, intrathecal, and epidural injection, and enema.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Omrnaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the Hydroxyiminopiperazine Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • the Hydroxyiminopiperazine Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al, Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and!- 353-365 (1989).
  • the Hydroxyiminopiperazine Compounds can be delivered in a confrolled-release system " or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other • controlled- or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used.
  • a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al, N. Engl. J. Med. 321:574 (1989)).
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol Chem.
  • a controlled- or sustained- release system can be placed in proximity of a target of the Hydroxyiminopiperazine Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
  • the present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper adminisfration to the animal.
  • Such a pharmaceutical excipient can be a liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is a particularly useful excipient. when the Hydroxyiminopiperazine Compound is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington '_ • Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
  • the Hydroxyiminopiperazine Compounds are formulated in accordance with routine procedures as a composition adapted for oral adminisfration to human beings.
  • Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes sunounding an osmotically active driving compound are also suitable for orally administered compositions.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.
  • the excipients are of pharmaceutical grade
  • the Hydroxyiminopiperazine Compounds can be formulated for intravenous administration.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necày, the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • the Hydroxyiminopiperazine Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Hydroxyiminopiperazine Compounds can be administered by confrolled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hy r dropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
  • Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non- sustained-release counterparts.
  • a controlled- or sustained-release composition comprises a minimal amount of a Hydroxyiminopiperazine Compound to treat or prevent the Condition in a minimum amount of time.
  • Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Hydroxyiminopiperazine Compound, and can thus reduce the occurrence of adverse side effects.
  • Controlled- or sustained-release compositions can initially release an amount of a Hydroxyiminopiperazine Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the
  • Hydroxyiminopiperazine Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the Hydroxyiminopiperazine Compound can be released from the dosage form at a rate that will replace the amount of Hydroxyiminopiperazine Compound being metabolized and excreted from the body.
  • Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concenfration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • the amount of the Hydroxyiminopiperazine Compound that is effective for the treatment or prevention of a Condition can be determined by standard clinical techniques.
  • in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed will also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of a practitioner and/or each animal's circumstances. Suitable effective dosage amounts, however, range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although they are typically about 100 mg/kg of body weight or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Hydroxyiminopiperazine Compound, in another embodiment, about 0.020 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
  • an effective dosage amount is administered about every 24 h until the Condition is abated.
  • an effective dosage amount is administered about every 12 h until the Condition is abated.
  • an effective dosage amount is administered about every 8 h until the Condition is abated.
  • an effective dosage amount is administered about every 6 h until the Condition is abated.
  • an effective dosage amount is administered about every 4 h until the Condition is abated.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one Hydroxyiminopiperazine Compound is administered, the effective dosage amounts correspond to the total amount administered.
  • the amount effective for inhibiting the VRl, mGluR5, or mGluRl receptor function in a cell will typically range from about 0.01 ⁇ g/L to about 5 mg/L, in one embodiment, from about 0.01 ⁇ g/L to about 2.5 mg/L, in another embodiment, from about 0.01 ⁇ g/L to about 0.5 mg/L, and in another embodiment, from about 0.01 ⁇ g/L to about 0.25 mg/L of a solution or suspension of a pharmaceutically acceptable carrier or excipient.
  • the volume of solution or suspension comprising the Hydroxyiminopiperazine Compound is from about 0.01 ⁇ L to about 1 mL. In another embodiment, the volume of solution or suspension is about 200 ⁇ L.
  • the amount effective for inhibiting the receptor function in a cell will typically range from about 0.01 mg kg of body weight to about 2500 mg/kg of body weight, although it typically ranges from about 100 mg/kg of body weight or less, hi one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Hydroxyiminopiperazine Compound, in another embodiment, about 0.02 mg/kg of body weight to about 50 mg kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
  • an effective dosage amount is administered about every 24 h. In another embodiment, an effective dosage amount is administered about every 12. In another embodiment, an effective dosage amount is administered about every 8. In another embodiment, an effective dosage amount is administered about every 6 h. In another embodiment, an effective dosage amount is administered about every 4 h.
  • Hydroxyiminopiperazine Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering to the animal being administered a Hydroxyiminopiperazine Compound another therapeutic agent.
  • the other therapeutic agent is administered in an effective amount.
  • the present methods for inhibiting VRl function in a cell capable of expressing VRl can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • the present methods for inhibiting n ⁇ GluR5 function in a cell capable of expressing mGluR5 can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • the present methods for inhibiting mGluRl function in a cell capable of expressing mGluRl can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • the other therapeutic agent includes, but is not limited to, an opioid agonist, a uon-opioid analgesic, a non-steroid anti-inflammatory agent, an antimigraine agent, a
  • Cox-II inhibitor an antiemetic, a ⁇ -adrenergic blocker, an anticonvulsant, an antidepressanl, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing UI, an agent for treating or preventing an ulcer, an agent for freating or preventing IBD, an agent for treating or preventing IBS, an agent for treating addictive disorder, an agent for treating Parkinson's disease and parkinsonism, an agent for freating anxiety, an agent for treating epilepsy, an agent for treating a stroke, an agent for treating a seizure, an agent for treating a pruritic condition, an agent for freating psychosis, an agent for treating Huntington's chorea, an agent for treating ALS, an agent for treating a cognitive disorder, an agent for treating a migraine, an agent for treating or inhibiting vomiting, an agent for treating dyskinesia, or an agent for treating depression, and mixtures thereof.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range. In one embodiment of the invention, where another therapeutic agent is administered to an animal, the effective amount of the Hydroxyiminopiperazine Compound is less than its effective amount would be where the other therapeutic agent is not administered, hi this case, without being bound by theory, it is believed that the Hydroxyiminopiperazine Compounds and the other therapeutic agent act synergistically to treat or prevent a Condition.
  • Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, bupreno hine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromo ⁇ hine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lof
  • the opioid agonist is selected from codeine, hydromo ⁇ hone, hydrocodone, oxycodone, dihydrocodeine, dihydromo ⁇ hine, mo ⁇ hine, tramadol, oxymo ⁇ hone, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • non-steroidal anti-inflammatory agents such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, ca ⁇ rofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic
  • non-steroidal anti-inflammatory agents such aspirin,
  • non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophennol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenyl)
  • useful antimigraine agents include, but are not limited to, alpiropride, diliydroergotamme, dolasetron, ergocomine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixtures thereof.
  • the other therapeutic agent can also be an antiemetic agent.
  • useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlo ⁇ erazine, promethazine, chlo ⁇ romazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine.
  • Examples of useful / S-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolo ⁇ , mo
  • useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenifroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobar
  • Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholori.de, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexipti
  • Ca2+-channel blockers examples include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.
  • useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, alfretamine, ambomycin, ametanfrone acetate, aminoglutethimide, amsacrine, anasfrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisanfrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedef ⁇ ngol
  • B betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bisfratene A; bizelesin; breflate; bropfrimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox TL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-po ⁇ hyrin; cladribine; clomifene analogues; clotrimazole; coll
  • plasminogen activator inhibitor platinum complex; platinum compounds; platinum-friamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; pu ⁇ urins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltifrexed; ramosefron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogle
  • B vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
  • useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine.
  • useful therapeutic agents for treating or preventing an ulcer include, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuth compounds such as bismuth subsalicylate and bismuth subzinte; H 2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;
  • K - ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as tetracycline, metronidazole, timidazole, clarithromycin, and amoxicillin.
  • useful therapeutic agents for treating or preventing IBD include, but are not limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized opium tincture; codeine; broad-spectrum antibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine; prednisone; azathioprine; mercaptopurine; and methofrexate.
  • useful therapeutic agents for treating or preventing IBS include, but are not limited to, propantheline; muscarine receptor antagonists such as pirenzapine, methocframine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methylbromide, and methantheline; and antidiarrheal drugs such as diphenoxylate and loperamide.
  • useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, bupreno ⁇ hine, an opiate agonist, 3-phenoxy ⁇ yridine, levomethadyl acetate hydrochloride, and serotonin antagonists.
  • Examples of useful therapeutic agents for treating or preventing Parkinson's disease and parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.
  • useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, and zaleplon; tranquili7ers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, me
  • useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, ⁇ -vinyl GABA, acetazolamide, and felbamate.
  • useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, agents that break up clots such as streptokinase or tissue plasminogen activator, agents mat reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid.
  • anticoagulants such as heparin
  • agents that break up clots such as streptokinase or tissue plasminogen activator
  • agents mat reduce swelling such as mannitol or corticosteroids
  • acetylsalicylic acid acetylsalicylic acid
  • useful therapeutic agents for treating or preventing a seizure include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, ⁇ -vinyl GABA, acetazolamide, and felbamate.
  • useful therapeutic agents for treating or preventing a pruritic condition include, but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those given below, menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.
  • useful therapeutic agents for treating or preventing psychosis include, but are not limited to, phenothiazines such as chlo ⁇ romazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapme succinate; molindone hydrochloride; pimozide; and ziprasidone.
  • phenothiazines such as chlo ⁇ romazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride
  • thioxanthenes such as chloroprothixene and thiothixene hydroch
  • Examples of useful therapeutic agents for treating or preventing Huntington's chorea include, but are or limited to, haloperidol and pimozide.
  • useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, neurotrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.
  • useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for freating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressant drugs such as those given below.
  • useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta- blockers such as propranolol, verapamil, and divalproex.
  • useful therapeutic agents for treating, preventing, or inhibiting vomiting include, but are not limited to, 5-HT 3 receptor antagonists such as ondansetron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlo ⁇ erazine, thiethylperazine, chlo ⁇ romazin, metoclopramide, and domperidone; glucocorticoids such as dexamethasone; and benzodiazepines such as lorazepam and alprazolam.
  • useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, rese ⁇ ine and tetrabenazine.
  • useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amitryptyline, amoxapine, bupropion, citalopram, (S)-citalopram, clomipramine, desipramine, doxepin, imipramine, maprotilinr, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlaflaxine; selective serotonin reuptake inhibitors such as fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimulants such as dextroamphetamine and msthylphenidate.
  • tricyclic antidepressants such as amitryptyline, amoxapine, bupropion
  • a Hydroxyiminopiperazine Compound and the other therapeutic agent can act additively or, in one embodiment, synergistically.
  • a Hydroxyiminopiperazine Compound is administered concurrently with another therapeutic agent.
  • a composition comprising an effective amount of a Hydroxyiminopiperazine Compound and an effective amount of another therapeutic agent can be administered.
  • a composition comprising an effective amount of a . Hydroxyiminopiperazine Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered.
  • an effective amount of a Hydroxyiminopiperazine Compound is administered prior or subsequent to administration of an effective amoxmt of another therapeutic agent.
  • the Hydroxyiminopiperazine Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Hydroxyiminopiperazine Compound exerts its preventative or therapeutic effect for freating or preventing a Condition in an animal.
  • a composition of the invention is prepared by a method comprising admixing a Hydroxyiminopiperazine Compound and a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods well known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient.
  • the Hydroxyiminopiperazine Compound is present in the composition in an effective amount.
  • kits that can simplify the adminisfration of a Hydioxyiminopiperazine Compound to an animal.
  • a typical kit of the invention comprises a unit dosage form of a Hydroxyiminopiperazine Compound.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a
  • the kit can further comprise a label or printed instructions instructing the use of the
  • the kit can also further comprise a unit dosage form of another therapeutic agent, for example, a container containing an effective amount of the other therapeutic agent.
  • the kit comprises a container containing an effective amount of a Hydroxyiminopiperazine Compound and an effective amount of another therapeutic agent.
  • other therapeutic agents include, but are not limited to, those listed above.
  • Kits of the invention can further comprise a device that is useful for administering the unit dosage forms.
  • a device includes, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
  • Examples 1-10 relate to the synthesis of illustrative Hydroxyiminopiperazine Compounds.
  • Compound Al(d) was prepared by a procedure that is analogous to that used to prepare Compound Al(c) except that (S)-2-methylpiperazine (Commercially available from Sigma- Aldrich, St. Louis, MO (www.sigma-aldrich.com)) was used in place of (R)-2- methylpiperazine.
  • Example 3 Synthesis of Compound Al(a)
  • Compound Al(a) was prepared by a procedure that is analagous to that used to prepare Compound Al(c) except that piperazine was used in place of (R)-2- methylpiperazine.
  • the identity of Compound Al(a) was confirmed using 1H NMR.
  • Compound A29(a) was prepared by a procedure that is analogous to that used to prepare Compound Al(a) except that 2- chloro-3-methyl ⁇ yridine was used in place of 2,3-dichloropyridine. The identity of Compound A29(a) was confirmed using 1H NMR.
  • Compound A35(a) was prepared by a procedure that is analogous to that used to prepare Compound A29(a) except that 4-(trifluoromethyl)-phenylisothiocyanate was used in place of 4-(tert-butyl)-phenyiisothiocyanate. The identity of Compound A35(a)was confirmed using 1H NMR.
  • Example 7 Synthesis of Compound Al 83(a)
  • Compound Al 83(a) was prepared by a procedure that is analogous to that used to prepare Compound Al(a) except that 2,3-dichloropyrazine was used in place of 2,3-dichloropyridine.
  • the identity of Compound A183(a) was confirmed using 1H NMR.
  • Example 8 Synthesis of Compound A267(a)
  • Compound A267(a) was prepared by a procedure that is analogous to that used to prepare Compound Al(a) except that 4,5-dichloro-2-thia-l,3-diazole was used in place of 2,3-dichloropyridine.
  • the identity of Compound A267(a) was confirmed using 1H NMR.
  • Compound A43(a) was prepared by a procedure that is analogous to that used to prepare Compound Al(a) except that 2-chloro-3-trifluoromethyl ⁇ yridine was used in place of 2,3-dichloropyridine. The identity of Compound A43(a)was confirmed using 1H
  • Example 10 Synthesis of Compound Bl(a) A solution of Compound Al(a) (77.4 mg, 0.20 mmol), prepared as described above in Example 5.3, in 1.5 mL of anhydrous dimethylformamide was added NaH (60 wt %, 8.4 mg, 0.21 mmol) and the resulting mixture was allowed to stir at room temperature (about 25°C) for about 0.5 h. Iodomethane (28.4 mg, 0.20 mmol) was then added to the reaction mixture and the mixture was allowed to stir at room temperature (about 25°C) for about 4 h. The reaction mixture was then quenched with water and extracted with diethyl ether.
  • Hydroxyiminopiperazine Compounds bind to mGluR5.
  • glial cultures are prepared from cortices of Sprague- Dawley 18 days old embryos. The cortices are dissected and then dissociated by trituration. The resulting cell homogenate is plated onto poly-D-lysine precoated T175 flasks (BIOCOAT, commercially available from Becton Dickinson and Company Inc. of Franklin Lakes, NJ ) in Dulbelcco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25 mM HEPES, and supplemented with 15% fetal calf serum ("FCS,” commercially available from Hyclone Laboratories Inc. of Omaha, NE ), and incubated at 37°C and 5% CO 2 .
  • BIOCOAT poly-D-lysine precoated T175 flasks
  • DMEM Dulbelcco's Modified Eagle's Medium
  • FCS fetal calf serum
  • FCS supplementation is reduced to 10%.
  • oligodendrocytes and microglia are removed by strongly tapping the sides of the flasks.
  • secondary astrocytes cultures are established by subplating onto 96 poly- D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000 cells/well in DMEM and 10% FCS.
  • the astrocytes are washed with serum free medium and then cultured in DMEM, without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/niL epidermal growth factor ("EGF"), 1 mM sodium pyruvate, and IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37°C and 5% CO 2 .
  • DMEM serum free medium
  • HEPES 10 ng/niL epidermal growth factor
  • IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37°C and 5% CO 2 .
  • the procedure allows the expression of the mGluR5 receptor by astrocytes, as demonstrated by S. Miller et al, J. Neuroscience !5(9):6103-6109 (1995).
  • Assay Protocol After 3-5 days incubation with EGF, the astrocytes are washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 700 mM NaH 2 PO 4 , 2 mM CaCl 2 , 5 mM NaHCO 3 , 8 mM HEPES, 10 mM Glucose at pH 7.4 ("Assay Buffer") and loaded with the dye Fluo-4 (commercially available from Molecular Probes Inc. of Eugene, OR) using 0.1 mL of Assay Buffer containing Fluo-4 (3 mM final).
  • Imaging Plate reader commercially available from Molecular Devices Co ⁇ oration of
  • DMSO solutions containing various concentrations of the Hydroxyiminopiperazine Compounds diluted in Assay Buffer 0.05 mL of 4X dilutions for competition curves
  • fluorescence is monitored for 2 minutes.
  • 0.05 mL of a 4X glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 mM.
  • Plate fluorescence is then monitored for an additional 60 seconds after agonist addition.
  • the final DMSO concenfration in the assay is 1.0%.
  • fluorescence is monitored as a function of time and the data analyzed using Microsoft Excel and GraphPad Prism. Dose- response curves are fit using a non-linear regression to determine IC 50 value. In each experiment, each data point is determined two times.
  • Test Animals Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral adminisfration of a Hydroxyiminopiperazine Compound when food is removed for 16 h before dosing.
  • a confrol. group acts as a comparison to rats freated with a Hydroxyiminopiperazine Compound. The confrol group is administered the carrier for the Hydroxyiminopiperazine Compound. The volume of carrier administered to the control group is the same as the volume of carrier and Hydroxyiminopiperazine Compound administered to the test group.
  • rat tail flick test can be used. Rats are placed inside a cotton pouch and the tail exposed to a focused beam of radiant heat at a point 3 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are defined as the interval between the onset of the thermal stimulus and the flick of the tail. Animals not responding within 15 seconds are removed from the tail flick unit and assigned a withdrawal latency of 15 seconds. Tail flick latencies are measured immediately before (pre-treatment) and 1, 3, and 6 h following administration of a Hydroxyiminopiperazine Compound. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 15 seconds, is calculated as follows:
  • Acute pain can also be assessed by measuring the animal's response to noxious mechanical stimuli by determining the paw withdrawal threshold (PWT), as described below.
  • PWT paw withdrawal threshold
  • FCA Freund's complete adjuvant
  • the left hind paw of each animal is administered a 50 ⁇ L intraplantar injection of 100% FCA. 24 h post injection, the animal is assessed for response to noxious mechanical stimuli by determining the PWT, as described below. Rats are then administered a single injection of 1, 3, 10, or 30 mg/Kg of either a Hydroxyiminopiperazine Compound, 30 mg/Kg indomethacin or carrier. Responses to noxious mechanical stimuli are then determined 2, 4, 6, and 24 h post administration. Percentage reversal of hyperalgesia for each animal is defined as:
  • the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al, "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under enflurane/O inhalation anaesthesia.
  • the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve.
  • a 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1/3 to 1/2 of the nerve thickness is held within the ligature.
  • the wound is closed with a single muscle suture (7-0 silk) and a Michelle clip. Following surgery, the wound area is dusted with antibiotic powder.
  • % reversal 100 - [(right pre-administration PWT- left post-adminisfration PWT) / ( right pre-administration PWT-left pre-admimsfration PWT)] x 100.
  • the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, themal hyperalgesia and tactile ailodynia in rats.
  • Surgery is performed under isoflurane/O 2 inhalation anaesthesia. Following induction of anaesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L 4 - S 2 levels. The L 6 fransverse process is carefully removed with a pair of small rongeurs to identify visually the L 4 - L 6 spinal nerves.
  • the left L 5 (or L 5 and L 6 ) spinal nerve(s) is isolated and tightly ligated with silk thread.
  • a complete hemostasis is confirmed and the wound is sutured using non-absorbable sutures, such as nylon sutures or stainless steel staples.
  • Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then be returned to their home cages until behavioral testing begins.
  • non-absorbable sutures such as nylon sutures or stainless steel staples.
  • the animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, immediately prior to and 1, 3, and 5 h after being administered a Hydroxyiminopiperazine Compound for both the left rear paw and right rear paw of the animal.
  • the animal can also be assessed for response to noxious thermal stimuli or for tactile ailodynia, as described below.
  • the Chung model for neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992).
  • the paw pressure assay can be used to assess mechanical hyperalgesia.
  • hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C. Stein, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacology Biochemistry and Behavior 31:451-455 (1988).
  • the maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw.
  • PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.
  • the plantar test can be used to assess thermal hyperalgesia.
  • hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by K. Hargreaves et al, "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(l):77-88 (1988).
  • the maximum exposure time is set at 32 seconds to avoid tissue damage and any directeil paw withdrawal from the heat source is taken as the end point. Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested.
  • Tactile Ailodynia To assess tactile ailodynia, rats are placed in clear, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw ate considered nociceptive behavioral responses.
  • the elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of Hydroxyiminopiperazine Compounds in rats or mice.
  • the Elevated Plus Maze Test The elevated plus maze consists of a platform with 4 arms, two open and two closed (50x10x50 cm enclosed with an open roof). Rats (or mice) are placed in the center of the platform, at the crossroad of the 4 arms, facing one of the closed arms. Time spent in the open arms vs the closed arms and number of open arm entries during the testing period are recorded. This test is conducted prior to drug administration and again after drug adminisfration. Test results are expressed as the mean time spent in open arms and the mean number of entries into open arms.
  • the Shock-Probe Burying Test For the shock-probe burying test the testing apparatus consists of a plexiglass box measuring 40x30x40 cm, evenly covered with approximately 5 cm of bedding material (odor absorbent kitty litter) with a small hole in one end through which a shock probe (6.5 cm long and 0.5 cm in diameter) is inserted. The plexiglass shock probe is helically wrapped with two copper wires through which an electric current is administered.
  • Rats are habituated to the testing apparatus for 30 min on 4 consecutive days without the shock probe in the box. On test day, rats are placed in one corner of the test chamber following drug administration. The probe is not electrified until the rat touches it with its snout or fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begins once the rat receives its first shock and the probe remains electrified for the remainder of the testing period. The shock elicits burying behavior by the rat.
  • the duration of time the rat spends spraying bedding material toward or over the probe with its snout or fore paws is measured as well as the number of contact-induced shocks the rat receives from the probe.
  • Known anxiolytic drugs reduce the amount of burying behavior, hi addition, an index of the rat's reactivity to each shock is scored on a 4 point scale. The total time spent immobile during the 15 min testing period is used as an index of general activity.
  • the shock-probe burying test is described in D. Treit, 1985, supra.
  • the condition place preference test or drug self-administration test can be used to assess the ability of Hydroxyiminopiperazine Compounds to attenuate the rewarding properties of known drugs of abuse.
  • the Condition Place Preference Test The apparatus for the conditioned place preference test consists of two large compartments (45x45x30 cm) made of wood with a plexiglass front wall. These two large compartments are distinctly different. Doors at the back of each large compartment lead to a smaller box (36x18x20 cm) box made of wood, painted grey, with a ceiling of wire mesh.
  • the two large compartments differ in terms of shading (white vs black), level of illumination (the plexiglass door of the white compartment is covered with aluminum foil except for a window of 7x7 cm), texture (the white compartment has a 3 cm thick floor board (40x40 cm) with nine equally spaced 5 cm diameter holes and the black has a wire mesh floor), and olfactory cues (saline in the white compartment and 1 mL of 10% acetic acid in the black compartment). On habituation and testing days, the doors to the small box remain open, giving the rat free access to both large compartments.
  • the first session that a rat is placed in the apparatus is a habituation session and entrances to the smaller grey compartment remain open giving the rat free access to both large compartments.
  • rats generally show no preference for either compartment.
  • rats are given 6 conditioning sessions. Rats are divided into 4 groups: carrier pre-treatment + carrier (control group), Hydroxyiminopiperazine Compound pre-treatment + carrier, carrier pre-treatment + , mo ⁇ hine, Hydroxyiminopiperazine Compound pre-treatment + mo ⁇ hine.
  • carrier pre-treatment + carrier control group
  • Hydroxyiminopiperazine Compound pre-treatment + carrier carrier pre-treatment +
  • mo ⁇ hine Hydroxyiminopiperazine Compound pre-treatment + mo ⁇ hine.
  • Each rat receives three conditioning sessions consisting of 3 drug combination-compartment and 3 carrier- compartment pairings.
  • the order of injections and the drug/compartment pairings are counterbalanced within groups.
  • rats are injected prior to testing (30 min to 1 h) with either mo ⁇ hine or carrier and the rat is placed in the apparatus, the doors to the grey compartment remain open and the rat is allowed to explore the entire apparatus for 20 min.
  • the time spent in each compartment is recorded.
  • Known drugs of abuse increase the time spent in the drug-paired compartment during the testing session.
PCT/US2003/030185 2002-09-24 2003-09-24 Therapeutic piperazine compounds WO2004029031A2 (en)

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